Handbook of Clinical Neurology, Vol. 123 (3rd series) Neurovirology A.C. Tselis and J. Booss, Editors © 2014 Elsevier B.V. All rights reserved

Chapter 23

Central nervous system HIV-1 infection MARIE F. GRILL1 AND RICHARD W. PRICE2* Department of Neurology, Division of Hospital Neurology, Mayo Clinic Hospital, Phoenix, AZ, USA

1 2

Department of Neurology, School of Medicine, University of California San Francisco, San Francisco, CA, USA

INTRODUCTION Human immunodeficiency virus type 1 (HIV-1) is a retrovirus, classified within the group of lentiviruses that can cause chronic infections and “slow” diseases (Gonda et al., 1985; Thormar, 2013). In the absence of treatment, systemic HIV-1 infection usually causes progressive immunodeficiency, leading ultimately to the acquired immunodeficiency syndrome (AIDS) and death. While this infection is associated with a variety of neurologic diseases involving almost all levels of the central and peripheral nervous systems, many with high morbidity and mortality (Price, 2003; Gendelman et al., 2011), this chapter focuses more narrowly on direct central nervous system (CNS) infection by HIV-1 and its resultant neurological disease. Before the advent of combination antiretroviral therapy (ART), what was then termed the AIDS dementia complex (ADC) and now more commonly designated HIV-associated dementia (HAD) was among the common causes of severe neurologic injury in young people in the United States (Price and Brew, 1988). Fortunately, the introduction and broad dissemination of effective combination ART have led to a marked decreased in HAD similar to the impact of ART on the severe systemic and CNS opportunistic diseases complicating HIV infection (d’Arminio Monforte et al., 2004; Bhaskaran et al., 2008; Lescure et al., 2011). However, despite this preventive benefit of treatment, HAD still afflicts untreated patients who continue to present with advanced HIV-1 infection in the developed world (Lesko et al., 2013) and a larger number in resource-poor settings where treatment is not yet widely available or is initiated during more advanced infection (Robertson et al., 2011; Sacktor et al., 2013). Additionally, milder CNS

injury and dysfunction that may also relate to CNS HIV-1 infection have been reported to have broader prevalence, including in patients treated with ART (Heaton et al., 2011). Hence, in the aggregate CNS injury related to HIV-1 remains an important consequence of infection and an important target of preventive intervention and direct treatment. This review focuses on the evolving nomenclature and classification of this CNS disorder, its viral pathogenesis, clinical presentation and diagnosis, and treatment.

HISTORYAND TERMINOLOGY A novel CNS disorder that was both relatively common and severe was identified early in the AIDS epidemic, first using the term subacute encephalitis and speculated to result from human cytomegalovirus (CMV) infection (Snider et al., 1983). Subsequently, its salient clinical characteristics and pathological substrate were more clearly defined and renamed the AIDS dementia complex to encompass a more or less coherent neurologic syndrome presenting with characteristic cognitive and motor impairment and generally consistent neuropathology not associated with CMV (Navia et al., 1986a, b). When HIV-1 was identified as the cause of AIDS, it was soon shown to infect the brain and cause ADC (Shaw et al., 1985; Koenig et al., 1986; Pumarola-Sune et al., 1987; Price et al., 1988). On the basis of its core clinical features that include impairment of attention and concentration, slowing of mental speed and agility, concomitant slowing of motor speed, and loss of initiative, ADC was classified among the subcortical dementias (Benson, 1987; Tross et al., 1988) and, in its more severe form, was associated with a limited survival without

*Correspondence to: Richard W. Price, MD, Neurology, UCSF, Neurology Service, Bldg 1 Room 101, Box 0870, San Francisco General Hospital, 1001 Potrero Ave, San Francisco, CA 94110, USA. Tel: þ1-415-206-4487, Fax: þ1-415-206-4055, E-mail: [email protected]

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treatment (Neaton et al., 1994; Price et al., 1999). Like other major complications of HIV-1 infection, ADC is characteristically a late complication, developing in the setting of depressed helper (CD4 þ) T-cell blood counts (usually, but not invariably, below 200 cells/mL) and uncontrolled viremia documented by relatively high plasma levels of HIV-1 RNA (viral load). An empirically derived ADC staging system (also referred to as Memorial Sloan-Kettering or MSK staging) was introduced to provide a vocabulary for describing the functional severity of this disorder for both clinical and investigative purposes (Table 23.1) (Price and Brew, 1988; Sidtis and Price, 1990). Importantly, this did not provide formal diagnostic criteria, but only a staging scheme based on clinical findings once the diagnosis was made, similar, for example, to functional staging measures in Parkinson’s disease or multiple sclerosis. It was based on the functional incapacity in cognitive and motor activities of work and daily living, corroborated by examination, and encompassed both brain and spinal cord dysfunction. The term was intended to exclude AIDS patients who were neurologically impaired for other reasons, for example due to another AIDS-related opportunistic infection like progressive multifocal leukoencephalopathy (PML), or as a result of unrelated CNS disease, such as prior head injury. Likewise, sensory, motor, or gait impairments caused by peripheral neuropathy rather than brain or spinal cord dysfunction did not contribute to ADC

staging. The stage 0.5 designation was introduced to classify patients without clear functional impairment but with neurologic symptoms (equivocal disease) or soft findings on neurologic examination (subclinical disease); this was meant to provide a designation for patients who were neither clearly normal nor functionally impaired and was an indication of the uncertainty of diagnosis in patients with milder symptoms and signs. By contrast, stage 1 ADC designated mild but definite dysfunction, sufficient only to render work or daily living more difficult, but without major incapacity. Stages 2–4 (moderate, severe, and end-stage) were applied to increasingly more severe dysfunction, and also established a degree of neurologic severity sufficient to meet criteria for a clinical AIDS diagnosis by earlier clinical criteria (Anonymous, 1992). Committees sponsored by the World Health Organization and American Academy of Neurology subsequently proposed alternative terminologies that could readily translate into the ADC staging (World Health Organization, 1990; American Academy of Neurology AIDS Task Force, 1991) and also included attempts to incorporate these into diagnostic criteria by formally excluding other causes of the observed neurologic dysfunction. This nomenclature and staging were more recently supplanted by a new terminology following a meeting in Frascati, Italy, and hence sometimes referred to as the Frascati criteria, to be applied to research studies (Antinori et al., 2007). This differed from ADC staging

Table 23.1 Definitions of human immunodeficiency virus (HIV)-related central nervous system diseases

Frascati HAND research criteria HAND diagnosis

Symptoms and functional status Major functional impairment

Neuropsychologic test performance Below 2 SD in >2 of 5–7 domains

Minor neurocognitive disorder (MND)

Mild symptoms and/or functional impairment

Below 1 SD in >2 of 5–7 domains

Asymptomatic neurocognitive impairment (ANI)

No symptoms or functional impairment

Below 1 SD in >2 of 5–7 domains

HIV-associated dementia (HAD)

Clinical designations Symptoms and functional status Major functional impairment: usually cognitive and motor dysfunction Mild but distinct functional impairment verified by examination Not applicable to bedside clinical diagnosis

HAND, HIV-associated neurocognitive disorders; ADC, AIDS dementia complex.

ADC equivalents Stage and descriptors Stages 1–4: difficulty with demanding activities to severe cognitive motor deficits Stages 0.5–1: minimal to distinct symptoms and difficulty with activities

Stage 0.5: signs of cognitive or motor dysfunction without symptoms or evident impairment in activities

CENTRAL NERVOUS SYSTEM HIV-1 INFECTION 489 in relying heavily on more quantitative evaluations Additionally, they were established as research criteria, using neuropsychologic test performance (Table 23.1). so in the strict sense should not be applied using only clinIndeed, as initially formulated, application of these ical bedside history and examination in the absence of criteria required rather extensive testing of five to seven formal quantitative testing. This actually is not a practifunctional “domains” with more than one test contributcal issue with HAD, where the severity of functional ing to each domain evaluation. Under the umbrella impairment and exam findings justify purely clinical designation, HIV-associated neurocognitive disorders diagnosis in the absence of alternative causes. It is less (HAND), three subcategories were included: the first clear for MND when symptoms and signs are equivocal, was HAD, defined by functional impairment of activiand, of course, ANI cannot be applied without formal ties of daily living and performance in two of these testing since symptoms are by definition absent. domains that was equal to or greater than two standard deviations below control population performance. Two CHARACTER AND EVOLUTION OF CSF categories of milder impairment were also included. HIV-1 INFECTION Secondly, for patients with mild symptoms or impairment in daily activities along with test performance that CNS HIV-1 infection has several salient features that distinguish it from other neuropathogenic viral infections. is equal to or greater than one standard deviation below It is a chronic infection that begins during the early stage control levels in two domains, the term minor neurocognitive disorder (MND) was introduced. Thirdly, patients of primary systemic infection and continues through without symptoms or discernible functional impairment the subsequent course of untreated systemic infection, but comparable reduction in test performance were a process that extends for many years without treatment designated as suffering asymptomatic neurocognitive intervention. Importantly, its character can change over impairment (ANI). While these three terms are sometime, as can its neurological consequences. Thus, over times used as if they represent a clear disease continmost of its course, this infection is clinically silent, though possibly not entirely innocent, despite being accompanied uum, the evidence for this is not conclusive, and thus by a local intrathecal inflammatory response (Gisslen it is important to use each term separately and avoid applying the term HAND as if it refers to a single clear et al., 1999; Price et al., 2013). However, in some individor continuous disease entity. uals, typically later in the course of systemic infection, It is also important to emphasize that this new termiit may cause brain injury and severe neurologic impairnology, like its predecessors, does not define objective ment. Fortunately, it is also largely treatable, so that effecdiagnostic criteria, but only outlines a necessary threshtive systemic therapy also suppresses CNS infection and old of severity. Other information is needed to relate this largely prevents or mitigates its more severe CNS impact, though with some exceptions. test impairment more clearly to CNS HIV-1 infection, Because much of what we have learned about these particularly historic information and laboratory studies that eliminate other conditions that can result in similar stages of infection derives from analysis of cerebrospitesting impairment. Indeed, one of the great difficulties nal fluid (CSF), the following discussion draws heavily with this condition is that there are no clearly formuon CSF studies. HIV-1 reaches the CNS early in the lated, objective criteria for diagnosis and it is by nature course of primary infection and initial viremia often a diagnosis of exclusion. (Spudich et al., 2011; Valcour et al., 2012), and HIV Table 23.1 outlines the newer HAND designations RNA can subsequently be detected in the CSF of nearly all viremic patients, indicating that infection of the CNS, and how they relate to the earlier ADC staging. For or at least of the leptomeninges, is a constant part of the the most part, HAD is equivalent to ADC stages 1–4, though MND overlaps with milder stages 1 and stage general “ecology” of this human infection (Ellis et al., 0.5 with equivocal complaints, while ANI relates most 1997; McArthur et al., 1997; Price and Spudich, 2008). closely to stage 0.5 with subclinical exam findings or In the great majority of such individuals, this chronic stage 0 with below-average testing performance. There infection is entirely asymptomatic, without overt effects is generally good correlation among the more severe on neurologic function or evidence of headache or other categories in ADC staging, similar to American meningeal signs, despite the fact that infection is frequently accompanied by a local meningeal lymphocytic Academy of Neurology AIDS Task Force (1991) criteria inflammatory response and evidence of elevated inflamand the Frascati criteria for HAD (Gandhi et al., 2010). Since formal neuropsychologic testing was not part of matory biomarkers (Eggers et al., 2003; Spudich et al., ADC staging, the newer HAND categories add an 2005b, 2006; Marra et al., 2007). important measure of quantitation to the earlier simple Figure 23.1 shows representative cross-sectional data clinical functional definitions, but also a burden, with the derived from our own University of California San need for extensive formal neuropsychologic testing. Francisco experience with 169 HIV-1-infected, untreated

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Fig. 23.1. Cerebrospinal fluid (CSF) in human immunodeficiency virus type 1 (HIV-1) infection. These cross-sectional data derive from our studies of untreated subjects at University of California San Francisco and update a previous figure (Spudich et al., 2005b). The open symbols depict findings in HIV-1-infected study volunteers recruited without consideration of neurologic symptoms but without opportunistic infections, while the filled symbols are HIV-associated dementia (HAD) patients who presented clinically. The graphs show the high prevalence of detectable cerebrospinal fluid (CSF) HIV-1 RNA across blood CD4 þ T-cell counts and its variable relationship to plasma HIV-1 RNA levels. The frequent presence of CSF pleocytosis is also shown. The vertical dotted line marks the blood CD4 þ count of 50 cells per mL and shows the generally high plasma, lower CSF, and high plasma–CSF log10 difference in HIV-1 RNA, along with the lower incidence of pleocytosis in these subjects. WBCs, white blood cells.

subjects who underwent lumbar punctures in the context of research studies rather than for diagnosis (open symbols). These individuals presented for study without referral for neurologic symptoms and for this discussion are referred to as neuroasymptmatic, though on questioning and testing several of them exhibited clear abnormalities, in some related to confounding factors (for example, drug abuse) whereas others did not have a defined alternative explanation. Data from 15 untreated patients presenting clinically with HAD are also included for comparison (filled symbols) (Spudich et al., 2005b, 2006; Price and Spudich, 2008). Plasma HIV-1 RNA concentrations were variable but tended to increase with falling blood CD4 þ T-cell counts. CSF HIV-1 RNA concentrations were also variable over the full range of blood CD4 þ counts, averaged about 10-fold lower than plasma, but tended to be even lower in subjects with CD4 þ counts < 50 cells/mL and as a result the

plasma–CSF difference was greater in this low T-cell range. Importantly, the plasma and CSF HIV-1 RNA levels in the HAD patients were much the same as those without HAD, showing that the magnitude of CSF infection alone cannot explain the development of HAD. The figure also shows that low-level pleocytosis, usually 4 years of effective highly active antiretroviral therapy. J Infect Dis 196: 1779–1783. Eden A, Fuchs D, Hagberg L et al. (2010). HIV-1 viral escape in cerebrospinal fluid of subjects on suppressive antiretroviral treatment. J Infect Dis 202: 1819–1825. Eggers C, Hertogs K, Sturenburg HJ et al. (2003). Delayed central nervous system virus suppression during highly active antiretroviral therapy is associated with HIV encephalopathy, but not with viral drug resistance or poor central nervous system drug penetration. AIDS 17: 1897–1906. Ellen SR, Judd FK, Mijch AM et al. (1999). Secondary mania in patients with HIV infection. Aust N Z J Psychiatry 33: 353–360. Ellis RJ, Hsia K, Spector SA et al. (1997). Cerebrospinal fluid human immunodeficiency virus type 1 RNA levels are elevated in neurocognitively impaired individuals with acquired immunodeficiency syndrome. HIV Neurobehavioral Research Center Group. Ann Neurol 42: 679–688. Ellis RJ, Gamst AC, Capparelli E et al. (2000). Cerebrospinal fluid HIV RNA originates from both local CNS and systemic sources. Neurology 54: 927–936. Ellis RJ, Badiee J, Vaida F et al. (2011). CD4 nadir is a predictor of HIV neurocognitive impairment in the era of combination antiretroviral therapy. AIDS 25: 1747–1751. Epstein LG, Gendelman HE (1993). Human immunodeficiency virus type 1 infection of the nervous system: pathogenetic mechanisms. Ann Neurol 33: 429–436. Ernst T, Yakupov R, Nakama H et al. (2009). Declined neural efficiency in cognitively stable human immunodeficiency virus patients. Ann Neurol 65: 316–325. Ernst T, Jiang CS, Nakama H et al. (2010). Lower brain glutamate is associated with cognitive deficits in HIV patients: a new mechanism for HIV-associated neurocognitive disorder. J Magn Reson Imaging 32: 1045–1053.

501

Everall I, Vaida F, Khanlou N et al. (2009). Cliniconeuropathologic correlates of human immunodeficiency virus in the era of antiretroviral therapy. J Neurovirol 15: 360–370. Fernandez F, Levy JK (1993). The use of molindone in the treatment of psychotic and delirious patients infected with the human immunodeficiency virus. Case reports. Gen Hosp Psychiatry 15: 31–35. Ferrando SJ, Wapenyi K (2002). Psychopharmacological treatment of patients with HIV and AIDS. Psychiatr Q 73: 33–49. Foga IO, Nath A, Hasinoff BB et al. (1997). Antioxidants and dipyridamole inhibit HIV-1 gp120-induced free radical-based oxidative damage to human monocytoid cells. J Acquir Immune Defic Syndr Hum Retrovirol 16: 223–229. Folstein MF, Folstein SE, McHugh PR (1975). “Mini-mental state”. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 12: 189–198. Gabuzda DH, Ho DD, de la Monte SM et al. (1986). Immunohistochemical identification of HTLV-III antigen in brains of patients with AIDS. Ann Neurol 20: 289–295. Gandhi NS, Moxley RT, Creighton J et al. (2010). Comparison of scales to evaluate the progression of HIV-associated neurocognitive disorder. HIV Ther 4: 371–379. Ge Y, Kolson DL, Babb JS et al. (2003). Whole brain imaging of HIV-infected patients: quantitative analysis of magnetization transfer ratio histogram and fractional brain volume. AJNR Am J Neuroradiol 24: 82–87. Gelman BB, Guinto Jr FC (1992). Morphometry, histopathology, and tomography of cerebral atrophy in the acquired immunodeficiency syndrome. Ann Neurol 32: 31–40. Gendelman HE, Grant I, Everall IP et al. (2011). The neurology of AIDS. Oxford University Press, Oxford, UK. Geraci A, Di Rocco A, Liu M et al. (2000). AIDS myelopathy is not associated with elevated HIV viral load in cerebrospinal fluid. Neurology 55: 440–442. Gisslen M, Fuchs D, Svennerholm B et al. (1999). Cerebrospinal fluid viral load, intrathecal immunoactivation, and cerebrospinal fluid monocytic cell count in HIV-1 infection. J Acquir Immune Defic Syndr 21: 271–276. Gisslen M, Hagberg L, Brew BJ et al. (2007). Elevated cerebrospinal fluid neurofilament light protein concentrations predict the development of AIDS dementia complex. J Infect Dis 195: 1774–1778. Gisslen M, Krut J, Andreasson U et al. (2009). Amyloid and tau cerebrospinal fluid biomarkers in HIV infection. BMC Neurol 9: 63. Gonda MA, Wong-Staal F, Gallo RC et al. (1985). Sequence homology and morphologic similarity of HTLV-III and visna virus, a pathogenic lentivirus. Science 227: 173–177. Gonzalez E, Rovin BH, Sen L et al. (2002). HIV-1 infection and AIDS dementia are influenced by a mutant MCP-1 allele linked to increased monocyte infiltration of tissues and MCP-1 levels. Proc Natl Acad Sci U S A 99: 13795–13800. Gonzalez-Perez MP, O’Connell O, Lin R et al. (2012). Independent evolution of macrophage-tropism and

502

M.F. GRILL AND R.W. PRICE

increased charge between HIV-1 R5 envelopes present in brain and immune tissue. Retrovirology 9: 20. Gonzalez-Scarano F, Martin-Garcia J (2005). The neuropathogenesis of AIDS. Nat Rev Immunol 5: 69–81. Griffin DE, McArthur JC, Cornblath DR (1991). Neopterin and interferon-gamma in serum and cerebrospinal fluid of patients with HIV-associated neurologic disease. Neurology 41: 69–74. Haddow LJ, Floyd S, Copas A et al. (2013). A systematic review of the screening accuracy of the HIV Dementia Scale and International HIV Dementia Scale. PLoS One 8: e61826. Hagberg L, Cinque P, Gisslen M et al. (2010). Cerebrospinal fluid neopterin: an informative biomarker of central nervous system immune activation in HIV-1 infection. AIDS Res Ther 7: 15. Harezlak J, Buchthal S, Taylor M et al. (2011). Persistence of HIV-associated cognitive impairment, inflammation, and neuronal injury in era of highly active antiretroviral treatment. AIDS 25: 625–633. Harrington PR, Schnell G, Letendre SL et al. (2009). Crosssectional characterization of HIV-1 env compartmentalization in cerebrospinal fluid over the full disease course. AIDS 23: 907–915. Heaton RK, Clifford DB, Franklin Jr DR et al. (2010). HIVassociated neurocognitive disorders persist in the era of potent antiretroviral therapy: CHARTER Study. Neurology 75: 2087–2096. Heaton RK, Franklin DR, Ellis RJ et al. (2011). HIVassociated neurocognitive disorders before and during the era of combination antiretroviral therapy: differences in rates, nature, and predictors. J Neurovirol 17: 3–16. Heyes MP, Brew BJ, Martin A et al. (1991). Quinolinic acid in cerebrospinal fluid and serum in HIV-1 infection: relationship to clinical and neurological status. Ann Neurol 29: 202–209. Ho EL, Ronquillo R, Altmeppen H et al. (2013). Cellular composition of cerebrospinal fluid in HIV-1 infected and uninfected subjects. PLoS One 8: e66188. Hunt PW (2012). HIV and inflammation: mechanisms and consequences. Curr HIV AIDS Rep 9: 139–147. Izumo S, Umehara F, Osame M (2000). HTLV-Iassociated myelopathy. Neuropathology 20 (Suppl): S65–S68. Jakobsen J, Gyldensted C, Brun B et al. (1989). Cerebral ventricular enlargement relates to neuropsychological measures in unselected AIDS patients. Acta Neurol Scand 79: 59–62. Jarvik JG, Hesselink JR, Kennedy C et al. (1988). Acquired immunodeficiency syndrome. Magnetic resonance patterns of brain involvement with pathologic correlation. Arch Neurol 45: 731–736. Jarvik JG, Lenkinski RE, Grossman RI et al. (1993). Proton MR spectroscopy of HIV-infected patients: characterization of abnormalities with imaging and clinical correlation. Radiology 186: 739–744. Kaul M (2009). HIV-1 associated dementia: update on pathological mechanisms and therapeutic approaches. Curr Opin Neurol 22: 315–320.

Kaul M, Garden GA, Lipton SA (2001). Pathways to neuronal injury and apoptosis in HIV-associated dementia. Nature 410: 988–994. Kelder W, McArthur JC, Nance-Sproson T et al. (1998). Betachemokines MCP-1 and RANTES are selectively increased in cerebrospinal fluid of patients with human immunodeficiency virus-associated dementia. Ann Neurol 44: 831–835. Koenig S, Gendelman HE, Orenstein JM et al. (1986). Detection of AIDS virus in macrophages in brain tissue from AIDS patients with encephalopathy. Science 233: 1089–1093. Lescure FX, Omland LH, Engsig FN et al. (2011). Incidence and impact on mortality of severe neurocognitive disorders in persons with and without HIV infection: a Danish nationwide cohort study. Clin Infect Dis 52: 235–243. Lesko CR, Cole SR, Zinski A et al. (2013). A systematic review and meta-regression of temporal trends in adult CD4(þ) cell count at presentation to HIV care, 1992–2011. Clin Infect Dis 57: 1027–1037. Letendre SL, Lanier ER, McCutchan JA (1999). Cerebrospinal fluid beta chemokine concentrations in neurocognitively impaired individuals infected with human immunodeficiency virus type 1. J Infect Dis 180: 310–319. Letendre S, Marquie-Beck J, Capparelli E et al. (2008). Validation of the CNS Penetration-Effectiveness rank for quantifying antiretroviral penetration into the central nervous system. Arch Neurol 65: 65–70. Lindl KA, Marks DR, Kolson DL et al. (2010). HIV-associated neurocognitive disorder: pathogenesis and therapeutic opportunities. J Neuroimmune Pharmacol 5: 294–309. Lipton SA (1994). AIDS-related dementia and calcium homeostasis. Ann N Y Acad Sci 747: 205–224. Marra CM, Maxwell CL, Collier AC et al. (2007). Interpreting cerebrospinal fluid pleocytosis in HIV in the era of potent antiretroviral therapy. BMC Infect Dis 7: 37. Masliah E, Achim CL, Ge N et al. (1994). Cellular neuropathology in HIV encephalitis. Res Publ Assoc Res Nerv Ment Dis 72: 119–131. Masliah E, Ge N, Achim CL et al. (1996). Patterns of neurodegeneration in HIV encephalitis. J Neuro Aids 1: 161–173. Maung R, Medders KE, Sejbuk NE et al. (2012). Genetic knockouts suggest a critical role for HIV co-receptors in models of HIV gp120-induced brain injury. J Neuroimmune Pharmacol 7: 306–318. McArthur JC, McClernon DR, Cronin MF et al. (1997). Relationship between human immunodeficiency virusassociated dementia and viral load in cerebrospinal fluid and brain. Ann Neurol 42: 689–698. Mind Exchange Working Group (2013). Assessment, diagnosis, and treatment of HIV-associated neurocognitive disorder: a consensus report of the mind exchange program. Clin Infect Dis 56: 1004–1017. Moeller AA, Backmund HC (1990). Ventricle brain ratio in the clinical course of HIV infection. Acta Neurol Scand 81: 512–515. Murphy EL, Fridey J, Smith JW et al. (1997). HTLVassociated myelopathy in a cohort of HTLV-I and HTLV-II-infected blood donors. The REDS investigators. Neurology 48: 315–320.

CENTRAL NERVOUS SYSTEM HIV-1 INFECTION Nath A, Conant K, Chen P et al. (1999). Transient exposure to HIV-1 Tat protein results in cytokine production in macrophages and astrocytes. A hit and run phenomenon. J Biol Chem 274: 17098–17102. Navia BA, Price RW (1987). The acquired immunodeficiency syndrome dementia complex as the presenting or sole manifestation of human immunodeficiency virus infection. Arch Neurol 44: 65–69. Navia BA, Cho ES, Petito CK et al. (1986a). The AIDS dementia complex: II. Neuropathology. Ann Neurol 19: 525–535. Navia BA, Jordan BD, Price RW (1986b). The AIDS dementia complex: I. Clinical features. Ann Neurol 19: 517–524. Neaton JD, Wentworth DN, Rhame F et al. (1994). Considerations in choice of a clinical endpoint for AIDS clinical trials. Terry Beirn Community Programs for Clinical Research on AIDS (CPCRA). Stat Med 13: 2107–2125. Osame M, Matsumoto M, Usuku K et al. (1987). Chronic progressive myelopathy associated with elevated antibodies to human T-lymphotropic virus type I and adult T-cell leukemia-like cells. Ann Neurol 21: 117–122. Overton ET, Azad TD, Parker N et al. (2013). The Alzheimer’s disease-8 and Montreal Cognitive Assessment as screening tools for neurocognitive impairment in HIV-infected persons. J Neurovirol 19: 109–116. Patton HK, Zhou ZH, Bubien JK et al. (2000). gp120-induced alterations of human astrocyte function: Na(þ)/H(þ) exchange, K(þ) conductance, and glutamate flux. Am J Physiol Cell Physiol 279: C700–C708. Peluso MJ, Ferretti F, Peterson J et al. (2012). Cerebrospinal fluid HIV escape associated with progressive neurologic dysfunction in patients on antiretroviral therapy with well controlled plasma viral load. AIDS 26: 1765–1774. Peters PJ, Duenas-Decamp MJ, Sullivan WM et al. (2007). Variation of macrophage tropism among HIV-1 R5 envelopes in brain and other tissues. J Neuroimmune Pharmacol 2: 32–41. Petito CK, Roberts B (1995). Evidence of apoptotic cell death in HIV encephalitis. Am J Pathol 146: 1121–1130. Petito CK, Navia BA, Cho ES et al. (1985). Vacuolar myelopathy pathologically resembling subacute combined degeneration in patients with the acquired immunodeficiency syndrome. N Engl J Med 312: 874–879. Petito CK, Vecchio D, Chen YT (1994). HIV antigen and DNA in AIDS spinal cords correlate with macrophage infiltration but not with vacuolar myelopathy. J Neuropathol Exp Neurol 53: 86–94. Petito CK, Kerza-Kwiatecki AP, Gendelman HE et al. (1999). Review: neuronal injury in HIV infection. J Neurovirol 5: 327–341. Pillai SK, Pond SL, Liu Y et al. (2006). Genetic attributes of cerebrospinal fluid-derived HIV-1 env. Brain 129: 1872–1883. Post MJ, Tate LG, Quencer RM et al. (1988). CT, MR, and pathology in HIV encephalitis and meningitis. AJR Am J Roentgenol 151: 373–380.

503

Post MJ, Berger JR, Quencer RM (1991). Asymptomatic and neurologically symptomatic HIV-seropositive individuals: prospective evaluation with cranial MR imaging. Radiology 178: 131–139. Power C, Kong PA, Crawford TO et al. (1993). Cerebral white matter changes in acquired immunodeficiency syndrome dementia: alterations of the blood–brain barrier. Ann Neurol 34: 339–350. Power C, McArthur JC, Johnson RT et al. (1995a). Distinct HIV-1 env sequences are associated with neurotropism and neurovirulence. Curr Top Microbiol Immunol 202: 89–104. Power C, Selnes OA, Grim JA et al. (1995b). HIV Dementia Scale: a rapid screening test. J Acquir Immune Defic Syndr Hum Retrovirol 8: 273–278. Price RW (1996). The cellular basis of central nervous system HIV-1 infection and the AIDS dementia complex: introduction. J NeuroAIDS 1: 1–29. Price RW (2003). Neurologic Disease. In: R Dolin, H Masur, MS Saag (Eds.), AIDS Therapy. Churchill-Livingstone, Philadelphia, pp. 737–757. Price RW, Brew BJ (1988). The AIDS dementia complex. J Infect Dis 158: 1079–1083. Price RW, Spudich S (2008). Antiretroviral therapy and central nervous system HIV type 1 infection. J Infect Dis 197 (Suppl 3): S294–S306. Price RW, Brew B, Sidtis J et al. (1988). The brain in AIDS: central nervous system HIV-1 infection and AIDS dementia complex. Science 239: 586–592. Price RW, Yiannoutsos CT, Clifford DB et al. (1999). Neurological outcomes in late HIV infection: adverse impact of neurological impairment on survival and protective effect of antiviral therapy. AIDS Clinical Trial Group and Neurological AIDS Research Consortium study team. AIDS 13: 1677–1685. Price RW, Peterson J, Fuchs D et al. (2013). Approach to cerebrospinal fluid (CSF) biomarker discovery and evaluation in HIV infection. J Neuroimmune Pharmacol 8: 1147–1158. Pumarola-Sune T, Navia BA, Cordon-Cardo C et al. (1987). HIV antigen in the brains of patients with the AIDS dementia complex. Ann Neurol 21: 490–496. Ragin AB, Storey P, Cohen BA et al. (2004a). Disease burden in HIV-associated cognitive impairment: a study of wholebrain imaging measures. Neurology 63: 2293–2297. Ragin AB, Storey P, Cohen BA et al. (2004b). Whole brain diffusion tensor imaging in HIV-associated cognitive impairment. AJNR Am J Neuroradiol 25: 195–200. Robertson K, Kumwenda J, Supparatpinyo K et al. (2011). A multinational study of neurological performance in antiretroviral therapy-naive HIV-1-infected persons in diverse resource-constrained settings. J Neurovirol 17: 438–447. Romanelli LC, Caramelli P, Martins ML et al. (2013). Incidence of human T cell lymphotropic virus type 1-associated myelopathy/tropical spastic paraparesis in a long-term prospective cohort study of initially asymptomatic individuals in Brazil. AIDS Res Hum Retroviruses 29: 1199–1202.

504

M.F. GRILL AND R.W. PRICE

Rosenblum MK (1990). Infection of the central nervous system by the human immunodeficiency virus type 1. Morphology and relation to syndromes of progressive encephalopathy and myelopathy in patients with AIDS. Pathol Annu 25: 117–169. Rosenblum M, Scheck AC, Cronin K et al. (1989). Dissociation of AIDS-related vacuolar myelopathy and productive HIV-1 infection of the spinal cord. Neurology 39: 892–896. Rottenberg DA, Moeller JR, Strother SC et al. (1987). The metabolic pathology of the AIDS dementia complex. Ann Neurol 22: 700–706. Sabri F, De Milito A, Pirskanen R et al. (2001). Elevated levels of soluble Fas and Fas ligand in cerebrospinal fluid of patients with AIDS dementia complex. J Neuroimmunol 114: 197–206. Sacktor N, Schifitto G, McDermott MP et al. (2000). Transdermal selegiline in HIV-associated cognitive impairment: pilot, placebo-controlled study. Neurology 54: 233–235. Sacktor N, Nakasujja N, Okonkwo O et al. (2013). Longitudinal neuropsychological test performance among HIV seropositive individuals in Uganda. J Neurovirol 19: 48–56. Saito M (2013). Neuroimmunological aspects of human T cell leukemia virus type 1-associated myelopathy/tropical spastic paraparesis. J Neurovirol (epub ahead of print). Schifitto G, Zhang J, Evans SR et al. (2007). A multicenter trial of selegiline transdermal system for HIV-associated cognitive impairment. Neurology 69: 1314–1321. Schifitto G, Zhong J, Gill D et al. (2009). Lithium therapy for human immunodeficiency virus type 1-associated neurocognitive impairment. J Neurovirol 15: 176–186. Schnell G, Spudich S, Harrington P et al. (2009). Compartmentalized human immunodeficiency virus type 1 originates from long-lived cells in some subjects with HIV-1-associated dementia. PLoS Pathog 5: e1000395. Schnell G, Price RW, Swanstrom R et al. (2010). Compartmentalization and clonal amplification of HIV-1 variants in the cerebrospinal fluid during primary infection. J Virol 84: 2395–2407. Schnell G, Joseph S, Spudich S et al. (2011). HIV-1 replication in the central nervous system occurs in two distinct cell types. PLoS Pathog 7: e1002286. Sewell DD, Jeste DV, Atkinson JH et al. (1994). HIVassociated psychosis: a study of 20 cases. San Diego HIV Neurobehavioral Research Center Group. Am J Psychiatry 151: 237–242. Shaw GM, Harper ME, Hahn BH et al. (1985). HTLV-III infection in brains of children and adults with AIDS encephalopathy. Science 227: 177–182. Sidtis JJ, Price RW (1990). Early HIV-1 infection and the AIDS dementia complex. Neurology 40: 323–326. Sidtis JJ, Gatsonis C, Price RW et al. (1993). Zidovudine treatment of the AIDS dementia complex: results of a placebocontrolled trial. AIDS Clinical Trials Group. Ann Neurol 33: 343–349. Simioni S, Cavassini M, Annoni JM et al. (2010). Cognitive dysfunction in HIV patients despite long-standing suppression of viremia. AIDS 24: 1243–1250.

Smit TK, Brew BJ, Tourtellotte W et al. (2004). Independent evolution of human immunodeficiency virus (HIV) drug resistance mutations in diverse areas of the brain in HIVinfected patients, with and without dementia, on antiretroviral treatment. J Virol 78: 10133–10148. Smurzynski M, Wu K, Letendre S et al. (2011). Effects of central nervous system antiretroviral penetration on cognitive functioning in the ALLRT cohort. AIDS 25: 357–365. Snider WD, Simpson DM, Nielsen S et al. (1983). Neurological complications of acquired immune deficiency syndrome: analysis of 50 patients. Ann Neurol 14: 403–418. Soulie C, Fourati S, Lambert-Niclot S et al. (2010). HIV genetic diversity between plasma and cerebrospinal fluid in patients with HIV encephalitis. AIDS 24: 2412–2414. Spudich S, Gonzalez-Scarano F (2012). HIV-1-related central nervous system disease: current issues in pathogenesis, diagnosis, and treatment. Cold Spring Harbor Perspect Med 2: a007120. Spudich SS, Huang W, Nilsson AC et al. (2005a). HIV-1 chemokine coreceptor utilization in paired cerebrospinal fluid and plasma samples: a survey of subjects with viremia. J Infect Dis 191: 890–898. Spudich SS, Nilsson AC, Lollo ND et al. (2005b). Cerebrospinal fluid HIV infection and pleocytosis: relation to systemic infection and antiretroviral treatment. BMC Infect Dis 5: 98. Spudich S, Lollo N, Liegler T et al. (2006). Treatment benefit on cerebrospinal fluid HIV-1 levels in the setting of systemic virological suppression and failure. J Infect Dis 194: 1686–1696. Spudich S, Gisslen M, Hagberg L et al. (2011). Central nervous system immune activation characterizes primary human immunodeficiency virus 1 infection even in participants with minimal cerebrospinal fluid viral burden. J Infect Dis 204: 753–760. Staprans S, Marlowe N, Glidden D et al. (1999). Time course of cerebrospinal fluid responses to antiretroviral therapy: evidence for variable compartmentalization of infection. AIDS 13: 1051–1061. Stoler MH, Eskin TA, Benn S et al. (1986). Human T-cell lymphotropic virus type III infection of the central nervous system. A preliminary in situ analysis. JAMA 256: 2360–2364. Strain MC, Letendre S, Pillai SK et al. (2005). Genetic composition of human immunodeficiency virus type 1 in cerebrospinal fluid and blood without treatment and during failing antiretroviral therapy. J Virol 79: 1772–1788. Sturdevant CB, Dow A, Jabara CB et al. (2012). Central nervous system compartmentalization of HIV-1 subtype C variants early and late in infection in young children. PLoS Pathog 8: e1003094. Takahashi K, Wesselingh SL, Griffin DE et al. (1996). Localization of HIV-1 in human brain using polymerase chain reaction/in situ hybridization and immunocytochemistry. Ann Neurol 39: 705–711. Tan SV, Guiloff RJ, Scaravilli F (1995). AIDS-associated vacuolar myelopathy. A morphometric study. Brain 118: 1247–1261.

CENTRAL NERVOUS SYSTEM HIV-1 INFECTION Thomas ER, Dunfee RL, Stanton J et al. (2007). Macrophage entry mediated by HIV Envs from brain and lymphoid tissues is determined by the capacity to use low CD4 levels and overall efficiency of fusion. Virology 360: 105–119. Thormar H (2013). The origin of lentivirus research: Maedivisna virus. Curr HIV Res 11: 2–9. Tornatore C, Meyers K, Atwood W et al. (1994). Temporal patterns of human immunodeficiency virus type 1 transcripts in human fetal astrocytes. J Virol 68: 93–102. Tracey I, Carr CA, Guimaraes AR et al. (1996). Brain cholinecontaining compounds are elevated in HIV-positive patients before the onset of AIDS dementia complex: A proton magnetic resonance spectroscopic study. Neurology 46: 783–788. Tross S, Price RW, Navia B et al. (1988). Neuropsychological characterization of the AIDS dementia complex: a preliminary report. AIDS 2: 81–88. Tyor WR, Wesselingh SL, Griffin JW et al. (1995). Unifying hypothesis for the pathogenesis of HIV-associated dementia complex, vacuolar myelopathy, and sensory neuropathy. J Acquir Immune Defic Syndr Hum Retrovirol 9: 379–388. Valcour V, Chalermchai T, Sailasuta N et al. (2012). CNS viral invasion and inflammation during acute HIV. J Infect Dis 206: 275–282. Vazeux R, Brousse N, Jarry A et al. (1987). AIDS subacute encephalitis. Identification of HIV-infected cells. Am J Pathol 126: 403–410. Wiley CA, Schrier RD, Nelson JA et al. (1986). Cellular localization of human immunodeficiency virus infection within

505

the brains of acquired immune deficiency syndrome patients. Proc Natl Acad Sci U S A 83: 7089–7093. Wilkinson ID, Miller RF, Miszkiel KA et al. (1997). Cerebral proton magnetic resonance spectroscopy in asymptomatic HIV infection. AIDS 11: 289–295. Williams DW, Eugenin EA, Calderon TM et al. (2012). Monocyte maturation, HIV susceptibility, and transmigration across the blood brain barrier are critical in HIV neuropathogenesis. J Leukoc Biol 91: 401–415. Wong JK, Ignacio CC, Torriani F et al. (1997). In vivo compartmentalization of human immunodeficiency virus: evidence from the examination of pol sequences from autopsy tissues. J Virol 71: 2059–2071. World Health Organization (1990). World Health Organization consultation on the neuropsychiatric aspects of HIV-1 infection. Geneva, 11–13 January 1990. AIDS 4: 935–936. Wu Y, Storey P, Cohen BA et al. (2006). Diffusion alterations in corpus callosum of patients with HIV. AJNR Am J Neuroradiol 27: 656–660. Yilmaz A, Verhofstede C, D’Avolio A et al. (2010). Treatment intensification has no effect on the HIV-1 central nervous system infection in patients on suppressive antiretroviral therapy. J Acquir Immune Defic Syndr 55: 590–596. Yilmaz A, Price RW, Gisslen M (2012). Antiretroviral drug treatment of CNS HIV-1 infection. J Antimicrob Chemother 67: 299–311. Zink MC, Uhrlaub J, DeWitt J et al. (2005). Neuroprotective and anti-human immunodeficiency virus activity of minocycline. JAMA 293: 2003–2011.