Clin. exp. Immunol. (1991) 84, 181-184
ADONIS
000991049100125A
EDITORIAL REVIEW
Antibody responses in HIV infection A. J. PINCHING Department of Immunology, St Mary's Hospital Medical School, London, England
(Acceptedfor publication 9 March 1991)
both (Ho, Pomeranz & Kaplan, 1987; Pinching, 1990), while macrophages generally persist, acting as an increasing internal reservoir ofinfection. The loss of CD4 cells plays a major part in causing other immune defects, but cellular dysfunction induced by HIV in the cells that remain constitutes another major pathogenetic mechanism. This applies to uninfected CD4 cells, infected or uninfected macrophages and related cells, and to B lymphocytes. While some of these functional changes result from cellular HIV infection or from the loss of CD4 lymphocyte-derived signals, other seem to result from cell dysfunction induced by HIV products, notably gp120. Recent evidence suggests that some of these changes may be due to chronic activation of signal transduction mechanisms (Pinching, 1990; Pinching & Nye, 1990). Polyclonal hypergammaglobulinaemia was noted as a feature of HIV disease from the earliest studies (Seligmann et al., 1984, 1987; Lane & Fauci, 1985; Pinching, 1990). Lane et al. (1983), in a seminal study, showed that peripheral blood lymphocytes from AIDS patients, in addition to reduced proliferative responses to phytohaemagglutinin (PHA), had reduced responses to the T cell-dependent B cell pokeweed mitogen (PWM) and to the B cell mitogen, Staphylococcus aureus Cowan strain 1. They showed that B cells had reduced immunoglobulin production in response to PWM, even if normal numbers of CD4 cells were provided, and that spontaneous antibody production was increased. They also studied symptomless homosexual men, at least some of whom will have been HIV positive, and showed similar but less severe abnormalities in them. Several studies have subsequently confirmed and extended these data (Hoffman et al., 1985; Martinez-Maza et al., 1987; Miedema et al., 1988; Rogers, Forster & Pinching, 1989). These studies have shown that reduced PWM proliferative response is an early event dependent in part on B cell dysfunction (Miedema et al., 1988) and is associated with increased risk of progression (Hoffman et al., 1985), and that B cells show evidence of immaturity-expression of CD1O (Martinez-Maza et al., 1987) and secretion of IgD (Rogers et al., 1989). In relating the changes in B cell function to clinical stage, it has been possible to separate B cell activation, B cell immaturity and loss of T celldependent B cell responses as discrete phenomena (Rogers et al., 1989). Despite the general hypergammaglobulinaemia of HIV infection, the IgG2 subclass, which is relatively T cell independent and mediates opsonization of capsulated organisms, may show a decrease (Aucouturier et al., 1986), and this has been shown to correlate with increased susceptibility to pyogenic infection (Parkin et al., 1989). Before reviewing the data on specific antibody responses, it is also pertinent to note some of the other observed changes in
INTRODUCTION HIV infection is associated with numerous abnormalities of immune responsiveness (Seligmann et al., 1984, 1987; Lane & Fauci, 1985; Pinching, 1990). These changes may be present during symptomless HIV infection, whether or not lymphadenopathy (persistent generalized lymphadenopathy, PGL) is present, but become more severe and extensive with advancing symptomatic disease (ARC or AIDS). AIDS is classically associated with defective cell-mediated immunity in terms of clinical susceptibility to facultative intracellular pathogens and herpesviruses. However, HIV-infected patients may also show defects in antibody responses and increased susceptibility to pyogenic infections. This is especially evident in children, who have a more limited antibody repertoire before the effects of HIV on immune responsiveness become apparent, but also affects adults to some degree. Several studies, including one reported in this issue (Opravil et al., 1991), have examined specific in vivo antibody responses to immunization with infective and other antigens, other than those of HIV itself, in HIV-infected patients. While some of the specific results show apparent differences, many of these can be accounted for in terms of the patient population under study, the antibody responses being evaluated and the criteria used to assess response. It is timely to review this evidence against the background of present understanding of the immunobiology of HIV infection and to relate it to current concepts of the cellular defects responsible. HIV-specific responses are not considered here since they represent responses to persistent antigens, exposure to which by definition precedes the effects of HIV on immune responsiveness; these aspects have been extensively reviewed elsewhere (Lange, de Wolf & Goudsmit, 1989; Bolognesi, 1989). I have also chosen not to include studies on in vitro responses to specific antigens since these assays may be subject to some different variables and have varying relatedness to in vivo responses. IMMUNOPATHOGENETIC BACKGROUND HIV infects CD4 lymphocytes and cells of the macrophage lineage, mainly through attachment of the envelope glycoprotein gp120 to the CD4 molecule followed by internalization; in the case of macrophages and related cells, entry by other routes such as Fc and C3b receptors may also apply. The effects on these two cell populations are very different: CD4 lymphocytes are progressively eliminated by viral or host cytopathic effects or Correspondence: Dr Anthony J. Pinching, Department of Immunology, St Mary's Hospital Medical School, Norfolk Place, London W2
lPG, UK.
181
182
A. J. Pinching
cells involved in antibody responses in HIV infection. Although it is in principle possible that specific subsets of CD4 cells are depleted or affected by HIV infection, the evidence implicating specific loss of helper/inducer or suppressor/inducer types is contradictory; similarly, data on memory cells are ambiguous. Dendritic cells and Langerhans' cells have a major antigenpresenting role, notably in primary responses. Decreased expression of HLA class II antigens has been noted in these cells (Belsito et al., 1984; Eales, Farrant & Pinching, 1988) and is associated with increasingly severe impairment of antigenpresenting function (Eales et al., 1988; Macatonia et al., 1990). In asymptomatic HIV infection, though not in PGL, and in symptomatic HIV disease, there is also depletion of circulating dendritic cells (Macatonia et al., 1990). These changes have been related to early and extensive HIV infection of these cells. The follicular dendritic reticulum cells (FDRC) of the germinal centres of lymphoid follicles also have a major role in antigen presentation, predominantly in secondary antibody responses. Patients with uncomplicated PGL show intact FDRC structure of germinal centres, while patients with ARC and AIDS show progressive destruction of this network, associated with other immunohistological changes (Janossy et al., 1985). Interestingly, the FDRC show evidence of extensive HIV infection in both settings (Tenner-Racz et al., 1986). SPECIFIC ANTIBODY RESPONSES
The published reports of antibody
responses
to immunization
with specific antigens (Masur et al., 1981; Lane et al., 1983; Ammann et al., 1984; Simberkoff et al., 1984; Bernstein et al., 1985; Ballet et al., 1987; Teeuwsen et al., 1987; Huang et al., 1987; Janoff et al., 1988; Klein et al., 1989; Teeuwsen et al., 1990; Opravil et al., 1991) are summarized in Table 1. Some studies have focused on AIDS or ARC, and others have concentrated on patients with asymptomatic HIV infection. Most studies have examined responses to pneumococcal vaccines, which can be regarded as largely T cell independent, and about half have tested secondary responses to tetanus toxoid, to which T cells may contribute. A few studies have examined isotype or subclass responses or responses to specific pneumococcal serotypes. Some other, largely T cell-dependent responses have been examined, including the neoantigens keyhole limpet haemocyanin (KLH) or bacteriophage OX 174.
Pneumococcal antibody responses Pre-immunization pneumococcal antibody responses were shown to be low in AIDS/ARC patients in three of the four studies that report these (Ammann et al., 1984; Simberkoffet al., 1984; Janoff et al., 1988), but the recent study by Opravil et al. (1991) shows them to be higher than controls, which the authors attribute to prior pneumococcal infections. Patients with symptomless infection (with or without PGL) had normal preimmunization levels in two studies (Ballet et al., 1987; Huang et al., 1987) and reduced levels in two (Janoffet al., 1988; Klein et al., 1989). Antibody responses to pneumococcal immunization,
Table 1. Published reports on specific antibody responses in t'to
Reference
n
Masur et al. (1981) Lane et al. (1983)
11
Ammann et al. (1984) Simberkoff et al. (1984) Bernstein et al. (1985) Ballet et al. (1987)
5
3 18 5
26
Group AIDS AIDS ASY.* AIDS AIDS AIDS PGL
TT
PNP
Patients Pre
Post
Pre
N
VL VL L L
Janoffet
ia.
(1988)
Klein et al. (1989)
5
10 25 13 14 21 9 12
Teeuwsen et al. (1990) Opravil et al. (1991)
5
6 4
AsY. AsY. PGL AsY. PGL AIDS AsY.)t PGL | AsY.* ARC)i AIDS |
Pre
Post
Correlation with:
VL
VL N/SL
Substantial rise in all 12 serotypes KLH KLH.* HIV status? * KLH 280% patients versus 69'S, control
VL*
VL* None
6/26 N
VL
Comments *
VL L L*
16/25 Teeuwsen et al. (1987) Huang et al. (1987)
Post
+9/11
+ 4/4*
VL L
Other
N*
N*
Later pneumococcal infection Paediatric*, OX174; ly and 2y PNP: Low IgM, IgA, IgG2; Normal IgGI TT: Low IgG4. *
Polio
Low to some types t Influenza antigen * Log IgM; normal IgG, IgA * Low IgM; normal IgG, IgA * Low IgM, IgA; normal IgG *
N
N/L*
L L L
N/L* N/L* N/L*
SL
L
Nt
None N
H
VL
Nt
N
N
N/L*
*
within 3/12 of seroconversion
* Some low resps. t PNP with PHA; TT with PHA, PWM, CD4
PNP, pneumococcal polysaccharide (multiple serotypes); TT, tetanus toxoid; Asy., asymptomatic HIV infection; PGL, persistent generalized lymphadenopathy; , not done; VL, very low; L, low; ?, not clear; N. normal; SL, slightly low; H, high; KLH, keyhole limpet haemocyanin; OX 174, bacteriophage OX174 (ly, 2y, primary and secondary responses). *
and t, see Comments.
Antibody response in HIV infection usually tested at 3-4 weeks, have generally been shown to be impaired or severely impaired in patients with AIDS or ARC (Ammann et al., 1984; Simberkoff et al., 1984; Bernstein et al., 1985; Opravil et al., 1991). Curiously, the early report by Masur et al. (1981) states that all four patients immunized showed a substantial rise in titre to all serotypes, but the criteria for a rise are not given relative to controls. The study by Janoff et al. (1988) shows a normal IgG response by 6 weeks (although it is lower than controls at 3 weeks), but reduced IgA and IgM response at both time-points in such patients. In symptomless HIV infection, the picture is less clear still. Ballet et al. (1987) showed impaired responses in 16 out of 25 PGL patients (the reductions being in IgG2, IgA and IgM) and Klein et al. (1989) showed generally lower antibody responses in asymptomatic/PGL subjects. Huang et al. (1987) report that IgG responses in asymptomatic/PGL subjects are generally similar to those of controls but that reduced responses are seen to some serotypes. Unfortunately the responses to some of the other serotypes were low in controls and there seems to be a trend for lower values in HIV-infected subjects for some of those. Thus the description of these responses as normal may rather reflect the fact that the study was too small to show a statistically significant difference. However, in the study by Janoffet al. (1988) the increment in IgG responses was similar to controls; the IgM responses were clearly less in HIV-infected subjects and there was a trend for lower values in IgA which did not reach significance. It should also be noted that the absolute values achieved were lower in all HIV-infected groups due to the lower initial values. Furthermore, the long-term IgG and IgA titres (at 49 weeks) were lower in asymptomatic HIV-infected subjects than in controls. Thus, while there are some discrepancies in these data, the general impression is of lower pre-immunization values in patients with AIDS or ARC and slightly lower values in some subjects with symptomless HIV infection. Pneumococcal vaccine responses seem to be typically impaired by standard criteria in AIDS/ARC and somewhat impaired in symptomless HIV infection. Whether the retention of limited responsiveness in these earlier stages would confer benefit in terms of protection against later pneumococcal infection has yet to be established, but such an approach should, if it is to be applied, be applied before symptomatic disease presents. Tetanus toxoid antibody responses Pre-immunization titres have not always been commented on due to variability in prior immunization history. When reported, the titres in adults with asymptomatic or symptomatic HIV infection have been normal. Low or undetectable levels have been reported in children with AIDS who had had at least one prior immunization (Bernstein et al., 1985), but these findings may reflect the more advanced immunodeficiency at the time of that first exposure. Post-immunization antibody titres in ARC/AIDS have been reported as being generally normal but reduced in a few patients (Masur et al., 1981; Opravil et al., 1991). Paediatric AIDS cases showed negligible responses (Bernstein et al., 1985). Similar findings have been obtained in PGL, where the mean titre was no different from controls but some patients showed a very low response (Ballet et al., 1987). However, a report on a few patients with symptomless infection (Teeuwsen et al., 1987) shows very low responses to this antigen; in a further study, the
183
same investigators found no such difference in recently (within 3 months) HIV-seroconverted subjects (Teeuwsen et al., 1990).
Other antibody responses Polio virus (Teeuwsen et al., 1987) and influenza (Huang et al., 1987) secondary antibody responses were normal in asymptomatic/PGL patients. AIDS patients showed very poor responses to the T cell-dependent neoantigen, KLH, in two studies (Lane et al., 1983; Ammann et al., 1984) and the first of these studies also suggested impaired responses in asymptomatic HIV infection. Bernstein et al., (1985) studying paediatric AIDS cases showed very poor primary and secondary antibody responses to the bacteriophage OX174. Although not included in this review, several studies have shown reduced responsiveness to hepatitis B vaccine in asymptomatic HIV-infected subjects, in terms of titre achieved and proportion of subjects responding to standard immunization schedules. CORRELATES OF IMPAIRED ANTIBODY RESPONSIVENESS Three studies have sought correlation between impairment of antibody response and other markers of HIV disease. Ballet et al. (1987) and Klein et al. (1989) found none; but Opravil et al. (1991) suggest on the basis of small numbers of patients that pneumococcal responses are correlated with PHA responsiveness, which is counter-intuitive, and that tetanus toxoid responses are correlated with PHA and pokeweed responses and with CD4 cell numbers, which seems more logical.
CONCLUSIONS Although there are some surprising discrepancies, specific antibody responses reported in the literature are generally in accord with the view that B cell and T cell responses are impaired in HIV disease and that in some respects the B cell changes are apparent at an earlier stage than at least some of those dependent on T cells. However, this rather over-simplistic view ignores the potential contribution of HIV induced defects in dendritic and/or follicular dendritic cells. Bacterial infections, including infections with pneumococcus and other capsulated organisms for which opsonic defence is of central importance, are relatively common in patients with HIV infection before and after the development of AIDS. The association of IgG2 subclass reduction with these problems (Parkin et al., 1989) suggests that loss of specific antibody against capsular polysaccharide may play a part. The question that remains is whether immunization with pneumococcal vaccines during symptomless infection would produce a useful protective response and whether such an approach would be cost-effective. The group of patients most likely to benefit would be the paediatric group, who will have had limited prior exposure and who have high pneumococcal infection rates. However, studies on specific antibody responses in symptomless HIV infected children do not appear to have been reported. REFERENCES AMMANN, A.J., SCHIFFMAN, G., ABRAMS, D., VOLBERDING, P., ZIEGLER, J. & CONANT, M. (1984) B-cell immunodeficiency in acquired immune deficiency syndrome. JAMA, 251, 1447.
184
A. J. Pinching
AOCUTURIER, P., COUDERC, L.J., GOUET, D., DANON, F., GOMBERT, J., MATHERON, S., SAIMOT, A.G., CLAUVEL, J.P. & PREUD'HOMME, J.L.
(1986) Serum immunoglobulin G subclass dysbalances in the lymphadenopathy syndrome and acquired immune deficiency syndrome. Clin. exp. Immunol. 63, 234. BALLET, J.-J., SULCEBE, G., COUDERC, L.-J., DANON, F., RABIAN, C.,
LATHROP, M., CLAUVEL, J.-P. & SELIGMANN, M. (1987) Impaired anti-pneumococcal antibody response in patients with AIDS-related persistent generalised lymphadenopathy. Clin. exp. Immunol. 68, 479. BELSITO, D.V., SANCHEZ, M.R., BAER, R.L., VALENTINE, F. & THORBECKE, G.J. (1984) Reduced Langerhans' cell la antigen and ATPase
activity in patients with the acquired immunodeficiency syndrome. N. Engl. J. Med. 310, 1279. BERNSTEIN, L.J., OCHS, H.D., WEDGWOOD, R.J. & RUBINSTEIN, A.
(1985) Defective humoral immunity in pediatric acquired immune deficiency syndrome. J. Paediat. 107, 352. BOLOGNESI, D.P. (1989) HIV antibodies and vaccine design. AIDS, 3 (Suppl. 1), S 111. EALES, L.-J., FARRANT, J. & PINCHING, A.J. (1988) Peripheral blood dendritic cells in persons with AIDS and AIDS-related complex: loss of cells expressing high intensity class II antigens. Clin. exp. Immunol. 71, 423. Ho, D.D., POMERANTZ, R.J. & KAPLAN, J.C. (1987) Pathogenesis of infection with human immunodeficiency virus. N. Engl. J. Med. 317, 278. HOFFMAN, B., LINDHARDT, B.O., GERSTOFT, J., PETERSEN, C.S., PLATZ,
P., RYDER, L.P., ODUM, N., DICKMEISS, E., NIELSEN, P.B., ULLMAN, S. & SVEJGAARD, A. (1987) Lymphocyte transformation response to pokeweed mitogen as a predictive marker for development of AIDS and AIDS related symptoms in homosexual men with HIV antibodies. Br. med. J. 295, 293. HUANG, K.-L., RUBEN, E.L., RINALDO, C.R., KINGSLEY, L., LYTER,
D.W. & Ho, M. (1987) Antibody responses after influenza and pneumococcal immunization in HIV-infected homosexual men. JAMA, 257, 2047. JANOFF, E.N., DOUGLAS, J.M.
JR,
GABRIEL, M., BLASER, M.J., DAVID-
SON, A.J., COHN, D.L. & JUDSON, F.N. (1988) Class-specific antibody response to pneumococcal capsular polysaccharides in men infected with human immunodeficiency virus type 1. J. infect. Dis. 158, 983. JANOSSY, G., PINCHING, A.J., BOFILL, M., WEBER, J., MCLAUGHLIN, J.E., ORNSTEIN, M., IVORY, K., HARRIS, J.R.W., FAVROT, M. & MACDONALD-BURNS, D.C. (1985) An immunohistological
approach to persistent lymphadenopathy and its relevance to AIDS. Clin. exp. Immunol. 59, 257. KLEIN, R.S., SELWYN, P.A., MAUDE, D., POLLARD, C., FREEMAN, K. &
SCHIFFMAN, G. (1989) Response to pneumococcal vaccine among asymptomatic heterosexual partners of persons with AIDS and intravenous drug users infected with human immunodeficiency virus. J. infect. Dis. 160, 826. LANE, H.C. & FAUCI, A.S. (1985) Immunological abnormalities in the acquired immunodeficiency syndrome. Annu. Rev. Immunol. 3,477. LANE, H.C., MASUR, H., EDGAR, L.C., WHALEN, G., ROOK, A.H. & FAUCI, A.S. (1983) Abnormalities of B cell activation and immunoregulation in patients with the acquired immunodeficiency syndrome. N. Engl. J. Med. 309, 453. LANGE, J.M.A., DE WOLF, F. & GOUDSMIT, J. (1989) Markers for progression in HIV infection. AIDS, 3 (Suppl. 1). S153. MACATONIA, S.E., LAU, R., PATTERSON, S., PINCHING, A.J. & KNIGHT, S.C. (1990) Dendritic cell depletion and dysfunction in HIV infection. Immunology, 71, 38.
MARTINEZ-MAZA, O., CRABB, E., MITSUYASU, R.T., FAHEY, J.L. & GIORGI, J.V. (1987) Infection with the human immunodeficiency virus (HIV) is associated with an in vivo increase in B lymphocyte activation and immaturity. J. Immunol. 138, 3720. MASUR, H., MICHELIS, M.A., GREENE, J.B., ONORATO, I., VANDE STOUWE, R.A., HOLZMAN, R.S., WORMSER, G., BRETTMAN, L., LANGE, M., MURRAY, H.W. & CUNNINGHAM-RUNDLES, S. (1981) An outbreak of community acquired Pneumocystis carinii pneumonia: initial manifestation of cellular immune dysfunction. N. Engl. J. Med. 305, 1431. MIEDEMA, F., PETIT, A.J.C., TERPSTRA, E.G., SCHATTENKERK, J.K.M.E., DE WOLF, F., AL, B.J.M., Roos, M., LANGE, J.M.A., DANNER, S.A., GOUDSMIT, J. & SCHELLEKENS, P.T.A. (1988) Immunological abnormalities in human immunodeficiency virus (HIV) infected asymptomatic homosexual men: HIV affects the immune system before CD4 T helper cell depletion occurs. J. clin. Invest. 82, 1908.
OPRAVIL, M., FIERZ, W., MATTER, L., BLASER, J. & LUTHY, R. (1991) Poor antibody response after tetanus and pneumococcal vaccination in immunocompromised, HIV-infected patients. Clin. exp. Immunol. 84, 185. PARKIN, J.M., HELBERT, M., HUGHES, C.L. & PINCHING, A.J. (1989) Immunoglobulin G subclass deficiency and susceptibility to pyogenic infection in patients with AIDS-related complex and AIDS. AIDS, 3, 37. PINCHING, A.J. (1990) Immunological consequences of human immunodeficiency virus infection. Rev. med. Micro. 1, 83. PINCHING, A.J. & NYE, K.E. (1990) Defective signal transduction-a common pathway for cellular dysfunction in HIV infection? Immunol. Today, 7, 256. ROGERS, L.A., FORSTER, S.M. & PINCHING, A.J. (1989) IgD production and other lymphocyte functions in HIV infection: immaturity and activation of B cells at different clinical stages. Clin. exp. Immunol. 75, 7. SELIGMANN, M., CHESS, L., FAHEY, J.L., FAUCI, A.S., LACHMANN, P.J., L'AGE-STEHR, J., NGU, J., PINCHING, A.J., SPIRA, T.J. & WYBRAN, J. (1984) AIDS-an immunologic reevaluation. N. Engl. J. Med. 311, 1286. SELIGMANN, M., PINCHING, A.J., ROSEN, F.S., FAHEY, J.L., KHAITOV, R.M., KLATZMANN, D., KOENIG, S., Luo, N., NGU, J., REITHMULLER, G. & SPIRA, T.J. (1987) Immunology of HIV infection and AIDS-an update. Ann. intern. Med. 17, 234. SIMBERKOFF, M.S., EL SADR, W., SCHIFFMAN, G. & RAHAL, J.J. JR (1984) Streptococcus pneumoniae infections and bacteraemia in patients with acquired immune deficiency syndrome, with report of a pneumococcal vaccine failure. Am. Rev. respir. Dis. 130, 1174. TEEUWSEN, V.J.P., LOGTENBERG, T., SIEBELINK, K.H.J., LANGE, J.M., GOUDSMIT, J., UYT DEHAAG, F.G.C.M. & OSTERHAUS, A.D.M.E. (1987) Analysis of the antigen- and mitogen-induced differentiation of B lymphocytes from asymptomatic human immunodeficiency virus-seropositive male homosexuals: discrepancy between T celldependent and T cell-independent activation. J. Immunol. 139,2929. TEEUWSEN, V.J.P., SIEBELINK, K.H.J., DE WOLF, E., GOUDSMIT, J., UYT DE HAAG, E.G.C.M. & OSTERHAUS, A.D.M.E. (1990) Impairment of in vitro immune responses occurs within 3 months after HIV-1 seroconversion. AIDS, 4, 77. TENNER-RACZ, K., RACZ, P., BOFILL, M., SCHULTZ-MEYER, A., DIETRICH, M., KERN, P., WEBER, J., PINCHING, A.J., VERONESEDIMARZO, F., GALLO, R.C., KLATZMANN, D., GLUCKMAN, J.-C. & JANOSSY, G. (1986) HTLV-III/LAV viral antigens in lymph nodes of homosexual men with persistent generalised lymphadenopathy. Am. J. Pathol. 123, 1.
ADONIS
000991049100125A
EDITORIAL REVIEW
Antibody responses in HIV infection A. J. PINCHING Department of Immunology, St Mary's Hospital Medical School, London, England
(Acceptedfor publication 9 March 1991)
both (Ho, Pomeranz & Kaplan, 1987; Pinching, 1990), while macrophages generally persist, acting as an increasing internal reservoir ofinfection. The loss of CD4 cells plays a major part in causing other immune defects, but cellular dysfunction induced by HIV in the cells that remain constitutes another major pathogenetic mechanism. This applies to uninfected CD4 cells, infected or uninfected macrophages and related cells, and to B lymphocytes. While some of these functional changes result from cellular HIV infection or from the loss of CD4 lymphocyte-derived signals, other seem to result from cell dysfunction induced by HIV products, notably gp120. Recent evidence suggests that some of these changes may be due to chronic activation of signal transduction mechanisms (Pinching, 1990; Pinching & Nye, 1990). Polyclonal hypergammaglobulinaemia was noted as a feature of HIV disease from the earliest studies (Seligmann et al., 1984, 1987; Lane & Fauci, 1985; Pinching, 1990). Lane et al. (1983), in a seminal study, showed that peripheral blood lymphocytes from AIDS patients, in addition to reduced proliferative responses to phytohaemagglutinin (PHA), had reduced responses to the T cell-dependent B cell pokeweed mitogen (PWM) and to the B cell mitogen, Staphylococcus aureus Cowan strain 1. They showed that B cells had reduced immunoglobulin production in response to PWM, even if normal numbers of CD4 cells were provided, and that spontaneous antibody production was increased. They also studied symptomless homosexual men, at least some of whom will have been HIV positive, and showed similar but less severe abnormalities in them. Several studies have subsequently confirmed and extended these data (Hoffman et al., 1985; Martinez-Maza et al., 1987; Miedema et al., 1988; Rogers, Forster & Pinching, 1989). These studies have shown that reduced PWM proliferative response is an early event dependent in part on B cell dysfunction (Miedema et al., 1988) and is associated with increased risk of progression (Hoffman et al., 1985), and that B cells show evidence of immaturity-expression of CD1O (Martinez-Maza et al., 1987) and secretion of IgD (Rogers et al., 1989). In relating the changes in B cell function to clinical stage, it has been possible to separate B cell activation, B cell immaturity and loss of T celldependent B cell responses as discrete phenomena (Rogers et al., 1989). Despite the general hypergammaglobulinaemia of HIV infection, the IgG2 subclass, which is relatively T cell independent and mediates opsonization of capsulated organisms, may show a decrease (Aucouturier et al., 1986), and this has been shown to correlate with increased susceptibility to pyogenic infection (Parkin et al., 1989). Before reviewing the data on specific antibody responses, it is also pertinent to note some of the other observed changes in
INTRODUCTION HIV infection is associated with numerous abnormalities of immune responsiveness (Seligmann et al., 1984, 1987; Lane & Fauci, 1985; Pinching, 1990). These changes may be present during symptomless HIV infection, whether or not lymphadenopathy (persistent generalized lymphadenopathy, PGL) is present, but become more severe and extensive with advancing symptomatic disease (ARC or AIDS). AIDS is classically associated with defective cell-mediated immunity in terms of clinical susceptibility to facultative intracellular pathogens and herpesviruses. However, HIV-infected patients may also show defects in antibody responses and increased susceptibility to pyogenic infections. This is especially evident in children, who have a more limited antibody repertoire before the effects of HIV on immune responsiveness become apparent, but also affects adults to some degree. Several studies, including one reported in this issue (Opravil et al., 1991), have examined specific in vivo antibody responses to immunization with infective and other antigens, other than those of HIV itself, in HIV-infected patients. While some of the specific results show apparent differences, many of these can be accounted for in terms of the patient population under study, the antibody responses being evaluated and the criteria used to assess response. It is timely to review this evidence against the background of present understanding of the immunobiology of HIV infection and to relate it to current concepts of the cellular defects responsible. HIV-specific responses are not considered here since they represent responses to persistent antigens, exposure to which by definition precedes the effects of HIV on immune responsiveness; these aspects have been extensively reviewed elsewhere (Lange, de Wolf & Goudsmit, 1989; Bolognesi, 1989). I have also chosen not to include studies on in vitro responses to specific antigens since these assays may be subject to some different variables and have varying relatedness to in vivo responses. IMMUNOPATHOGENETIC BACKGROUND HIV infects CD4 lymphocytes and cells of the macrophage lineage, mainly through attachment of the envelope glycoprotein gp120 to the CD4 molecule followed by internalization; in the case of macrophages and related cells, entry by other routes such as Fc and C3b receptors may also apply. The effects on these two cell populations are very different: CD4 lymphocytes are progressively eliminated by viral or host cytopathic effects or Correspondence: Dr Anthony J. Pinching, Department of Immunology, St Mary's Hospital Medical School, Norfolk Place, London W2
lPG, UK.
181
182
A. J. Pinching
cells involved in antibody responses in HIV infection. Although it is in principle possible that specific subsets of CD4 cells are depleted or affected by HIV infection, the evidence implicating specific loss of helper/inducer or suppressor/inducer types is contradictory; similarly, data on memory cells are ambiguous. Dendritic cells and Langerhans' cells have a major antigenpresenting role, notably in primary responses. Decreased expression of HLA class II antigens has been noted in these cells (Belsito et al., 1984; Eales, Farrant & Pinching, 1988) and is associated with increasingly severe impairment of antigenpresenting function (Eales et al., 1988; Macatonia et al., 1990). In asymptomatic HIV infection, though not in PGL, and in symptomatic HIV disease, there is also depletion of circulating dendritic cells (Macatonia et al., 1990). These changes have been related to early and extensive HIV infection of these cells. The follicular dendritic reticulum cells (FDRC) of the germinal centres of lymphoid follicles also have a major role in antigen presentation, predominantly in secondary antibody responses. Patients with uncomplicated PGL show intact FDRC structure of germinal centres, while patients with ARC and AIDS show progressive destruction of this network, associated with other immunohistological changes (Janossy et al., 1985). Interestingly, the FDRC show evidence of extensive HIV infection in both settings (Tenner-Racz et al., 1986). SPECIFIC ANTIBODY RESPONSES
The published reports of antibody
responses
to immunization
with specific antigens (Masur et al., 1981; Lane et al., 1983; Ammann et al., 1984; Simberkoff et al., 1984; Bernstein et al., 1985; Ballet et al., 1987; Teeuwsen et al., 1987; Huang et al., 1987; Janoff et al., 1988; Klein et al., 1989; Teeuwsen et al., 1990; Opravil et al., 1991) are summarized in Table 1. Some studies have focused on AIDS or ARC, and others have concentrated on patients with asymptomatic HIV infection. Most studies have examined responses to pneumococcal vaccines, which can be regarded as largely T cell independent, and about half have tested secondary responses to tetanus toxoid, to which T cells may contribute. A few studies have examined isotype or subclass responses or responses to specific pneumococcal serotypes. Some other, largely T cell-dependent responses have been examined, including the neoantigens keyhole limpet haemocyanin (KLH) or bacteriophage OX 174.
Pneumococcal antibody responses Pre-immunization pneumococcal antibody responses were shown to be low in AIDS/ARC patients in three of the four studies that report these (Ammann et al., 1984; Simberkoffet al., 1984; Janoff et al., 1988), but the recent study by Opravil et al. (1991) shows them to be higher than controls, which the authors attribute to prior pneumococcal infections. Patients with symptomless infection (with or without PGL) had normal preimmunization levels in two studies (Ballet et al., 1987; Huang et al., 1987) and reduced levels in two (Janoffet al., 1988; Klein et al., 1989). Antibody responses to pneumococcal immunization,
Table 1. Published reports on specific antibody responses in t'to
Reference
n
Masur et al. (1981) Lane et al. (1983)
11
Ammann et al. (1984) Simberkoff et al. (1984) Bernstein et al. (1985) Ballet et al. (1987)
5
3 18 5
26
Group AIDS AIDS ASY.* AIDS AIDS AIDS PGL
TT
PNP
Patients Pre
Post
Pre
N
VL VL L L
Janoffet
ia.
(1988)
Klein et al. (1989)
5
10 25 13 14 21 9 12
Teeuwsen et al. (1990) Opravil et al. (1991)
5
6 4
AsY. AsY. PGL AsY. PGL AIDS AsY.)t PGL | AsY.* ARC)i AIDS |
Pre
Post
Correlation with:
VL
VL N/SL
Substantial rise in all 12 serotypes KLH KLH.* HIV status? * KLH 280% patients versus 69'S, control
VL*
VL* None
6/26 N
VL
Comments *
VL L L*
16/25 Teeuwsen et al. (1987) Huang et al. (1987)
Post
+9/11
+ 4/4*
VL L
Other
N*
N*
Later pneumococcal infection Paediatric*, OX174; ly and 2y PNP: Low IgM, IgA, IgG2; Normal IgGI TT: Low IgG4. *
Polio
Low to some types t Influenza antigen * Log IgM; normal IgG, IgA * Low IgM; normal IgG, IgA * Low IgM, IgA; normal IgG *
N
N/L*
L L L
N/L* N/L* N/L*
SL
L
Nt
None N
H
VL
Nt
N
N
N/L*
*
within 3/12 of seroconversion
* Some low resps. t PNP with PHA; TT with PHA, PWM, CD4
PNP, pneumococcal polysaccharide (multiple serotypes); TT, tetanus toxoid; Asy., asymptomatic HIV infection; PGL, persistent generalized lymphadenopathy; , not done; VL, very low; L, low; ?, not clear; N. normal; SL, slightly low; H, high; KLH, keyhole limpet haemocyanin; OX 174, bacteriophage OX174 (ly, 2y, primary and secondary responses). *
and t, see Comments.
Antibody response in HIV infection usually tested at 3-4 weeks, have generally been shown to be impaired or severely impaired in patients with AIDS or ARC (Ammann et al., 1984; Simberkoff et al., 1984; Bernstein et al., 1985; Opravil et al., 1991). Curiously, the early report by Masur et al. (1981) states that all four patients immunized showed a substantial rise in titre to all serotypes, but the criteria for a rise are not given relative to controls. The study by Janoff et al. (1988) shows a normal IgG response by 6 weeks (although it is lower than controls at 3 weeks), but reduced IgA and IgM response at both time-points in such patients. In symptomless HIV infection, the picture is less clear still. Ballet et al. (1987) showed impaired responses in 16 out of 25 PGL patients (the reductions being in IgG2, IgA and IgM) and Klein et al. (1989) showed generally lower antibody responses in asymptomatic/PGL subjects. Huang et al. (1987) report that IgG responses in asymptomatic/PGL subjects are generally similar to those of controls but that reduced responses are seen to some serotypes. Unfortunately the responses to some of the other serotypes were low in controls and there seems to be a trend for lower values in HIV-infected subjects for some of those. Thus the description of these responses as normal may rather reflect the fact that the study was too small to show a statistically significant difference. However, in the study by Janoffet al. (1988) the increment in IgG responses was similar to controls; the IgM responses were clearly less in HIV-infected subjects and there was a trend for lower values in IgA which did not reach significance. It should also be noted that the absolute values achieved were lower in all HIV-infected groups due to the lower initial values. Furthermore, the long-term IgG and IgA titres (at 49 weeks) were lower in asymptomatic HIV-infected subjects than in controls. Thus, while there are some discrepancies in these data, the general impression is of lower pre-immunization values in patients with AIDS or ARC and slightly lower values in some subjects with symptomless HIV infection. Pneumococcal vaccine responses seem to be typically impaired by standard criteria in AIDS/ARC and somewhat impaired in symptomless HIV infection. Whether the retention of limited responsiveness in these earlier stages would confer benefit in terms of protection against later pneumococcal infection has yet to be established, but such an approach should, if it is to be applied, be applied before symptomatic disease presents. Tetanus toxoid antibody responses Pre-immunization titres have not always been commented on due to variability in prior immunization history. When reported, the titres in adults with asymptomatic or symptomatic HIV infection have been normal. Low or undetectable levels have been reported in children with AIDS who had had at least one prior immunization (Bernstein et al., 1985), but these findings may reflect the more advanced immunodeficiency at the time of that first exposure. Post-immunization antibody titres in ARC/AIDS have been reported as being generally normal but reduced in a few patients (Masur et al., 1981; Opravil et al., 1991). Paediatric AIDS cases showed negligible responses (Bernstein et al., 1985). Similar findings have been obtained in PGL, where the mean titre was no different from controls but some patients showed a very low response (Ballet et al., 1987). However, a report on a few patients with symptomless infection (Teeuwsen et al., 1987) shows very low responses to this antigen; in a further study, the
183
same investigators found no such difference in recently (within 3 months) HIV-seroconverted subjects (Teeuwsen et al., 1990).
Other antibody responses Polio virus (Teeuwsen et al., 1987) and influenza (Huang et al., 1987) secondary antibody responses were normal in asymptomatic/PGL patients. AIDS patients showed very poor responses to the T cell-dependent neoantigen, KLH, in two studies (Lane et al., 1983; Ammann et al., 1984) and the first of these studies also suggested impaired responses in asymptomatic HIV infection. Bernstein et al., (1985) studying paediatric AIDS cases showed very poor primary and secondary antibody responses to the bacteriophage OX174. Although not included in this review, several studies have shown reduced responsiveness to hepatitis B vaccine in asymptomatic HIV-infected subjects, in terms of titre achieved and proportion of subjects responding to standard immunization schedules. CORRELATES OF IMPAIRED ANTIBODY RESPONSIVENESS Three studies have sought correlation between impairment of antibody response and other markers of HIV disease. Ballet et al. (1987) and Klein et al. (1989) found none; but Opravil et al. (1991) suggest on the basis of small numbers of patients that pneumococcal responses are correlated with PHA responsiveness, which is counter-intuitive, and that tetanus toxoid responses are correlated with PHA and pokeweed responses and with CD4 cell numbers, which seems more logical.
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