REVIEW URRENT C OPINION
Mucosal immunity in HIV infection: what can be done to restore gastrointestinal-associated lymphoid tissue function? Michael D. George a and David M. Asmuth a,b
Purpose of review This review describes the impact of HIV infection on gut-associated lymphoid tissue, the mechanisms for persistent gut-associated lymphoid tissue dysfunction despite effective antiretroviral therapy, and potential strategies to restore gut-associated lymphoid tissue function and promote immune reconstitution. Recent findings Recent studies indicate that unresolved microbial translocation and intestinal dysbiosis may continue to promote enteropathy as well as HIV-associated and non-HIV-associated conditions in many HIV patients who otherwise maintain therapeutic control of systemic viral replication. Summary Several novel therapeutic approaches to reduce intestinal inflammation and mitigate microbial translocation may hold promise for restoring gastrointestinal health and thereby increasing the efficacy of immune reconstitution in HIV-infected patients undergoing antiretroviral therapy. Keywords dysbiosis, gut-associated lymphoid tissue, HIV-enteropathy, microbial translocation
INTRODUCTION Not long after the onset of the AIDS epidemic in the 1980s, it became clear to researchers and clinicians that the gastrointestinal tract was the primary site of HIV infection and pathogenesis, irrespective of the mode of acquisition. Indeed, before development of effective and readily available antiretroviral therapy, the vast majority of HIV-infected individuals suffered devastating gastrointestinal complications accompanied by a rapid decline in health from malnutrition and ‘wasting’ [1–4]. Early histologic studies of gut-associated lymphoid tissue (GALT) from chronic and AIDS stage patients with gastrointestinal manifestations revealed that HIV infection led to substantial deterioration of gastrointestinal architecture characterized by villus atrophy [5–8] and an inflammatory infiltrate intriguingly devoid of CD4þ T cells [6,9]. Physiologically, patients were often plagued by chronic intestinal inflammation, malabsorption, and debilitating diarrhea [10]. Three decades later, although much more is known about the dynamics and even subset specificities of CD4þ T-cell depletion from GALT during
HIV infection, the mechanisms underlying the collective deterioration of gastrointestinal functions known as ‘enteropathy’ are still poorly understood. Moreover, it remains unclear why many clinical manifestations of enteropathy remain unresolved despite control of HIV replication at or near undetectable levels with combinatorial antiretroviral therapy (cART) [11]. Increasingly, however, investigations are unraveling questions about how a small residual pool of actively and latently HIVinfected cells that remains can continue to perpetuate mucosal immune dysfunction. In this review, we will discuss current research and opinions on the role of GALT in the control of HIV infection, the persistence of GALT dysfunction a
University of California Davis, Davis and bUniversity of California Davis Medical Center, Sacramento, California, USA Correspondence to David M. Asmuth, MD, Professor, University of California Davis Medical Center, 4150 V Street, PSSB G-500, Sacramento, CA 95617, USA. Tel: +1 916 734 8695; fax: +1 916 734 7766; e-mail: [email protected] Curr Opin Infect Dis 2014, 27:275–281 DOI:10.1097/QCO.0000000000000059
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KEY POINTS
a predictive biomarker of systemic immune activation [20 ]. Taken together, these studies suggest that the maintenance of Th17 cells and healthy GALT function is a key factor in controlling HIV pathogenesis. Further support for this model of persistent systemic inflammation and immune activation comes from investigations of HIV-infected elite controllers and pathogenic and nonpathogenic SIV infections of nonhuman primates. Although it has been known for some time that CD4þ T cells are maintained at healthy levels in GALT of infected individuals who control HIV replication without cART [21,22], recent evidence suggests that such individuals also retain the important Th17 subset [23]. Comparative studies of nonhuman primates that are either susceptible or resistant to pathogenic SIV infection have provided additional insights. Although natural nonhuman primate SIV hosts such as African green monkeys and sooty mangabeys show similar patterns of high viral replication and mucosal CD4þ T-cell depletion as HIV-infected humans and SIV-infected rhesus macaques, they neither exhibit chronic immune activation nor develop AIDS [24–26]. Moreover, it seems that CD4þ T-cell loss is not sustained in these naturally resistant species [27]. Thus, these data imply that although CD4þ T-cell depletion is one mechanism leading to microbial translocation, it may well not be sufficient in the setting of retroviral infection. &
Depletion of GALT CD4þ T cells plays a critical role in establishment of gastrointestinal enteropathy and dysbiosis during HIV infection. New insights into the role of Th17 lymphocyte cell loss in the maintenance of abnormal mucosal immune function have been discovered over the review period and promise to provide new insights into the pathophysiology of failed immune reconstitution. Suppressive cART improves but often does not reverse enteropathy, microbial translocation, or the adverse effects of chronic systemic inflammation. Promising therapeutic strategies are emerging that seek to promote host–microbe homeostasis and epithelial health, inactivate proinflammatory molecules, or prevent gastrointestinal inflammation altogether.
despite suppressive cART, the impact of microbial translocation on immune activation and chronic inflammation in GALT, and the potential role of the commensal microbiome and host–microbe dysbiosis in promoting GALT pathogenesis. Finally, we will conclude by examining emerging strategies for maintaining and restoring GALT structure and function that are likely to be critical to the success of any future therapeutic approaches designed to provide a functional cure or eradicate HIV from the body.
GUT-ASSOCIATED LYMPHOID TISSUE FUNCTION IS CRITICAL FOR CONTROL OF HIV
PERSISTENCE OF GUT-ASSOCIATED LYMPHOID TISSUE DYSFUNCTION DESPITE HIGHLY ACTIVE ANTIRETROVIRAL THERAPY
Shortly after pioneering studies of rhesus macaques infected with pathogenic simian immunodeficiency virus (SIV) revealed that the vast majority of susceptible CD4þ T cells in GALT are infected and killed within the first weeks of infection [12,13], the same swift and severe decimation was confirmed in primary HIV infection [14]. Importantly, subsequent studies showed that HIV/SIV preferentially targets a subset of CD4þ helper T cells (Th) characterized by its production of the cytokines IL-17 and IL-22 [15,16]. Because these ‘Th17’ cells are also involved in maintenance of the intestinal tight junction integrity [17 ,18,19], their loss is presumed to lead to a breakdown in barrier function that in turn permits systemic immune activation (and by extension, viral replication) through continuous exposure of the underlying lamina propria antigen-presenting cells to luminal antigens. Recent investigations support this hypothesis, indicating that alteration of Th17 functions in GALT can be
Advances over the last decade in the safety and the efficacy of administration of antiretroviral cocktails have dramatically increased the life expectancy of HIV patients [28]. However, despite the success of cART in controlling HIV replication and restoring circulating CD4þ T-cell populations, restoration of GALT structure and function is markedly delayed if it occurs at all [29,30 ]. Moreover, initiation of cART early in infection does not appear to promote significant maintenance of CD4þ T cells in GALT [31 ]. In addition, histological studies reveal that intestinal epithelial damage characterized by disruption of tight junctions [32 ] and enterocyte apoptosis [33] persists in patients on long-term therapy. Gene expression studies have provided broad insights, showing that multiple biomarkers of mucosal growth remain repressed in GALT during chronic HIV infection despite suppressive therapy [22,34]. More recent evidence suggests that this residual immune dysregulation is most prevalent when cART
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fails to increase circulating CD4þ T cells to normal levels [35 ]. Although the mechanisms that impair CD4þ T-cell reconstitution in GALT during therapy are not fully defined, investigations continue to highlight several potential contributing factors. Multiple studies in the last few years have focused on the impact of residual viral reservoirs and ongoing viral replication in GALT despite systemic HIV suppression [36 ,37 ,38]. Other investigations have shown that chronic residual CD8þ T-cell activation may play an important role [39]. Still others suggest that altered expression of mucosal homing and retention biomarkers may impair trafficking and thereby prevent re-establishment of normalized CD4þ T-cell populations in GALT [40]. The potential for inflammation-associated fibrosis of the extracellular matrix to impair migration of CD4þ T cells into the lamina propria has also been explored [41], as well as the contribution from sustained immune activation in GALT that may ‘exhaust’ available pools of lymphocyte progenitors [30 ,42]. Thus, the mechanisms that promote persistent mucosal immune dysregulation in the face of suppressive cART appear to be broad-ranged and are likely to be intricately interwoven. &
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GUT-ASSOCIATED LYMPHOID TISSUE, MICROBIAL TRANSLOCATION, AND IMMUNE ACTIVATION In recent years, several lines of research have focused on the hypothesis that translocation of gut microbe antigens across a leaky intestinal epithelial barrier plays an important role in the chronic immune activation and inflammation that defines HIV disease progression. In 2006, Brenchley et al. [43] first reported increased circulating lipopolysaccharide (LPS) in both HIV-infected humans and SIV-infected rhesus macaques during chronic infection as compared with uninfected controls. While controversy persists whether LPS is an optimal surrogate marker for microbial translocation, many studies have since corroborated the initial findings [44–46] and characterized additional biomarkers [47 ,48 ]. More recently, clinical investigations [49 ,50 ] have confirmed that microbial translocation is also a major source of immune activation and may contribute to the rapid disease progression common in HIVinfected children. Mechanistically, microbial translocation appears to trigger innate immune activation through engagement of pathogen recognition receptor signaling [51,52]. In turn, the sustained activation is believed to fuel a downward spiraling pathogenic cycle whereby new susceptible HIV targets are created &
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and incessant antiviral and cytotoxic responses increase damage to the intestinal epithelium and stimulate further translocation. Notably, several investigators [53] have shown that the magnitude of immune activation is a strong predictor of HIV disease progression, independent of viral burden. Currently, investigations are increasingly focused on understanding the relationship between microbial translocation, immune activation, and the manifestation of HIV-associated and non-HIV-associated (HANA) conditions [54 ]. It has been known for some time that HIV infection leads to a higherthan-expected risk of degenerative diseases that are often associated with the aging process [55 ]. In the last few years, new data have emerged suggesting that microbial translocation may play an important role in the development of liver [56,57 ], cardiovascular [58 ,59], and neurocognitive disease [60] in HIV patients. Clearly, these findings have profound implications, and numerous studies are underway to continue characterizing biomarkers of positive and negative clinical outcomes and evaluate strategies for intervention. Given the plethora of reports over the last decade of impaired and delayed immune reconstitution in GALT during therapy, it is not surprising that more recent studies have revealed that microbial translocation also often persists when HIV replication is controlled through cART. Indeed, many of these investigations have demonstrated that the persistence in translocation was associated with chronic inflammation [61 ,62 ] and impaired reconstitution of intestinal CD4þ T cells [63,64]. Intriguingly, investigations of nonhuman primates demonstrate that microbial translocation does not occur in nonpathogenic SIV infection of natural hosts such as sooty mangabeys and African green monkeys [65 ]. By analogy, these findings imply that valuable knowledge regarding the mechanisms of protection from microbial translocation may also be gained through carefully designed comparative studies of treatment naı¨ve HIV elite controllers. &
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GUT-ASSOCIATED LYMPHOID TISSUE AND MICROBIAL COMMUNITY INTERACTIONS IN HIV INFECTION The completion of the Human Microbiome Project has provided HIV researchers an unprecedented understanding of the diversity and proportional distributions of the commensal bacterial species inhabiting the upper and lower gastrointestinal tract. In light of the known relationship between the microbiome and lamina propria CD4þ T cells [18,66 ,67], it has long been hypothesized that the microbiome could play a critical role in HIV
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pathogenesis and susceptibility to secondary infections. During chronic HIV infection, increasing immune suppression caused by CD4þ T-cell depletion as well as T- and B-cell dysfunction [68,69] contributes to elevated susceptibility to routine pathogens such as those associated with bacterial and mycobacterial disease. In addition, immune deficiency could alter normal homeostatic interactions with microbial communities and thereby fuel episodic outgrowth of commensal opportunistic pathogens that have the capacity to exploit inflammatory environments for metabolic advantage. Gori et al. [70] were the first to report evidence of gastrointestinal dysbiosis in HIV-infected individuals, observing an increased abundance of Pseudomonas aeruginosa and Candida albicans and a reduction of Bifidobacteria and lactobacilli in fecal samples as compared with healthy controls. In 2011, an investigation by Ellis et al. [71] described a positive association between stool Bacteroidales and systemic CD8þ T-cell activation and negative associations between Enterobacteriales and duodenal lamina propria CD4þ T-cell counts in untreated HIV-infected patients. Subsequent research by Lozupone et al. [72 ] has shown that the fecal microbiome of HIV-infected patients with gastrointestinal inflammation presents a bacterial species profile that is distinct from that of other intestinal inflammatory diseases and often persists during cART. Interestingly, a recent study [73 ] of bacterial communities in the rectal mucosa of untreated and treated HIV-1-infected individuals revealed that dysbiosis was associated with elevated levels of tryptophan catabolism and increases in multiple biomarkers of inflammation and disease progression. Furthermore, they found that the dysbiosis was persistent in HIV-infected patients undergoing cART. More recently, Dillon et al. [74 ] showed that HIV-1-infected individuals had increased abundances of Proteobacteria and decreased abundances of Firmicutes in the colonic mucosa. At the genus level, significant outgrowth of Prevotella and decrease of Bacteroides were detected. Changes in mucosal microbiota were linked with local elevation in activated T-cell and myeloid dendritic cell numbers and increased microbial translocation. Importantly, the study also demonstrated that the bacterial modulations identified in colonic mucosal tissues were not well reflected in microbiome analyses of fecal material. Collectively, these early studies demonstrate that HIV infection is consistently associated with significant disruption of homeostatic bacterial communities throughout the gastrointestinal tract. Given the substantial variability of the microbiome stemming from genetic [75 ,76], dietary [77 ,78 ], &
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and even temporal [79 ,80 ] factors, it is clear that more studies are needed to understand which disruptions are stable and directly contribute to pathogenesis, the mechanisms by which this occurs, and how to correct it. Such comprehensive objectives will undoubtedly benefit from, and indeed may be dependent on, further development of SIV models in which confounding variables such as diet, housing, social interactions, and genetic background can be controlled.
CONCLUSION In light of increases in our understanding of the pathogenic impact of intestinal dysbiosis and microbial translocation, novel therapeutic strategies are clearly needed to counteract their cause and downstream effects on HIV disease progression and the development of HANA conditions. To that end, a variety of inspiring approaches have already been and continue to be investigated in HIV-infected humans and in several animal models. In rodent models of intestinal inflammation, investigators have shown that the immunoglobulins present in serum-derived bovine immunoglobulin (SBI) can improve epithelial barrier integrity and reduce inflammation by neutralizing LPS and other bacterial toxins [81,82]. SBI is an oral, medical food that has been used safely in many human studies, including pediatric populations [28]. Encouragingly, this strategy has been recently employed with similar success in a pilot study of eight individuals with HIV enteropathy [83 ]. The dramatic decline in HIV enteropathy-related symptoms noted upon initiation of SBI is encouraging for patients who have persistent symptoms despite a negative workup for chronic diarrhea. A modest decline in biomarkers of bacterial translocation and reduction in systemic parameters of monocyte activation is encouraging evidence that neutralization of proinflammatory bacterial antigen in the gut lumen can lead to systemic reduction in inflammation. This was the first study that also demonstrated a sharp increase in duodenal lamina propria CD4þ T lymphocytes that otherwise remain severely depleted despite long-term viral suppression and systemic immune reconstitution [83 ]. A large multicenter placebo-controlled randomized study is underway to validate and extend these findings of the initial pilot study. Several compounds are being considered for their application in the setting of HIV infection. Administration of IL-22 has also been utilized to reduce inflammation in murine models of ulcerative colitis [84]. In the rhesus macaque SIV model, &&
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recent studies demonstrate that a programmed death 1 blockade in chronic stage infection can be effective at reducing immune activation and microbial translocation [85]. The use of probiotics in combination with cART is also under investigation in the macaque model. Interestingly, after 5 months of treatment in SIVmac239-infected pigtail macaques, researchers observed an increase in frequency of antigen-presenting cells, enhanced Th17 functionality, and a reduction of T-cell activation [86 ]. Recent investigations of probiotic therapy in HIV-infected humans have shown similar promising results. A study of HIV-infected individuals in Tanzania found that diet supplementation with probiotic yogurt increased CD4þ T-cell numbers in comparison to controls who did not consume yogurt [87]. In addition, symbiotic approaches that combine prebiotic and probiotic treatment have been efficacious in elevating CD4þ T-cell levels, and increasing growth of beneficial bacteria (e.g. Bifidobacterium) compared to HIV patients receiving placebo. Other HIV investigations suggest that certain inherent bacterial community profiles might provide protective benefits throughout the course of HIV infection. For example, elevated CD4þ T-cell counts, lower viral loads, and reduced microbial translocation have been linked with greater proportions of Lactobacillales in early untreated HIV infection, and these relationships were sustained following initiation of cART [88 ]. Ongoing and future investigations will continue to yield additional insights and optimize therapeutic strategies to block microbial translocation, dampen immune activation and enteropathy, and thereby improve the health and increase the life expectancy of HIVinfected individuals. &
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Acknowledgements None. Search terms used: HIV, malnutrition, wasting, diarrhea, CD4þ T-cell depletion, gut-associated lymphoid tissue, GALT, inflammation, immune activation, microbial translocation, SIV, antiretroviral therapy, microbiome, microbiota, commensal, bacteria, T helper cells, Th17, IL-17, IL-22, nonprogressors, African green monkeys, sooty mangabeys, rhesus macaques, immune dysregulation syndrome, LPS, sCD14, 16S rDNA, circadian, probiotics, prebiotics, immune reconstitution. Conflicts of interest M.D.G. has no conflicts of interest. D.M.A is the site Principal Investigator for pharmaceutical-sponsored and investigator-initiated clinical trials – Argos, BioNor, EnteraHealth, Gilead, Merck, Pfizer, Tibotec, and ViiV.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Hoyt MJ, Staats JA. Wasting and malnutrition in patients with HIV/AIDS. J Assoc Nurses AIDS Care 1991; 2:16–28. 2. Griffin GE. Malabsorption, malnutrition and HIV disease. Baillieres Clin Gastroenterol 1990; 4:361–373. 3. Kotler DP. Malnutrition in HIV infection and AIDS. AIDS 1989; 3 (Suppl 1): S175–S180. 4. DuPont HL, Marshall GD. HIV-associated diarrhoea and wasting. Lancet 1995; 346:352–356. 5. Cummins AG, LaBrooy JT, Stanley DP, et al. Quantitative histological study of enteropathy associated with HIV infection. Gut 1990; 31:317–321. 6. Ullrich R, Zeitz M, Heise W, et al. Mucosal atrophy is associated with loss of activated T cells in the duodenal mucosa of human immunodeficiency virus (HIV)-infected patients. Digestion 1990; 46 (Suppl 2):302–307. 7. Cramp ME, Hing MC, Marriott DJ, et al. Bile acid malabsorption in HIV infected patients with chronic diarrhoea. Aust N Z J Med 1996; 26:368–371. 8. Ehrenpreis ED, Patterson BK, Brainer JA, et al. Histopathologic findings of duodenal biopsy specimens in HIV-infected patients with and without diarrhea and malabsorption. Am J Clin Pathol 1992; 97:21–28. 9. Lim SG, Condez A, Lee CA, et al. Loss of mucosal CD4 lymphocytes is an early feature of HIV infection. Clin Exp Immunol 1993; 92:448–454. 10. Kotler DP. HIV infection and the gastrointestinal tract. AIDS 2005; 19:107– 117. 11. Siddiqui U, Bini EJ, Chandarana K, et al. Prevalence and impact of diarrhea on health-related quality of life in HIV-infected patients in the era of highly active antiretroviral therapy. J Clin Gastroenterol 2007; 41:484–490. 12. Mattapallil JJ, Smit-McBride Z, McChesney M, et al. Intestinal intraepithelial lymphocytes are primed for gamma interferon and MIP-1beta expression and display antiviral cytotoxic activity despite severe CD4(þ) T-cell depletion in primary simian immunodeficiency virus infection. J Virol 1998; 72:6421– 6429. 13. Veazey RS, DeMaria M, Chalifoux LV, et al. Gastrointestinal tract as a major site of CD4þ T cell depletion and viral replication in SIV infection. Science 1998; 280:427–431. 14. Guadalupe M, Reay E, Sankaran S, et al. Severe CD4þ T-cell depletion in gut lymphoid tissue during primary human immunodeficiency virus type 1 infection and substantial delay in restoration following highly active antiretroviral therapy. J Virol 2003; 77:11708–11717. 15. Raffatellu M, Santos RL, Verhoeven DE, et al. Simian immunodeficiency virusinduced mucosal interleukin-17 deficiency promotes Salmonella dissemination from the gut. Nat Med 2008; 14:421–428. 16. Dandekar S, George MD, Baumler AJ. Th17 cells, HIV and the gut mucosal barrier. Curr Opin HIV AIDS 2010; 5:173–178. 17. Troncone E, Marafini I, Pallone F, Monteleone G. Th17 cytokines in inflam& matory bowel diseases: discerning the good from the bad. Int Rev Immunol 2013; 32:526–533. A comprehensive review of data on the dual role of Th17 cells in gut homeostasis and inflammation. 18. Cao AT, Yao S, Gong B, et al. Th17 cells upregulate polymeric Ig receptor and intestinal IgA and contribute to intestinal homeostasis. J Immunol 2012; 189:4666–4673. 19. Zaph C, Du Y, Saenz SA, et al. Commensal-dependent expression of IL-25 regulates the IL-23-IL-17 axis in the intestine. J Exp Med 2008; 205:2191– 2198. 20. Kim CJ, McKinnon LR, Kovacs C, et al. Mucosal Th17 cell function is altered & during HIV infection and is an independent predictor of systemic immune activation. J Immunol 2013; 191:2164–2173. Study indicating that strategies to preserve or to more rapidly restore mucosal Th17 function may have important therapeutic benefits in HIV-infected individuals. 21. Ling B, Veazey RS, Hart M, et al. Early restoration of mucosal CD4 memory CCR5 T cells in the gut of SIV-infected rhesus predicts long term nonprogression. AIDS 2007; 21:2377–2385. 22. Sankaran S, Guadalupe M, Reay E, et al. Gut mucosal T cell responses and gene expression correlate with protection against disease in long-term HIV-1infected nonprogressors. Proc Natl Acad Sci U S A 2005; 102:9860–9865. 23. Ciccone EJ, Greenwald JH, Lee PI, et al. CD4þ T cells, including Th17 and cycling subsets, are intact in the gut mucosa of HIV-1-infected long-term nonprogressors. J Virol 2011; 85:5880–5888. 24. Gordon SN, Klatt NR, Bosinger SE, et al. Severe depletion of mucosal CD4þ T cells in AIDS-free simian immunodeficiency virus-infected sooty mangabeys. J Immunol 2007; 179:3026–3034. 25. Paiardini M, Pandrea I, Apetrei C, Silvestri G. Lessons learned from the natural hosts of HIV-related viruses. Annu Rev Med 2009; 60:485–495. 26. Pandrea IV, Gautam R, Ribeiro RM, et al. Acute loss of intestinal CD4þ T cells is not predictive of simian immunodeficiency virus virulence. J Immunol 2007; 179:3035–3046.
0951-7375 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
www.co-infectiousdiseases.com
279
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Pathogenesis and immune response 27. Paiardini M, Frank I, Pandrea I, et al. Mucosal immune dysfunction in AIDS pathogenesis. AIDS Rev 2008; 10:36–46. 28. Palella FJ Jr, Baker RK, Moorman AC, et al. Mortality in the highly active antiretroviral therapy era: changing causes of death and disease in the HIV outpatient study. J Acquir Immune Defic Syndr 2006; 43: 27–34. 29. Macal M, Sankaran S, Chun TW, et al. Effective CD4þ T-cell restoration in gut-associated lymphoid tissue of HIV-infected patients is associated with enhanced Th17 cells and polyfunctional HIV-specific T-cell responses. Mucosal Immunol 2008; 1:475–488. 30. Hayes TL, Asmuth DM, Critchfield JW, et al. Impact of highly active antire& troviral therapy initiation on CD4(þ) T-cell repopulation in duodenal and rectal mucosa. AIDS 2013; 27:867–877. Study highlighting rapid immunological benefits of highly active antiretroviral therapy despite incomplete CD4þ T-cell reconstitution. 31. Karris MY, Kao YT, Patel D, et al. Predictors of virologic response in persons & who start antiretroviral therapy during recent HIV infection. AIDS 2014; 28:841–849. Study showing that age and microbial translocation were associated with detectable HIV RNA and that antiretroviral therapy did not improve CD4 T-cell counts in GALT. 32. Tugizov SM, Herrera R, Chin-Hong P, et al. HIV-associated disruption of & mucosal epithelium facilitates paracellular penetration by human papillomavirus. Virology 2013; 446:378–388. Research suggesting that HIV-associated tight junction disruption of mucosal epithelia may potentiate human papilloma virus (HPV) and HPV-associated neoplasia. 33. Buccigrossi V, Laudiero G, Nicastro E, et al. The HIV-1 transactivator factor (Tat) induces enterocyte apoptosis through a redox-mediated mechanism. PLoS One 2011; 6:e29436. 34. Guadalupe M, Sankaran S, George MD, et al. Viral suppression and immune restoration in the gastrointestinal mucosa of human immunodeficiency virus type 1-infected patients initiating therapy during primary or chronic infection. J Virol 2006; 80:8236–8247. 35. Lederman MM, Funderburg NT, Sekaly RP, et al. Residual immune dys& regulation syndrome in treated HIV infection. Adv Immunol 2013; 119:51– 83. Review of current research on the mechanisms of residual immune dysregulation syndrome (RIDS) in HIV patients on cART. 36. Yukl SA, Shergill AK, Ho T, et al. The distribution of HIV DNA and RNA in cell & subsets differs in gut and blood of HIV-positive patients on ART: implications for viral persistence. J Infect Dis 2013; 208:1212–1220. Comparative study demonstrating higher levels of HIV DNA and RNA in both CD4þ T cells and non-CD4þ T leukocytes in the ileum of HIV patients, whereas the rectum had higher HIV DNA levels in both cell types but lower RNA levels in CD4þ T cells. 37. Hatano H, Somsouk M, Sinclair E, et al. Comparison of HIV DNA and RNA in & gut-associated lymphoid tissue of HIV-infected controllers and noncontrollers. AIDS 2013; 27:2255–2260. Study comparing the mechanisms and efficacy of ‘natural’ viral control of controllers versus long-term antiretroviral therapy. 38. Eisele E, Siliciano RF. Redefining the viral reservoirs that prevent HIV-1 eradication. Immunity 2012; 37:377–388. 39. Rueda CM, Velilla PA, Chougnet CA, et al. HIV-induced T-cell activation/ exhaustion in rectal mucosa is controlled only partially by antiretroviral treatment. PLoS One 2012; 7:e30307. 40. Mavigner M, Cazabat M, Dubois M, et al. Altered CD4þ T cell homing to the gut impairs mucosal immune reconstitution in treated HIV-infected individuals. J Clin Invest 2012; 122:62–69. 41. Estes J, Baker JV, Brenchley JM, et al. Collagen deposition limits immune reconstitution in the gut. J Infect Dis 2008; 198:456–464. 42. Asmuth DM, Ma ZM, Mann S, et al. Gastrointestinal-associated lymphoid tissue immune reconstitution in a randomized clinical trial of raltegravir versus nonnucleoside reverse transcriptase inhibitor-based regimens. AIDS 2012; 26:1625–1634. 43. Brenchley JM, Price DA, Schacker TW, et al. Microbial translocation is a cause of systemic immune activation in chronic HIV infection. Nat Med 2006; 12:1365–1371. 44. Redd AD, Dabitao D, Bream JH, et al. Microbial translocation, the innate cytokine response, and HIV-1 disease progression in Africa. Proc Natl Acad Sci U S A 2009; 106:6718–6723. 45. Jiang W, Lederman MM, Hunt P, et al. Plasma levels of bacterial DNA correlate with immune activation and the magnitude of immune restoration in persons with antiretroviral-treated HIV infection. J Infect Dis 2009; 199:1177–1185. 46. Ancuta P, Kamat A, Kunstman KJ, et al. Microbial translocation is associated with increased monocyte activation and dementia in AIDS patients. PLoS One 2008; 3:e2516. 47. Marks MA, Rabkin CS, Engels EA, et al. Markers of microbial translocation and & risk of AIDS-related lymphoma. AIDS 2013; 27:469–474. Study suggesting that the links between sCD14, LPS, and non-Hodgkin’s lymphoma risk support an etiologic role for gut microbial translocation in lymphomagenesis among HIV-infected individuals.
280
www.co-infectiousdiseases.com
48. Abad-Fernandez M, Vallejo A, Hernandez-Novoa B, et al. Correlation between different methods to measure microbial translocation and its association with immune activation in long-term suppressed HIV-1-infected individuals. J Acquir Immune Defic Syndr 2013; 64:149–153. Investigation showing correlation between LPS, sCD14, and LPS-binding protein levels as measures of microbial translocation, but not bacterial 16S rDNA. 49. Pilakka-Kanthikeel S, Arheart K, Selvaraj A, et al. Immune activation is & associated with increased gut microbial translocation in treatment naive HIV infected children in a resource limited setting. J Acquir Immune Defic Syndr 2013. [Epub ahead of print] Study indicating that microbial translocation is more pronounced in HIV-infected children who were not on therapy and immunocompromised. 50. Fitzgerald F, Harris K, Doyle R, et al. Short communication: evidence that & microbial translocation occurs in HIV-infected children in the United Kingdom. AIDS Res Hum Retroviruses 2013; 29:1589–1593. Research demonstrating microbial translocation in a cohort of HIV-infected children in the United Kingdom. 51. Troseid M, Sonnerborg A, Nowak P. High mobility group box protein-1 in HIV1 infection. Curr HIV Res 2011; 9:6–10. 52. Mureith MW, Chang JJ, Lifson JD, et al. Exposure to HIV-1-encoded Toll-like receptor 8 ligands enhances monocyte response to microbial encoded Tolllike receptor 2/4 ligands. AIDS 2010; 24:1841–1848. 53. Deeks SG, Kitchen CM, Liu L, et al. Immune activation set point during early HIV infection predicts subsequent CD4þ T-cell changes independent of viral load. Blood 2004; 104:942–947. 54. Torres RA, Lewis W. Aging and HIV/AIDS: pathogenetic role of therapeutic & side effects. Lab Invest 2014; 94:120–128. Report that the toxic side effects of HAART may both resemble and promote events of aging. 55. Deeks SG, Tracy R, Douek DC. Systemic effects of inflammation on health && during chronic HIV infection. Immunity 2013; 39:633–645. Comprehensive review of the mechanisms of systemic inflammation in chronically HIV-infected individuals and the combined role of inflammation and excess clotting in the development of end-organ disease. 56. Marchetti G, Nasta P, Bai F, et al. Circulating sCD14 is associated with virological response to pegylated-interferon-alpha/ribavirin treatment in HIV/ HCV co-infected patients. PLoS One 2012; 7:e32028. 57. French AL, Evans CT, Agniel DM, et al. Microbial translocation and liver & disease progression in women coinfected with HIV and hepatitis C virus. J Infect Dis 2013; 208:679–689. Study presenting evidence that the association of sCD14, intestinal fatty acid binding protein, and IL-6 levels with liver disease progression in HIV patients may result from impairment of gut epithelial integrity and consequent microbial translocation. 58. Hudson CL, Zemlin AE, Ipp H. The cardiovascular risk marker asymmetric & dimethylarginine is elevated in asymptomatic, untreated HIV-1 infection and correlates with markers of immune activation and disease progression. Ann Clin Biochem 2013. [Epub ahead of print] Study demonstrating correlations between elevated asymmetric dimethylarginine, CD8/38 T lymphocytes, IgG, and adenosine deaminase in cART naive HIVinfected patients with relatively well preserved CD4 counts. 59. Merlini E, Luzi K, Suardi E, et al. T-cell phenotypes, apoptosis and inflammation in HIVþ patients on virologically effective cART with early atherosclerosis. PLoS One 2012; 7:e46073. 60. Lyons JL, Uno H, Ancuta P, et al. Plasma sCD14 is a biomarker associated with impaired neurocognitive test performance in attention and learning domains in HIV infection. J Acquir Immune Defic Syndr 2011; 57:371– 379. 61. Erlandson KM, Allshouse AA, Jankowski CM, et al. Association of functional & impairment with inflammation and immune activation in HIV type 1-infected adults receiving effective antiretroviral therapy. J Infect Dis 2013; 208:249– 259. Aging study utilizing markers of inflammation, T-cell activation, microbial translocation, immunosenescence, and immune recovery to estimate functional status of HIV patients 45–65 years old. 62. Reus S, Portilla J, Sanchez-Paya J, et al. Low-level HIV viremia is associated & with microbial translocation and inflammation. J Acquir Immune Defic Syndr 2013; 62:129–134. Research showing that patients on cART with undetectable HIV burden have reduced microbial translocation compared to those with moderate viral loads, and that translocation is associated with levels of inflammation markers, independent of viral burden. 63. Ciccone EJ, Read SW, Mannon PJ, et al. Cycling of gut mucosal CD4þ T cells decreases after prolonged antiretroviral therapy and is associated with plasma LPS levels. Mucosal Immunol 2010; 3:172–181. 64. Marchetti G, Bellistri GM, Borghi E, et al. Microbial translocation is associated with sustained failure in CD4þ T-cell reconstitution in HIV-infected patients on long-term highly active antiretroviral therapy. AIDS 2008; 22:2035–2038. 65. Marchetti G, Tincati C, Silvestri G. Microbial translocation in the pathogenesis && of HIV infection and AIDS. Clin Microbiol Rev 2013; 26:2–18. Comprehensive review of the causes and downstream effects of microbial translocation in HIV infection and the emergence of several recent therapeutic strategies aimed at preventing and reversing these phenomena. &
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Mucosal immunity in HIV infection George and Asmuth 66. Korn LL, Thomas HL, Hubbeling HG, et al. Conventional CD4þ T cells regulate IL-22-producing intestinal innate lymphoid cells. Mucosal Immunol 2014. [Epub ahead of print] Mouse study showing that IL-22 level is mediated by conventional CD4þ T cells and is T-cell receptor dependent. 67. Slack E, Hapfelmeier S, Stecher B, et al. Innate and adaptive immunity cooperate flexibly to maintain host–microbiota mutualism. Science 2009; 325:617–620. 68. Jiang W. Microbial translocation and B cell dysfunction in human immunodeficiency virus disease. Am J Immunol 2012; 8:44–51. 69. Erikstrup C, Kronborg G, Lohse N, et al. T-cell dysfunction in HIV-1-infected patients with impaired recovery of CD4 cells despite suppression of viral replication. J Acquir Immune Defic Syndr 2010; 53:303–310. 70. Gori A, Tincati C, Rizzardini G, et al. Early impairment of gut function and gut flora supporting a role for alteration of gastrointestinal mucosa in human immunodeficiency virus pathogenesis. J Clin Microbiol 2008; 46:757–758. 71. Ellis CL, Ma ZM, Mann SK, et al. Molecular characterization of stool microbiota in HIV-infected subjects by panbacterial and order-level 16S ribosomal DNA (rDNA) quantification and correlations with immune activation. J Acquir Immune Defic Syndr 2011; 57:363–370. 72. Lozupone CA, Li M, Campbell TB, et al. Alterations in the gut microbiota & associated with HIV-1 infection. Cell Host Microbe 2013; 14:329–339. Study showing that the microbiota profile of HIV patients with gastrointestinal inflammation has limited similarity with other inflammatory states, displays increased, rather than decreased, diversity, and, in the United States, is reflective of a carbohydrate-rich, protein-poor and fat-poor diet. 73. Vujkovic-Cvijin I, Dunham RM, Iwai S, et al. Dysbiosis of the gut microbiota is & associated with HIV disease progression and tryptophan catabolism. Sci Transl Med 2013; 5:193ra191. Investigation demonstrating a link between mucosal-adherent colonic bacteria and immunopathogenesis during progressive HIV infection in the setting of viral suppression during cART. 74. Dillon SM, Lee EJ, Kotter CV, et al. An altered intestinal mucosal microbiome & in HIV-1 infection is associated with mucosal and systemic immune activation and endotoxemia. Mucosal Immunol 2014. [Epub ahead of print] Recent report of HIV-related changes in the microbiome associated with increased mucosal cellular immune activation, microbial translocation, and blood T-cell activation. 75. Olivares M, Laparra JM, Sanz Y. Host genotype, intestinal microbiota and & inflammatory disorders. Br J Nutr 2013; 109 (Suppl 2):S76–S80. Review of the role of intestinal microbiota in influencing human physiology and disease risk because of mediation of appropriate immune responses to harmful and innocuous antigens. 76. McKnite AM, Perez-Munoz ME, Lu L, et al. Murine gut microbiota is defined by host genetics and modulates variation of metabolic traits. PLoS One 2012; 7:e39191. 77. Rothe M, Blaut M. Evolution of the gut microbiota and the influence of diet. & Benef Microbes 2013; 4:31–37. Study implicating that upregulated proteins in GALT enable intestinal Escherichia coli to better cope with diet-induced osmotic stress. &
78. Scott KP, Gratz SW, Sheridan PO, et al. The influence of diet on the gut microbiota. Pharmacol Res 2013; 69:52–60. Review of current knowledge and opinions on the influence of diet and the gut microbiota on human health. 79. Mukherji A, Kobiita A, Ye T, Chambon P. Homeostasis in intestinal epithelium & is orchestrated by the circadian clock and microbiota cues transduced by TLRs. Cell 2013; 153:812–827. Study of intraepithelial cell expression of circadian rhythmic proteins in conjunction with microbiota signaling through Toll-like receptors to enable timing of homeostatic functions. 80. Henao-Mejia J, Strowig T, Flavell RA. Microbiota keep the intestinal clock & ticking. Cell 2013; 153:741–743. Research on the role of commensal bacteria in the circadian regulation of glucocorticoid production by intestinal epithelial cells. 81. Perez-Bosque A, Miro L, Polo J, et al. Dietary plasma proteins modulate the immune response of diffuse gut-associated lymphoid tissue in rats challenged with Staphylococcus aureus enterotoxin B. J Nutr 2008; 138:533– 537. 82. Perez-Bosque A, Miro L, Polo J, et al. Dietary plasma protein supplements prevent the release of mucosal proinflammatory mediators in intestinal inflammation in rats. J Nutr 2010; 140:25–30. 83. Asmuth DM, Ma ZM, Albanese A, et al. Oral serum-derived bovine immuno&& globulin improves duodenal immune reconstitution and absorption function in patients with HIV enteropathy. AIDS 2013; 27:2207–2217. Study demonstrating that serum-derived bovine immunoglobulin treatment significantly increases intestinal mucosal CD4 lymphocyte counts, improves duodenal function, and may promote intestinal repair in the setting of HIV enteropathy. 84. Sugimoto K, Ogawa A, Mizoguchi E, et al. IL-22 ameliorates intestinal inflammation in a mouse model of ulcerative colitis. J Clin Invest 2008; 118:534–544. 85. Dyavar Shetty R, Velu V, et al. PD-1 blockade during chronic SIV infection reduces hyperimmune activation and microbial translocation in rhesus macaques. J Clin Invest 2012; 122:1712–1716. 86. Klatt NR, Canary LA, Sun X, et al. Probiotic/prebiotic supplementation of & antiretrovirals improves gastrointestinal immunity in SIV-infected macaques. J Clin Invest 2013; 123:903–907. Study suggesting that supplementation of cART with synbiotics (prebiotics þ probiotics) supplementation in HIV-infected individuals may improve gastrointestinal tract immunity and mitigate inflammation. 87. Irvine SL, Hummelen R, Hekmat S. Probiotic yogurt consumption may improve gastrointestinal symptoms, productivity, and nutritional intake of people living with human immunodeficiency virus in Mwanza, Tanzania. Nutr Res 2011; 31:875–881. 88. Perez-Santiago J, Gianella S, Massanella M, et al. Gut Lactobacillales are & associated with higher CD4 and less microbial translocation during HIV infection. AIDS 2013; 27:1921–1931. Research indicating that shaping the gut microbiome, especially proportions of Lactobacillales, might help to preserve immune function during HIV infection. &
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Mucosal immunity in HIV infection: what can be done to restore gastrointestinal-associated lymphoid tissue function? Michael D. George a and David M. Asmuth a,b
Purpose of review This review describes the impact of HIV infection on gut-associated lymphoid tissue, the mechanisms for persistent gut-associated lymphoid tissue dysfunction despite effective antiretroviral therapy, and potential strategies to restore gut-associated lymphoid tissue function and promote immune reconstitution. Recent findings Recent studies indicate that unresolved microbial translocation and intestinal dysbiosis may continue to promote enteropathy as well as HIV-associated and non-HIV-associated conditions in many HIV patients who otherwise maintain therapeutic control of systemic viral replication. Summary Several novel therapeutic approaches to reduce intestinal inflammation and mitigate microbial translocation may hold promise for restoring gastrointestinal health and thereby increasing the efficacy of immune reconstitution in HIV-infected patients undergoing antiretroviral therapy. Keywords dysbiosis, gut-associated lymphoid tissue, HIV-enteropathy, microbial translocation
INTRODUCTION Not long after the onset of the AIDS epidemic in the 1980s, it became clear to researchers and clinicians that the gastrointestinal tract was the primary site of HIV infection and pathogenesis, irrespective of the mode of acquisition. Indeed, before development of effective and readily available antiretroviral therapy, the vast majority of HIV-infected individuals suffered devastating gastrointestinal complications accompanied by a rapid decline in health from malnutrition and ‘wasting’ [1–4]. Early histologic studies of gut-associated lymphoid tissue (GALT) from chronic and AIDS stage patients with gastrointestinal manifestations revealed that HIV infection led to substantial deterioration of gastrointestinal architecture characterized by villus atrophy [5–8] and an inflammatory infiltrate intriguingly devoid of CD4þ T cells [6,9]. Physiologically, patients were often plagued by chronic intestinal inflammation, malabsorption, and debilitating diarrhea [10]. Three decades later, although much more is known about the dynamics and even subset specificities of CD4þ T-cell depletion from GALT during
HIV infection, the mechanisms underlying the collective deterioration of gastrointestinal functions known as ‘enteropathy’ are still poorly understood. Moreover, it remains unclear why many clinical manifestations of enteropathy remain unresolved despite control of HIV replication at or near undetectable levels with combinatorial antiretroviral therapy (cART) [11]. Increasingly, however, investigations are unraveling questions about how a small residual pool of actively and latently HIVinfected cells that remains can continue to perpetuate mucosal immune dysfunction. In this review, we will discuss current research and opinions on the role of GALT in the control of HIV infection, the persistence of GALT dysfunction a
University of California Davis, Davis and bUniversity of California Davis Medical Center, Sacramento, California, USA Correspondence to David M. Asmuth, MD, Professor, University of California Davis Medical Center, 4150 V Street, PSSB G-500, Sacramento, CA 95617, USA. Tel: +1 916 734 8695; fax: +1 916 734 7766; e-mail: [email protected] Curr Opin Infect Dis 2014, 27:275–281 DOI:10.1097/QCO.0000000000000059
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KEY POINTS
a predictive biomarker of systemic immune activation [20 ]. Taken together, these studies suggest that the maintenance of Th17 cells and healthy GALT function is a key factor in controlling HIV pathogenesis. Further support for this model of persistent systemic inflammation and immune activation comes from investigations of HIV-infected elite controllers and pathogenic and nonpathogenic SIV infections of nonhuman primates. Although it has been known for some time that CD4þ T cells are maintained at healthy levels in GALT of infected individuals who control HIV replication without cART [21,22], recent evidence suggests that such individuals also retain the important Th17 subset [23]. Comparative studies of nonhuman primates that are either susceptible or resistant to pathogenic SIV infection have provided additional insights. Although natural nonhuman primate SIV hosts such as African green monkeys and sooty mangabeys show similar patterns of high viral replication and mucosal CD4þ T-cell depletion as HIV-infected humans and SIV-infected rhesus macaques, they neither exhibit chronic immune activation nor develop AIDS [24–26]. Moreover, it seems that CD4þ T-cell loss is not sustained in these naturally resistant species [27]. Thus, these data imply that although CD4þ T-cell depletion is one mechanism leading to microbial translocation, it may well not be sufficient in the setting of retroviral infection. &
Depletion of GALT CD4þ T cells plays a critical role in establishment of gastrointestinal enteropathy and dysbiosis during HIV infection. New insights into the role of Th17 lymphocyte cell loss in the maintenance of abnormal mucosal immune function have been discovered over the review period and promise to provide new insights into the pathophysiology of failed immune reconstitution. Suppressive cART improves but often does not reverse enteropathy, microbial translocation, or the adverse effects of chronic systemic inflammation. Promising therapeutic strategies are emerging that seek to promote host–microbe homeostasis and epithelial health, inactivate proinflammatory molecules, or prevent gastrointestinal inflammation altogether.
despite suppressive cART, the impact of microbial translocation on immune activation and chronic inflammation in GALT, and the potential role of the commensal microbiome and host–microbe dysbiosis in promoting GALT pathogenesis. Finally, we will conclude by examining emerging strategies for maintaining and restoring GALT structure and function that are likely to be critical to the success of any future therapeutic approaches designed to provide a functional cure or eradicate HIV from the body.
GUT-ASSOCIATED LYMPHOID TISSUE FUNCTION IS CRITICAL FOR CONTROL OF HIV
PERSISTENCE OF GUT-ASSOCIATED LYMPHOID TISSUE DYSFUNCTION DESPITE HIGHLY ACTIVE ANTIRETROVIRAL THERAPY
Shortly after pioneering studies of rhesus macaques infected with pathogenic simian immunodeficiency virus (SIV) revealed that the vast majority of susceptible CD4þ T cells in GALT are infected and killed within the first weeks of infection [12,13], the same swift and severe decimation was confirmed in primary HIV infection [14]. Importantly, subsequent studies showed that HIV/SIV preferentially targets a subset of CD4þ helper T cells (Th) characterized by its production of the cytokines IL-17 and IL-22 [15,16]. Because these ‘Th17’ cells are also involved in maintenance of the intestinal tight junction integrity [17 ,18,19], their loss is presumed to lead to a breakdown in barrier function that in turn permits systemic immune activation (and by extension, viral replication) through continuous exposure of the underlying lamina propria antigen-presenting cells to luminal antigens. Recent investigations support this hypothesis, indicating that alteration of Th17 functions in GALT can be
Advances over the last decade in the safety and the efficacy of administration of antiretroviral cocktails have dramatically increased the life expectancy of HIV patients [28]. However, despite the success of cART in controlling HIV replication and restoring circulating CD4þ T-cell populations, restoration of GALT structure and function is markedly delayed if it occurs at all [29,30 ]. Moreover, initiation of cART early in infection does not appear to promote significant maintenance of CD4þ T cells in GALT [31 ]. In addition, histological studies reveal that intestinal epithelial damage characterized by disruption of tight junctions [32 ] and enterocyte apoptosis [33] persists in patients on long-term therapy. Gene expression studies have provided broad insights, showing that multiple biomarkers of mucosal growth remain repressed in GALT during chronic HIV infection despite suppressive therapy [22,34]. More recent evidence suggests that this residual immune dysregulation is most prevalent when cART
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fails to increase circulating CD4þ T cells to normal levels [35 ]. Although the mechanisms that impair CD4þ T-cell reconstitution in GALT during therapy are not fully defined, investigations continue to highlight several potential contributing factors. Multiple studies in the last few years have focused on the impact of residual viral reservoirs and ongoing viral replication in GALT despite systemic HIV suppression [36 ,37 ,38]. Other investigations have shown that chronic residual CD8þ T-cell activation may play an important role [39]. Still others suggest that altered expression of mucosal homing and retention biomarkers may impair trafficking and thereby prevent re-establishment of normalized CD4þ T-cell populations in GALT [40]. The potential for inflammation-associated fibrosis of the extracellular matrix to impair migration of CD4þ T cells into the lamina propria has also been explored [41], as well as the contribution from sustained immune activation in GALT that may ‘exhaust’ available pools of lymphocyte progenitors [30 ,42]. Thus, the mechanisms that promote persistent mucosal immune dysregulation in the face of suppressive cART appear to be broad-ranged and are likely to be intricately interwoven. &
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GUT-ASSOCIATED LYMPHOID TISSUE, MICROBIAL TRANSLOCATION, AND IMMUNE ACTIVATION In recent years, several lines of research have focused on the hypothesis that translocation of gut microbe antigens across a leaky intestinal epithelial barrier plays an important role in the chronic immune activation and inflammation that defines HIV disease progression. In 2006, Brenchley et al. [43] first reported increased circulating lipopolysaccharide (LPS) in both HIV-infected humans and SIV-infected rhesus macaques during chronic infection as compared with uninfected controls. While controversy persists whether LPS is an optimal surrogate marker for microbial translocation, many studies have since corroborated the initial findings [44–46] and characterized additional biomarkers [47 ,48 ]. More recently, clinical investigations [49 ,50 ] have confirmed that microbial translocation is also a major source of immune activation and may contribute to the rapid disease progression common in HIVinfected children. Mechanistically, microbial translocation appears to trigger innate immune activation through engagement of pathogen recognition receptor signaling [51,52]. In turn, the sustained activation is believed to fuel a downward spiraling pathogenic cycle whereby new susceptible HIV targets are created &
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and incessant antiviral and cytotoxic responses increase damage to the intestinal epithelium and stimulate further translocation. Notably, several investigators [53] have shown that the magnitude of immune activation is a strong predictor of HIV disease progression, independent of viral burden. Currently, investigations are increasingly focused on understanding the relationship between microbial translocation, immune activation, and the manifestation of HIV-associated and non-HIV-associated (HANA) conditions [54 ]. It has been known for some time that HIV infection leads to a higherthan-expected risk of degenerative diseases that are often associated with the aging process [55 ]. In the last few years, new data have emerged suggesting that microbial translocation may play an important role in the development of liver [56,57 ], cardiovascular [58 ,59], and neurocognitive disease [60] in HIV patients. Clearly, these findings have profound implications, and numerous studies are underway to continue characterizing biomarkers of positive and negative clinical outcomes and evaluate strategies for intervention. Given the plethora of reports over the last decade of impaired and delayed immune reconstitution in GALT during therapy, it is not surprising that more recent studies have revealed that microbial translocation also often persists when HIV replication is controlled through cART. Indeed, many of these investigations have demonstrated that the persistence in translocation was associated with chronic inflammation [61 ,62 ] and impaired reconstitution of intestinal CD4þ T cells [63,64]. Intriguingly, investigations of nonhuman primates demonstrate that microbial translocation does not occur in nonpathogenic SIV infection of natural hosts such as sooty mangabeys and African green monkeys [65 ]. By analogy, these findings imply that valuable knowledge regarding the mechanisms of protection from microbial translocation may also be gained through carefully designed comparative studies of treatment naı¨ve HIV elite controllers. &
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GUT-ASSOCIATED LYMPHOID TISSUE AND MICROBIAL COMMUNITY INTERACTIONS IN HIV INFECTION The completion of the Human Microbiome Project has provided HIV researchers an unprecedented understanding of the diversity and proportional distributions of the commensal bacterial species inhabiting the upper and lower gastrointestinal tract. In light of the known relationship between the microbiome and lamina propria CD4þ T cells [18,66 ,67], it has long been hypothesized that the microbiome could play a critical role in HIV
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pathogenesis and susceptibility to secondary infections. During chronic HIV infection, increasing immune suppression caused by CD4þ T-cell depletion as well as T- and B-cell dysfunction [68,69] contributes to elevated susceptibility to routine pathogens such as those associated with bacterial and mycobacterial disease. In addition, immune deficiency could alter normal homeostatic interactions with microbial communities and thereby fuel episodic outgrowth of commensal opportunistic pathogens that have the capacity to exploit inflammatory environments for metabolic advantage. Gori et al. [70] were the first to report evidence of gastrointestinal dysbiosis in HIV-infected individuals, observing an increased abundance of Pseudomonas aeruginosa and Candida albicans and a reduction of Bifidobacteria and lactobacilli in fecal samples as compared with healthy controls. In 2011, an investigation by Ellis et al. [71] described a positive association between stool Bacteroidales and systemic CD8þ T-cell activation and negative associations between Enterobacteriales and duodenal lamina propria CD4þ T-cell counts in untreated HIV-infected patients. Subsequent research by Lozupone et al. [72 ] has shown that the fecal microbiome of HIV-infected patients with gastrointestinal inflammation presents a bacterial species profile that is distinct from that of other intestinal inflammatory diseases and often persists during cART. Interestingly, a recent study [73 ] of bacterial communities in the rectal mucosa of untreated and treated HIV-1-infected individuals revealed that dysbiosis was associated with elevated levels of tryptophan catabolism and increases in multiple biomarkers of inflammation and disease progression. Furthermore, they found that the dysbiosis was persistent in HIV-infected patients undergoing cART. More recently, Dillon et al. [74 ] showed that HIV-1-infected individuals had increased abundances of Proteobacteria and decreased abundances of Firmicutes in the colonic mucosa. At the genus level, significant outgrowth of Prevotella and decrease of Bacteroides were detected. Changes in mucosal microbiota were linked with local elevation in activated T-cell and myeloid dendritic cell numbers and increased microbial translocation. Importantly, the study also demonstrated that the bacterial modulations identified in colonic mucosal tissues were not well reflected in microbiome analyses of fecal material. Collectively, these early studies demonstrate that HIV infection is consistently associated with significant disruption of homeostatic bacterial communities throughout the gastrointestinal tract. Given the substantial variability of the microbiome stemming from genetic [75 ,76], dietary [77 ,78 ], &
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and even temporal [79 ,80 ] factors, it is clear that more studies are needed to understand which disruptions are stable and directly contribute to pathogenesis, the mechanisms by which this occurs, and how to correct it. Such comprehensive objectives will undoubtedly benefit from, and indeed may be dependent on, further development of SIV models in which confounding variables such as diet, housing, social interactions, and genetic background can be controlled.
CONCLUSION In light of increases in our understanding of the pathogenic impact of intestinal dysbiosis and microbial translocation, novel therapeutic strategies are clearly needed to counteract their cause and downstream effects on HIV disease progression and the development of HANA conditions. To that end, a variety of inspiring approaches have already been and continue to be investigated in HIV-infected humans and in several animal models. In rodent models of intestinal inflammation, investigators have shown that the immunoglobulins present in serum-derived bovine immunoglobulin (SBI) can improve epithelial barrier integrity and reduce inflammation by neutralizing LPS and other bacterial toxins [81,82]. SBI is an oral, medical food that has been used safely in many human studies, including pediatric populations [28]. Encouragingly, this strategy has been recently employed with similar success in a pilot study of eight individuals with HIV enteropathy [83 ]. The dramatic decline in HIV enteropathy-related symptoms noted upon initiation of SBI is encouraging for patients who have persistent symptoms despite a negative workup for chronic diarrhea. A modest decline in biomarkers of bacterial translocation and reduction in systemic parameters of monocyte activation is encouraging evidence that neutralization of proinflammatory bacterial antigen in the gut lumen can lead to systemic reduction in inflammation. This was the first study that also demonstrated a sharp increase in duodenal lamina propria CD4þ T lymphocytes that otherwise remain severely depleted despite long-term viral suppression and systemic immune reconstitution [83 ]. A large multicenter placebo-controlled randomized study is underway to validate and extend these findings of the initial pilot study. Several compounds are being considered for their application in the setting of HIV infection. Administration of IL-22 has also been utilized to reduce inflammation in murine models of ulcerative colitis [84]. In the rhesus macaque SIV model, &&
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recent studies demonstrate that a programmed death 1 blockade in chronic stage infection can be effective at reducing immune activation and microbial translocation [85]. The use of probiotics in combination with cART is also under investigation in the macaque model. Interestingly, after 5 months of treatment in SIVmac239-infected pigtail macaques, researchers observed an increase in frequency of antigen-presenting cells, enhanced Th17 functionality, and a reduction of T-cell activation [86 ]. Recent investigations of probiotic therapy in HIV-infected humans have shown similar promising results. A study of HIV-infected individuals in Tanzania found that diet supplementation with probiotic yogurt increased CD4þ T-cell numbers in comparison to controls who did not consume yogurt [87]. In addition, symbiotic approaches that combine prebiotic and probiotic treatment have been efficacious in elevating CD4þ T-cell levels, and increasing growth of beneficial bacteria (e.g. Bifidobacterium) compared to HIV patients receiving placebo. Other HIV investigations suggest that certain inherent bacterial community profiles might provide protective benefits throughout the course of HIV infection. For example, elevated CD4þ T-cell counts, lower viral loads, and reduced microbial translocation have been linked with greater proportions of Lactobacillales in early untreated HIV infection, and these relationships were sustained following initiation of cART [88 ]. Ongoing and future investigations will continue to yield additional insights and optimize therapeutic strategies to block microbial translocation, dampen immune activation and enteropathy, and thereby improve the health and increase the life expectancy of HIVinfected individuals. &
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Acknowledgements None. Search terms used: HIV, malnutrition, wasting, diarrhea, CD4þ T-cell depletion, gut-associated lymphoid tissue, GALT, inflammation, immune activation, microbial translocation, SIV, antiretroviral therapy, microbiome, microbiota, commensal, bacteria, T helper cells, Th17, IL-17, IL-22, nonprogressors, African green monkeys, sooty mangabeys, rhesus macaques, immune dysregulation syndrome, LPS, sCD14, 16S rDNA, circadian, probiotics, prebiotics, immune reconstitution. Conflicts of interest M.D.G. has no conflicts of interest. D.M.A is the site Principal Investigator for pharmaceutical-sponsored and investigator-initiated clinical trials – Argos, BioNor, EnteraHealth, Gilead, Merck, Pfizer, Tibotec, and ViiV.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Hoyt MJ, Staats JA. Wasting and malnutrition in patients with HIV/AIDS. J Assoc Nurses AIDS Care 1991; 2:16–28. 2. Griffin GE. Malabsorption, malnutrition and HIV disease. Baillieres Clin Gastroenterol 1990; 4:361–373. 3. Kotler DP. Malnutrition in HIV infection and AIDS. AIDS 1989; 3 (Suppl 1): S175–S180. 4. DuPont HL, Marshall GD. HIV-associated diarrhoea and wasting. Lancet 1995; 346:352–356. 5. Cummins AG, LaBrooy JT, Stanley DP, et al. Quantitative histological study of enteropathy associated with HIV infection. Gut 1990; 31:317–321. 6. Ullrich R, Zeitz M, Heise W, et al. Mucosal atrophy is associated with loss of activated T cells in the duodenal mucosa of human immunodeficiency virus (HIV)-infected patients. Digestion 1990; 46 (Suppl 2):302–307. 7. Cramp ME, Hing MC, Marriott DJ, et al. Bile acid malabsorption in HIV infected patients with chronic diarrhoea. Aust N Z J Med 1996; 26:368–371. 8. Ehrenpreis ED, Patterson BK, Brainer JA, et al. Histopathologic findings of duodenal biopsy specimens in HIV-infected patients with and without diarrhea and malabsorption. Am J Clin Pathol 1992; 97:21–28. 9. Lim SG, Condez A, Lee CA, et al. Loss of mucosal CD4 lymphocytes is an early feature of HIV infection. Clin Exp Immunol 1993; 92:448–454. 10. Kotler DP. HIV infection and the gastrointestinal tract. AIDS 2005; 19:107– 117. 11. Siddiqui U, Bini EJ, Chandarana K, et al. Prevalence and impact of diarrhea on health-related quality of life in HIV-infected patients in the era of highly active antiretroviral therapy. J Clin Gastroenterol 2007; 41:484–490. 12. Mattapallil JJ, Smit-McBride Z, McChesney M, et al. Intestinal intraepithelial lymphocytes are primed for gamma interferon and MIP-1beta expression and display antiviral cytotoxic activity despite severe CD4(þ) T-cell depletion in primary simian immunodeficiency virus infection. J Virol 1998; 72:6421– 6429. 13. Veazey RS, DeMaria M, Chalifoux LV, et al. Gastrointestinal tract as a major site of CD4þ T cell depletion and viral replication in SIV infection. Science 1998; 280:427–431. 14. Guadalupe M, Reay E, Sankaran S, et al. Severe CD4þ T-cell depletion in gut lymphoid tissue during primary human immunodeficiency virus type 1 infection and substantial delay in restoration following highly active antiretroviral therapy. J Virol 2003; 77:11708–11717. 15. Raffatellu M, Santos RL, Verhoeven DE, et al. Simian immunodeficiency virusinduced mucosal interleukin-17 deficiency promotes Salmonella dissemination from the gut. Nat Med 2008; 14:421–428. 16. Dandekar S, George MD, Baumler AJ. Th17 cells, HIV and the gut mucosal barrier. Curr Opin HIV AIDS 2010; 5:173–178. 17. Troncone E, Marafini I, Pallone F, Monteleone G. Th17 cytokines in inflam& matory bowel diseases: discerning the good from the bad. Int Rev Immunol 2013; 32:526–533. A comprehensive review of data on the dual role of Th17 cells in gut homeostasis and inflammation. 18. Cao AT, Yao S, Gong B, et al. Th17 cells upregulate polymeric Ig receptor and intestinal IgA and contribute to intestinal homeostasis. J Immunol 2012; 189:4666–4673. 19. Zaph C, Du Y, Saenz SA, et al. Commensal-dependent expression of IL-25 regulates the IL-23-IL-17 axis in the intestine. J Exp Med 2008; 205:2191– 2198. 20. Kim CJ, McKinnon LR, Kovacs C, et al. Mucosal Th17 cell function is altered & during HIV infection and is an independent predictor of systemic immune activation. J Immunol 2013; 191:2164–2173. Study indicating that strategies to preserve or to more rapidly restore mucosal Th17 function may have important therapeutic benefits in HIV-infected individuals. 21. Ling B, Veazey RS, Hart M, et al. Early restoration of mucosal CD4 memory CCR5 T cells in the gut of SIV-infected rhesus predicts long term nonprogression. AIDS 2007; 21:2377–2385. 22. Sankaran S, Guadalupe M, Reay E, et al. Gut mucosal T cell responses and gene expression correlate with protection against disease in long-term HIV-1infected nonprogressors. Proc Natl Acad Sci U S A 2005; 102:9860–9865. 23. Ciccone EJ, Greenwald JH, Lee PI, et al. CD4þ T cells, including Th17 and cycling subsets, are intact in the gut mucosa of HIV-1-infected long-term nonprogressors. J Virol 2011; 85:5880–5888. 24. Gordon SN, Klatt NR, Bosinger SE, et al. Severe depletion of mucosal CD4þ T cells in AIDS-free simian immunodeficiency virus-infected sooty mangabeys. J Immunol 2007; 179:3026–3034. 25. Paiardini M, Pandrea I, Apetrei C, Silvestri G. Lessons learned from the natural hosts of HIV-related viruses. Annu Rev Med 2009; 60:485–495. 26. Pandrea IV, Gautam R, Ribeiro RM, et al. Acute loss of intestinal CD4þ T cells is not predictive of simian immunodeficiency virus virulence. J Immunol 2007; 179:3035–3046.
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www.co-infectiousdiseases.com
279
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Pathogenesis and immune response 27. Paiardini M, Frank I, Pandrea I, et al. Mucosal immune dysfunction in AIDS pathogenesis. AIDS Rev 2008; 10:36–46. 28. Palella FJ Jr, Baker RK, Moorman AC, et al. Mortality in the highly active antiretroviral therapy era: changing causes of death and disease in the HIV outpatient study. J Acquir Immune Defic Syndr 2006; 43: 27–34. 29. Macal M, Sankaran S, Chun TW, et al. Effective CD4þ T-cell restoration in gut-associated lymphoid tissue of HIV-infected patients is associated with enhanced Th17 cells and polyfunctional HIV-specific T-cell responses. Mucosal Immunol 2008; 1:475–488. 30. Hayes TL, Asmuth DM, Critchfield JW, et al. Impact of highly active antire& troviral therapy initiation on CD4(þ) T-cell repopulation in duodenal and rectal mucosa. AIDS 2013; 27:867–877. Study highlighting rapid immunological benefits of highly active antiretroviral therapy despite incomplete CD4þ T-cell reconstitution. 31. Karris MY, Kao YT, Patel D, et al. Predictors of virologic response in persons & who start antiretroviral therapy during recent HIV infection. AIDS 2014; 28:841–849. Study showing that age and microbial translocation were associated with detectable HIV RNA and that antiretroviral therapy did not improve CD4 T-cell counts in GALT. 32. Tugizov SM, Herrera R, Chin-Hong P, et al. HIV-associated disruption of & mucosal epithelium facilitates paracellular penetration by human papillomavirus. Virology 2013; 446:378–388. Research suggesting that HIV-associated tight junction disruption of mucosal epithelia may potentiate human papilloma virus (HPV) and HPV-associated neoplasia. 33. Buccigrossi V, Laudiero G, Nicastro E, et al. The HIV-1 transactivator factor (Tat) induces enterocyte apoptosis through a redox-mediated mechanism. PLoS One 2011; 6:e29436. 34. Guadalupe M, Sankaran S, George MD, et al. Viral suppression and immune restoration in the gastrointestinal mucosa of human immunodeficiency virus type 1-infected patients initiating therapy during primary or chronic infection. J Virol 2006; 80:8236–8247. 35. Lederman MM, Funderburg NT, Sekaly RP, et al. Residual immune dys& regulation syndrome in treated HIV infection. Adv Immunol 2013; 119:51– 83. Review of current research on the mechanisms of residual immune dysregulation syndrome (RIDS) in HIV patients on cART. 36. Yukl SA, Shergill AK, Ho T, et al. The distribution of HIV DNA and RNA in cell & subsets differs in gut and blood of HIV-positive patients on ART: implications for viral persistence. J Infect Dis 2013; 208:1212–1220. Comparative study demonstrating higher levels of HIV DNA and RNA in both CD4þ T cells and non-CD4þ T leukocytes in the ileum of HIV patients, whereas the rectum had higher HIV DNA levels in both cell types but lower RNA levels in CD4þ T cells. 37. Hatano H, Somsouk M, Sinclair E, et al. Comparison of HIV DNA and RNA in & gut-associated lymphoid tissue of HIV-infected controllers and noncontrollers. AIDS 2013; 27:2255–2260. Study comparing the mechanisms and efficacy of ‘natural’ viral control of controllers versus long-term antiretroviral therapy. 38. Eisele E, Siliciano RF. Redefining the viral reservoirs that prevent HIV-1 eradication. Immunity 2012; 37:377–388. 39. Rueda CM, Velilla PA, Chougnet CA, et al. HIV-induced T-cell activation/ exhaustion in rectal mucosa is controlled only partially by antiretroviral treatment. PLoS One 2012; 7:e30307. 40. Mavigner M, Cazabat M, Dubois M, et al. Altered CD4þ T cell homing to the gut impairs mucosal immune reconstitution in treated HIV-infected individuals. J Clin Invest 2012; 122:62–69. 41. Estes J, Baker JV, Brenchley JM, et al. Collagen deposition limits immune reconstitution in the gut. J Infect Dis 2008; 198:456–464. 42. Asmuth DM, Ma ZM, Mann S, et al. Gastrointestinal-associated lymphoid tissue immune reconstitution in a randomized clinical trial of raltegravir versus nonnucleoside reverse transcriptase inhibitor-based regimens. AIDS 2012; 26:1625–1634. 43. Brenchley JM, Price DA, Schacker TW, et al. Microbial translocation is a cause of systemic immune activation in chronic HIV infection. Nat Med 2006; 12:1365–1371. 44. Redd AD, Dabitao D, Bream JH, et al. Microbial translocation, the innate cytokine response, and HIV-1 disease progression in Africa. Proc Natl Acad Sci U S A 2009; 106:6718–6723. 45. Jiang W, Lederman MM, Hunt P, et al. Plasma levels of bacterial DNA correlate with immune activation and the magnitude of immune restoration in persons with antiretroviral-treated HIV infection. J Infect Dis 2009; 199:1177–1185. 46. Ancuta P, Kamat A, Kunstman KJ, et al. Microbial translocation is associated with increased monocyte activation and dementia in AIDS patients. PLoS One 2008; 3:e2516. 47. Marks MA, Rabkin CS, Engels EA, et al. Markers of microbial translocation and & risk of AIDS-related lymphoma. AIDS 2013; 27:469–474. Study suggesting that the links between sCD14, LPS, and non-Hodgkin’s lymphoma risk support an etiologic role for gut microbial translocation in lymphomagenesis among HIV-infected individuals.
280
www.co-infectiousdiseases.com
48. Abad-Fernandez M, Vallejo A, Hernandez-Novoa B, et al. Correlation between different methods to measure microbial translocation and its association with immune activation in long-term suppressed HIV-1-infected individuals. J Acquir Immune Defic Syndr 2013; 64:149–153. Investigation showing correlation between LPS, sCD14, and LPS-binding protein levels as measures of microbial translocation, but not bacterial 16S rDNA. 49. Pilakka-Kanthikeel S, Arheart K, Selvaraj A, et al. Immune activation is & associated with increased gut microbial translocation in treatment naive HIV infected children in a resource limited setting. J Acquir Immune Defic Syndr 2013. [Epub ahead of print] Study indicating that microbial translocation is more pronounced in HIV-infected children who were not on therapy and immunocompromised. 50. Fitzgerald F, Harris K, Doyle R, et al. Short communication: evidence that & microbial translocation occurs in HIV-infected children in the United Kingdom. AIDS Res Hum Retroviruses 2013; 29:1589–1593. Research demonstrating microbial translocation in a cohort of HIV-infected children in the United Kingdom. 51. Troseid M, Sonnerborg A, Nowak P. High mobility group box protein-1 in HIV1 infection. Curr HIV Res 2011; 9:6–10. 52. Mureith MW, Chang JJ, Lifson JD, et al. Exposure to HIV-1-encoded Toll-like receptor 8 ligands enhances monocyte response to microbial encoded Tolllike receptor 2/4 ligands. AIDS 2010; 24:1841–1848. 53. Deeks SG, Kitchen CM, Liu L, et al. Immune activation set point during early HIV infection predicts subsequent CD4þ T-cell changes independent of viral load. Blood 2004; 104:942–947. 54. Torres RA, Lewis W. Aging and HIV/AIDS: pathogenetic role of therapeutic & side effects. Lab Invest 2014; 94:120–128. Report that the toxic side effects of HAART may both resemble and promote events of aging. 55. Deeks SG, Tracy R, Douek DC. Systemic effects of inflammation on health && during chronic HIV infection. Immunity 2013; 39:633–645. Comprehensive review of the mechanisms of systemic inflammation in chronically HIV-infected individuals and the combined role of inflammation and excess clotting in the development of end-organ disease. 56. Marchetti G, Nasta P, Bai F, et al. Circulating sCD14 is associated with virological response to pegylated-interferon-alpha/ribavirin treatment in HIV/ HCV co-infected patients. PLoS One 2012; 7:e32028. 57. French AL, Evans CT, Agniel DM, et al. Microbial translocation and liver & disease progression in women coinfected with HIV and hepatitis C virus. J Infect Dis 2013; 208:679–689. Study presenting evidence that the association of sCD14, intestinal fatty acid binding protein, and IL-6 levels with liver disease progression in HIV patients may result from impairment of gut epithelial integrity and consequent microbial translocation. 58. Hudson CL, Zemlin AE, Ipp H. The cardiovascular risk marker asymmetric & dimethylarginine is elevated in asymptomatic, untreated HIV-1 infection and correlates with markers of immune activation and disease progression. Ann Clin Biochem 2013. [Epub ahead of print] Study demonstrating correlations between elevated asymmetric dimethylarginine, CD8/38 T lymphocytes, IgG, and adenosine deaminase in cART naive HIVinfected patients with relatively well preserved CD4 counts. 59. Merlini E, Luzi K, Suardi E, et al. T-cell phenotypes, apoptosis and inflammation in HIVþ patients on virologically effective cART with early atherosclerosis. PLoS One 2012; 7:e46073. 60. Lyons JL, Uno H, Ancuta P, et al. Plasma sCD14 is a biomarker associated with impaired neurocognitive test performance in attention and learning domains in HIV infection. J Acquir Immune Defic Syndr 2011; 57:371– 379. 61. Erlandson KM, Allshouse AA, Jankowski CM, et al. Association of functional & impairment with inflammation and immune activation in HIV type 1-infected adults receiving effective antiretroviral therapy. J Infect Dis 2013; 208:249– 259. Aging study utilizing markers of inflammation, T-cell activation, microbial translocation, immunosenescence, and immune recovery to estimate functional status of HIV patients 45–65 years old. 62. Reus S, Portilla J, Sanchez-Paya J, et al. Low-level HIV viremia is associated & with microbial translocation and inflammation. J Acquir Immune Defic Syndr 2013; 62:129–134. Research showing that patients on cART with undetectable HIV burden have reduced microbial translocation compared to those with moderate viral loads, and that translocation is associated with levels of inflammation markers, independent of viral burden. 63. Ciccone EJ, Read SW, Mannon PJ, et al. Cycling of gut mucosal CD4þ T cells decreases after prolonged antiretroviral therapy and is associated with plasma LPS levels. Mucosal Immunol 2010; 3:172–181. 64. Marchetti G, Bellistri GM, Borghi E, et al. Microbial translocation is associated with sustained failure in CD4þ T-cell reconstitution in HIV-infected patients on long-term highly active antiretroviral therapy. AIDS 2008; 22:2035–2038. 65. Marchetti G, Tincati C, Silvestri G. Microbial translocation in the pathogenesis && of HIV infection and AIDS. Clin Microbiol Rev 2013; 26:2–18. Comprehensive review of the causes and downstream effects of microbial translocation in HIV infection and the emergence of several recent therapeutic strategies aimed at preventing and reversing these phenomena. &
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Mucosal immunity in HIV infection George and Asmuth 66. Korn LL, Thomas HL, Hubbeling HG, et al. Conventional CD4þ T cells regulate IL-22-producing intestinal innate lymphoid cells. Mucosal Immunol 2014. [Epub ahead of print] Mouse study showing that IL-22 level is mediated by conventional CD4þ T cells and is T-cell receptor dependent. 67. Slack E, Hapfelmeier S, Stecher B, et al. Innate and adaptive immunity cooperate flexibly to maintain host–microbiota mutualism. Science 2009; 325:617–620. 68. Jiang W. Microbial translocation and B cell dysfunction in human immunodeficiency virus disease. Am J Immunol 2012; 8:44–51. 69. Erikstrup C, Kronborg G, Lohse N, et al. T-cell dysfunction in HIV-1-infected patients with impaired recovery of CD4 cells despite suppression of viral replication. J Acquir Immune Defic Syndr 2010; 53:303–310. 70. Gori A, Tincati C, Rizzardini G, et al. Early impairment of gut function and gut flora supporting a role for alteration of gastrointestinal mucosa in human immunodeficiency virus pathogenesis. J Clin Microbiol 2008; 46:757–758. 71. Ellis CL, Ma ZM, Mann SK, et al. Molecular characterization of stool microbiota in HIV-infected subjects by panbacterial and order-level 16S ribosomal DNA (rDNA) quantification and correlations with immune activation. J Acquir Immune Defic Syndr 2011; 57:363–370. 72. Lozupone CA, Li M, Campbell TB, et al. Alterations in the gut microbiota & associated with HIV-1 infection. Cell Host Microbe 2013; 14:329–339. Study showing that the microbiota profile of HIV patients with gastrointestinal inflammation has limited similarity with other inflammatory states, displays increased, rather than decreased, diversity, and, in the United States, is reflective of a carbohydrate-rich, protein-poor and fat-poor diet. 73. Vujkovic-Cvijin I, Dunham RM, Iwai S, et al. Dysbiosis of the gut microbiota is & associated with HIV disease progression and tryptophan catabolism. Sci Transl Med 2013; 5:193ra191. Investigation demonstrating a link between mucosal-adherent colonic bacteria and immunopathogenesis during progressive HIV infection in the setting of viral suppression during cART. 74. Dillon SM, Lee EJ, Kotter CV, et al. An altered intestinal mucosal microbiome & in HIV-1 infection is associated with mucosal and systemic immune activation and endotoxemia. Mucosal Immunol 2014. [Epub ahead of print] Recent report of HIV-related changes in the microbiome associated with increased mucosal cellular immune activation, microbial translocation, and blood T-cell activation. 75. Olivares M, Laparra JM, Sanz Y. Host genotype, intestinal microbiota and & inflammatory disorders. Br J Nutr 2013; 109 (Suppl 2):S76–S80. Review of the role of intestinal microbiota in influencing human physiology and disease risk because of mediation of appropriate immune responses to harmful and innocuous antigens. 76. McKnite AM, Perez-Munoz ME, Lu L, et al. Murine gut microbiota is defined by host genetics and modulates variation of metabolic traits. PLoS One 2012; 7:e39191. 77. Rothe M, Blaut M. Evolution of the gut microbiota and the influence of diet. & Benef Microbes 2013; 4:31–37. Study implicating that upregulated proteins in GALT enable intestinal Escherichia coli to better cope with diet-induced osmotic stress. &
78. Scott KP, Gratz SW, Sheridan PO, et al. The influence of diet on the gut microbiota. Pharmacol Res 2013; 69:52–60. Review of current knowledge and opinions on the influence of diet and the gut microbiota on human health. 79. Mukherji A, Kobiita A, Ye T, Chambon P. Homeostasis in intestinal epithelium & is orchestrated by the circadian clock and microbiota cues transduced by TLRs. Cell 2013; 153:812–827. Study of intraepithelial cell expression of circadian rhythmic proteins in conjunction with microbiota signaling through Toll-like receptors to enable timing of homeostatic functions. 80. Henao-Mejia J, Strowig T, Flavell RA. Microbiota keep the intestinal clock & ticking. Cell 2013; 153:741–743. Research on the role of commensal bacteria in the circadian regulation of glucocorticoid production by intestinal epithelial cells. 81. Perez-Bosque A, Miro L, Polo J, et al. Dietary plasma proteins modulate the immune response of diffuse gut-associated lymphoid tissue in rats challenged with Staphylococcus aureus enterotoxin B. J Nutr 2008; 138:533– 537. 82. Perez-Bosque A, Miro L, Polo J, et al. Dietary plasma protein supplements prevent the release of mucosal proinflammatory mediators in intestinal inflammation in rats. J Nutr 2010; 140:25–30. 83. Asmuth DM, Ma ZM, Albanese A, et al. Oral serum-derived bovine immuno&& globulin improves duodenal immune reconstitution and absorption function in patients with HIV enteropathy. AIDS 2013; 27:2207–2217. Study demonstrating that serum-derived bovine immunoglobulin treatment significantly increases intestinal mucosal CD4 lymphocyte counts, improves duodenal function, and may promote intestinal repair in the setting of HIV enteropathy. 84. Sugimoto K, Ogawa A, Mizoguchi E, et al. IL-22 ameliorates intestinal inflammation in a mouse model of ulcerative colitis. J Clin Invest 2008; 118:534–544. 85. Dyavar Shetty R, Velu V, et al. PD-1 blockade during chronic SIV infection reduces hyperimmune activation and microbial translocation in rhesus macaques. J Clin Invest 2012; 122:1712–1716. 86. Klatt NR, Canary LA, Sun X, et al. Probiotic/prebiotic supplementation of & antiretrovirals improves gastrointestinal immunity in SIV-infected macaques. J Clin Invest 2013; 123:903–907. Study suggesting that supplementation of cART with synbiotics (prebiotics þ probiotics) supplementation in HIV-infected individuals may improve gastrointestinal tract immunity and mitigate inflammation. 87. Irvine SL, Hummelen R, Hekmat S. Probiotic yogurt consumption may improve gastrointestinal symptoms, productivity, and nutritional intake of people living with human immunodeficiency virus in Mwanza, Tanzania. Nutr Res 2011; 31:875–881. 88. Perez-Santiago J, Gianella S, Massanella M, et al. Gut Lactobacillales are & associated with higher CD4 and less microbial translocation during HIV infection. AIDS 2013; 27:1921–1931. Research indicating that shaping the gut microbiome, especially proportions of Lactobacillales, might help to preserve immune function during HIV infection. &
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