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The role of CD4+ T helper cells in the cytotoxic T lymphocyte response to HIV-1
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The role of CD4+ T helper cells in the cytotoxic T lymphocyte response to HIV-1 Marcus Altfeld* and Eric S Rosenberg† Virus-specific CD4+ T cell help and CD8+ cytotoxic T cell (CTL) responses are critical for the maintenance of effective immunity in chronic viral infections. HIV-1 infection presents a unique situation in which HIV-1-specific T helper cell responses are characteristically impaired and virus-specific CTLs wane over time as disease progresses; a relationship exists between T cell help and CTL responses in HIV-1 infection. Addresses *Partners AIDS Research Center, Massachusetts General Hospital and Harvard Medical School, 13th Street, Building 149, 5th Floor, Charlestown, MA 02114, USA; e-mail: [email protected] † Infectious disease Unit, Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114, USA; e-mail: [email protected] Correspondence: Eric S Rosenberg Current Opinion in Immunology 2000, 12:375–380 0952-7915/00/$ — see front matter © 2000 Elsevier Science Ltd. All rights reserved. Abbreviations CMV cytomegalovirus CTL cytotoxic T lymphocyte HAART highly active antiretroviral therapy HCV hepatitis C virus LCMV lymphocytic choriomenigitis virus
Introduction The outcome of many viral infections is containment rather than eradication and the immune system plays a central role in viral control. Increasing data indicate the important role of cytotoxic T lymphocytes (CTLs) in HIV-1 infection [1]. However, less is known about the role of HIV-1-specific CD4+ T helper cells. It has been shown in a murine model that virus-specific CD4+ T helper cell responses are critical for the maintenance of effective CTL function in chronic viral infection [2]. The negative correlation of strong HIV-1-specific CD4+ T helper cell responses and viral load indicates that CD4+ T helper cells may also play an important role in the immune response to HIV-1 [3]. Furthermore, recent data suggest a functional link between HIV-1-specific CTLs and CD4+ T helper cell responses [4•]. This review will assess advances in the past few years in our understanding of the role of CD4+ T helper cells in the CTL response to viral infections, focusing on HIV-1 infection.
The role of CD4+ T helper cells in the CTL response to viral infections in animal models Virus-specific CD4+ T helper cell responses are known to be essential for the maintenance of effective immunity in chronic viral infections in animals. The most thoroughly characterized system demonstrating the critical importance of virus-specific CD4+ T helper cell responses and
their role in maintaining CTL function is in a murine model of lymphocytic choriomeningitis virus (LCMV). In acute LCMV infection, mice develop strong virus-specific CTL responses that are associated with control of viremia. However, during chronic LCMV infection, virusspecific CTL responses decline over time when LCMV-specific CD4+ T helper cells are experimentally depleted — suggesting that CD4+ T cell help plays a critical role in the maintenance of CTL responses during the chronic phase of infection. [2,5–7]. The progressive loss of virus-specific CTL responses in the absence of CD4+ T cell help has also been described for other murine viral infections [8–11]. Furthermore, the importance of a strong CD4+ T helper cell response for an effective CTL response in vivo has been supported by recent vaccine studies in animals [12–14]. Over the past few years, several technical advances have provided greater insight into the functionality of the cellular immune system. The development of new techniques that directly visualize antigen-specific CTLs using peptide–MHC-class-I tetramers [15] and detection of antigen-specific IFN-γ production of activated T cells by Elispot assay have provided the possibility to quantify the cellular immune system in more detail. Using these techniques in the murine LCMV model, it was shown that CD4+ T helper cell deficiency may impair CTL responses and that antiviral CTLs persist in an inactive state in the absence of sufficient CD4+ T cell help [16]. These findings underscore the importance of the interplay between CD4+ and CD8+ T cells in the maintenance of a functional, effective immune response that is able to control chronic viral infections.
The role of CD4+ T helper cells in the CTL response to viral infections in humans In accordance with the observations in animal models, several groups have confirmed the important role of antigen-specific CD4+ T cells in the control of chronic viral infections in humans. The absence of cytomegalovirus (CMV)-specific CTL responses after bone marrow transplantation is associated with recurrence of CMV-mediated disease [17]. Success in transfusing CMV-specific CD8+ T cell clones in bone marrow recipients has shed light on the potential key role of CD4+ T helper cells in sustaining effective immune function [18]. Restoration and maintenance of cellular immunity against CMV after allogeneic bone marrow transplantation was only successful in recipients possessing adequate antigen-specific CD4+ T helper cells. In contrast, CMV-specific CTL activity declined in subjects deficient in virus-specific T cell help — demonstrating
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T helper cell responses are essential in providing protection from CMV disease in HIV-1-infected individuals [19,20].
Figure 1
Relative magnitude
(a)
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Th CTL
Time (b) Th
Relative magnitude
CTL
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HAART Th
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Taken together, these studies underscore the key role of CD4+ T helper cells in inducing an effective immune response during acute viral infection and orchestrating effective immune function in chronic human viral infections.
The role of CD4+ T helper cells in the CTL response to HIV-1
Time
(c)
The role of cellular immune responses has also been investigated in hepatitis C virus (HCV) infection [21]. Studies of the T cell responses in subjects with acute HCV infection have demonstrated a close association of antigen-specific CD4+ T helper cell responses with viral clearance and resolution of disease [22,23]. A recent study [24•] showed that HCV-specific CD4+ T helper cell responses are essential for eliminating virus during the acute phase of disease and must be permanently maintained to achieve long-term viral control. Subjects who lost virus-specific CD4+ T helper cell responses — after temporally controlling the virus during acute infection — experienced recurrence of viremia. The importance of HCV-specific CD4+ T helper cell responses in viral control has also been suggested in HCV/HIV co-infection, in which the late stage of AIDS with low CD4+ T cell counts often leads to rapid progression of liver disease [25].
CTL
VL Time Current Opinion in Immunology
Relative changes of HIV-1 viral load (VL), HIV-1-specific CD4+ T helper cell (Th) responses and HIV-1-specific CTL responses during HIV-1 infection. (a) With progressive HIV-1 infection, Th responses are lost and CTL responses subsequently decline. This is associated with an increase in VL. (b) In long-term nonprogressive HIV-1 infection, Th and CTL responses are maintained — resulting in effective immunological control of VL in the absence of antiretroviral treatment. (c) When acute HIV-1 infection is treated prior to, or at the time of, seroconversion Th and CTL responses are maintained and can be persistently enhanced by re-exposure to HIV-1 during treatment interruption. Adapted, with permission, from [60].
that T helper cell function is needed for the persistence of adoptively transferred CTL activity [18]. Furthermore, it has been demonstrated that CMV-specific CD4 +
HIV-1 infection is characterized by both the absence of HIV-1-specific CD4+ T helper cell responses and eventual decline in virus-specific CTLs, inevitably resulting in disease progression (Figure 1a). Increasing data indicate the importance of virus-specific CTLs in HIV-1 infection [1]. In chronic HIV-1 infection, Gag-specific CTL responses have been inversely associated with HIV-1 load [26]. Virus-specific CTL activity appears to be critically important in containment of viral replication, beginning in acute HIV-1 infection. During untreated acute HIV-1 infection, virus-specific CTL activity is associated with the initial decrease of plasma viremia [27,28]. Furthermore, in vitro studies have demonstrated potent inhibition of viral replication by CTLs, mediated by both lytic and non-lytic mechanisms [29]. In addition, animalmodel data have shown that CD8+ T cell depletion is associated with a dramatic increase in viral load [30•,31•] in SIV-infected macaques. Despite the dramatic antiviral effect of CD8+ T cells in vitro and in vivo, the majority of infected persons have persistent uncontrolled viremia and progressive HIV-1 disease. Although the hallmark of progressive HIV-1 infection is a decline in the number of CD4+ T helper cells, qualitative impairment of CD4+ lymphocyte function occurs very early in the course of infection prior to quantitative decreases in CD4+ T helper cell numbers [32–34]. Activated CD4+ T helper cells are the main target of HIV-1 and are killed by infection [35] and HIV-1-induced apoptosis [36,37]. Early
T helper cells in the cytotoxic T lymphocyte response to HIV-1 Altfeld and Rosenberg
studies looking at the T helper cell proliferative responses to HIV-1 have shown these responses to be weak or undetectable [38–40], leading to the conclusion that the virus was not capable of inducing strong virus-specific CD4+ T helper cell responses. Most of these studies were performed in persons with progressive disease in which a decline of virus-specific CTL responses has also been described [41,42]. A recent study using tetramers of peptide with MHC class I showed that HIV-1-specific CTLs could persist for prolonged periods in the absence of circulating, peripheral, virus-specific CD4+ T cells [43•]. The ability of these CTLs to produce IFN-γ to specific stimulation was, however, impaired — suggesting a lack of direct effector activity of these cells [16]. These observations are consistent with previous findings in other human and animal viral infection supporting the idea that maintenance of effective virus-specific CTL responses is not possible in the absence of CD4+ T cell help. The most notable exception to the above observation — of absent HIV-1-specific CD4+ T helper cell function and subsequent loss of virus-specific CTL activity — is in a small subset of chronically infected individuals with long-term nonprogressive HIV-1 infection. These persons remain clinically asymptomatic and maintain a low or undetectable HIV-1 virus load in the absence of antiretroviral therapy despite infection, in some cases for more than 20 years. In these subjects persistently low viral loads have been associated with strong CTL responses [41,42,44,45] (Figure 1b). What do we know about HIV-1-specific CD4+ T cell activity in these subjects? An early report [46] in a long-term nonprogressor demonstrated for the first time the ability of HIV-1 to induce virus-specific T helper cell responses under certain conditions. Additionally, robust, Th1-like, p24-specific CD4+ T helper cell responses were observed in a small cohort of HIV-1-infected long-term nonprogressors [3] (Figure 1b). The presence of strong HIV-1-specific T helper cells in individuals controlling viral replication raised the question of whether a relationship exists between T helper cell responses to HIV-1 antigen and viral load. Analyzing untreated individuals who had chronic HIV-1 infection and a wide range of plasma HIV-1 viral loads, a highly significant negative correlation between lymphoproliferative responses to HIV-1 p24 and viral load was observed [3]. Individuals with the strongest gag-specific CD4+ T cell responses had the lowest viral loads and, conversely, those with higher HIV-1 viral load had markedly diminished ability to respond to HIV-1 antigen. Furthermore, recent data indicate an association between robust HIV-1-specific CTLs and strong T helper cell responses [4•,47], providing additional evidence that these two effector mechanisms of the immune system are linked in HIV-1 infection. Further support for the linkage between HIV-1-specific CD4+ T cells and CTL activity derives from a recent cross-sectional study using a sensitive flow cytometric assay to analyze antigen-specific IFN-γ
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production by CD4+ T cells [48••]. Upon stimulation with p55 (Gag), significant levels of IFN-γ were detected in subjects with long-term nonprogressive HIV-1 infection. Furthermore, in chronically infected individuals, a decline in HIV-1-specific IFN-γ-producing CD4+ T cells was observed with prolonged viral suppression under highly active antiretroviral therapy (HAART). These data are consistent with the observation of declining HIV-1-specific CTL responses after initiation of effective antiretroviral treatment in chronically infected individuals [49,50], providing additional support for the hypothesis that T helper cells may mediate their antiviral effect through facilitation of CTL responses. In addition, HIV-1-specific IFN-γ-producing CD4+ T cells were shown to persist in subjects with chronic untreated HIV-1 infection with varying viral loads [48••]. However, the functionality of these cells is unknown. Recent, preliminary data demonstrate that HIV1-specific CD4+ T cells, measured by antigen-specific IFN-γ production, are maintained in untreated patients with and without proliferative responses to HIV-1. These IFN-γ-producing cells did not differ significantly between a cohort of long-term nonprogressors with strong lymphoproliferative responses to HIV-1 antigen and a cohort of untreated patients with similar CD4+ T cell counts but without lymphoproliferative responses (AC McNeil, abstract 187, 7th Conference on Retroviruses and Opportunistic Infections 2000, San Francisco, January 30th to February 2nd, 2000). Although deletion of antigen-specific CD4+ T helper cells may occur early in the course of infection, it appears that populations of antigen-specific T helper cells remain but may have impaired proliferative function due to other mechanisms. The recent arrival of HLA class II tetramers [51•] will be used to further explore the functional role of T helper cells in HIV-1 infection [52]. The observations described above lead to the hypothesis that very early initiation of effective antiretroviral treatment may prevent the loss of HIV-1-specific CD4+ T cell activity and allow for sufficient T cell help to maintain a functional effective CTL response to HIV-1 [53]. Subjects treated effectively with HAART prior to or around the time of HIV-1 seroconversion generate strong virusspecific CD4+ T cell responses [3,54]. In contrast to the increased T helper cell responses in treated acute infection, HIV-1-specific CTL responses were of low magnitude and narrowly directed against a few epitopes [55] (M Altfeld, ES Rosenberg, PJR Goulder, BD Walker, unpublished data). However, CTL responses persisted in these individuals with strong virus-specific CD4+ T helper cell function during the first year of treatment with HAART (M Altfeld, ES Rosenberg, PJR Goulder, BD Walker, unpublished data) and were not lost, as described in treated chronically infected individuals [56,57]. In two recent reports [58•,59•] both virus-specific CD4+ T helper cell and CTL responses were enhanced during re-exposure to HIV-1 following treatment interruptions (Figure 1c); this may ultimately translate into improved immunological control of HIV-1
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replication. These recent findings underscore the important role of virus-specific CD4+ T cell help for the induction and maintenance of CTL responses to HIV-1.
Conclusions It has been shown that virus-specific CD4+ T helper cell responses are critical for the maintenance of effective immunity to chronic viral infections. However, HIV-1 infection presents a unique challenge to the cellular immune system because it impairs HIV-1-specific T helper function very early in the course of disease. Recent reports indicate that HIV-1-specific cellular immune responses are functionally relevant and can be augmented in infected individuals. These observations underscore the rationale for further investigation of immunotherapeutic approaches and shed insight into relevant immune responses that may be critical for vaccine development.
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Acknowledgements We are indebted to Bruce D Walker for thoughtful and critical review of this manuscript.
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58. Ortiz GM, Nixon DF, Trkola A, Binley J, Jin X, Bonhoeffer S, Kuebler PJ, • Donahoe SM, Demoitie MA, Kakimoto WM et al.: HIV-1-specific immune responses in subjects who temporarily contain virus replication after discontinuation of highly active antiretroviral therapy. J Clin Invest 1999, 104:R13-R18. See annotation to [59•].
59. Lisziewicz J, Rosenberg E, Lieberman J, Jessen H, Lopalco L, • Siliciano R, Walker B, Lori F: Control of HIV despite the discontinuation of antiretroviral therapy. N Engl J Med 1999, 340:1683-1684. These reports [58•,59•] describe HIV-1-infected individuals who were treated early after primary infection and who interrupted antiretroviral treatment. Re-exposure to HIV-1 during treatment interruption increased virus-specific cellular immune responses in these individuals and was associated in some individuals with spontaneous control of HIV-1 viremia without any treatment. These reports are interesting but are limited by the small number of subjects and retrospective analysis of data. 60. Goulder PJR: Treat acute HIV at an early stage. HIV & AIDS Current Trends 1999, 5:6-8.
The role of CD4+ T helper cells in the cytotoxic T lymphocyte response to HIV-1 Marcus Altfeld* and Eric S Rosenberg† Virus-specific CD4+ T cell help and CD8+ cytotoxic T cell (CTL) responses are critical for the maintenance of effective immunity in chronic viral infections. HIV-1 infection presents a unique situation in which HIV-1-specific T helper cell responses are characteristically impaired and virus-specific CTLs wane over time as disease progresses; a relationship exists between T cell help and CTL responses in HIV-1 infection. Addresses *Partners AIDS Research Center, Massachusetts General Hospital and Harvard Medical School, 13th Street, Building 149, 5th Floor, Charlestown, MA 02114, USA; e-mail: [email protected] † Infectious disease Unit, Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114, USA; e-mail: [email protected] Correspondence: Eric S Rosenberg Current Opinion in Immunology 2000, 12:375–380 0952-7915/00/$ — see front matter © 2000 Elsevier Science Ltd. All rights reserved. Abbreviations CMV cytomegalovirus CTL cytotoxic T lymphocyte HAART highly active antiretroviral therapy HCV hepatitis C virus LCMV lymphocytic choriomenigitis virus
Introduction The outcome of many viral infections is containment rather than eradication and the immune system plays a central role in viral control. Increasing data indicate the important role of cytotoxic T lymphocytes (CTLs) in HIV-1 infection [1]. However, less is known about the role of HIV-1-specific CD4+ T helper cells. It has been shown in a murine model that virus-specific CD4+ T helper cell responses are critical for the maintenance of effective CTL function in chronic viral infection [2]. The negative correlation of strong HIV-1-specific CD4+ T helper cell responses and viral load indicates that CD4+ T helper cells may also play an important role in the immune response to HIV-1 [3]. Furthermore, recent data suggest a functional link between HIV-1-specific CTLs and CD4+ T helper cell responses [4•]. This review will assess advances in the past few years in our understanding of the role of CD4+ T helper cells in the CTL response to viral infections, focusing on HIV-1 infection.
The role of CD4+ T helper cells in the CTL response to viral infections in animal models Virus-specific CD4+ T helper cell responses are known to be essential for the maintenance of effective immunity in chronic viral infections in animals. The most thoroughly characterized system demonstrating the critical importance of virus-specific CD4+ T helper cell responses and
their role in maintaining CTL function is in a murine model of lymphocytic choriomeningitis virus (LCMV). In acute LCMV infection, mice develop strong virus-specific CTL responses that are associated with control of viremia. However, during chronic LCMV infection, virusspecific CTL responses decline over time when LCMV-specific CD4+ T helper cells are experimentally depleted — suggesting that CD4+ T cell help plays a critical role in the maintenance of CTL responses during the chronic phase of infection. [2,5–7]. The progressive loss of virus-specific CTL responses in the absence of CD4+ T cell help has also been described for other murine viral infections [8–11]. Furthermore, the importance of a strong CD4+ T helper cell response for an effective CTL response in vivo has been supported by recent vaccine studies in animals [12–14]. Over the past few years, several technical advances have provided greater insight into the functionality of the cellular immune system. The development of new techniques that directly visualize antigen-specific CTLs using peptide–MHC-class-I tetramers [15] and detection of antigen-specific IFN-γ production of activated T cells by Elispot assay have provided the possibility to quantify the cellular immune system in more detail. Using these techniques in the murine LCMV model, it was shown that CD4+ T helper cell deficiency may impair CTL responses and that antiviral CTLs persist in an inactive state in the absence of sufficient CD4+ T cell help [16]. These findings underscore the importance of the interplay between CD4+ and CD8+ T cells in the maintenance of a functional, effective immune response that is able to control chronic viral infections.
The role of CD4+ T helper cells in the CTL response to viral infections in humans In accordance with the observations in animal models, several groups have confirmed the important role of antigen-specific CD4+ T cells in the control of chronic viral infections in humans. The absence of cytomegalovirus (CMV)-specific CTL responses after bone marrow transplantation is associated with recurrence of CMV-mediated disease [17]. Success in transfusing CMV-specific CD8+ T cell clones in bone marrow recipients has shed light on the potential key role of CD4+ T helper cells in sustaining effective immune function [18]. Restoration and maintenance of cellular immunity against CMV after allogeneic bone marrow transplantation was only successful in recipients possessing adequate antigen-specific CD4+ T helper cells. In contrast, CMV-specific CTL activity declined in subjects deficient in virus-specific T cell help — demonstrating
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T helper cell responses are essential in providing protection from CMV disease in HIV-1-infected individuals [19,20].
Figure 1
Relative magnitude
(a)
VL
Th CTL
Time (b) Th
Relative magnitude
CTL
VL
HAART
HAART Th
Relative magnitude
Taken together, these studies underscore the key role of CD4+ T helper cells in inducing an effective immune response during acute viral infection and orchestrating effective immune function in chronic human viral infections.
The role of CD4+ T helper cells in the CTL response to HIV-1
Time
(c)
The role of cellular immune responses has also been investigated in hepatitis C virus (HCV) infection [21]. Studies of the T cell responses in subjects with acute HCV infection have demonstrated a close association of antigen-specific CD4+ T helper cell responses with viral clearance and resolution of disease [22,23]. A recent study [24•] showed that HCV-specific CD4+ T helper cell responses are essential for eliminating virus during the acute phase of disease and must be permanently maintained to achieve long-term viral control. Subjects who lost virus-specific CD4+ T helper cell responses — after temporally controlling the virus during acute infection — experienced recurrence of viremia. The importance of HCV-specific CD4+ T helper cell responses in viral control has also been suggested in HCV/HIV co-infection, in which the late stage of AIDS with low CD4+ T cell counts often leads to rapid progression of liver disease [25].
CTL
VL Time Current Opinion in Immunology
Relative changes of HIV-1 viral load (VL), HIV-1-specific CD4+ T helper cell (Th) responses and HIV-1-specific CTL responses during HIV-1 infection. (a) With progressive HIV-1 infection, Th responses are lost and CTL responses subsequently decline. This is associated with an increase in VL. (b) In long-term nonprogressive HIV-1 infection, Th and CTL responses are maintained — resulting in effective immunological control of VL in the absence of antiretroviral treatment. (c) When acute HIV-1 infection is treated prior to, or at the time of, seroconversion Th and CTL responses are maintained and can be persistently enhanced by re-exposure to HIV-1 during treatment interruption. Adapted, with permission, from [60].
that T helper cell function is needed for the persistence of adoptively transferred CTL activity [18]. Furthermore, it has been demonstrated that CMV-specific CD4 +
HIV-1 infection is characterized by both the absence of HIV-1-specific CD4+ T helper cell responses and eventual decline in virus-specific CTLs, inevitably resulting in disease progression (Figure 1a). Increasing data indicate the importance of virus-specific CTLs in HIV-1 infection [1]. In chronic HIV-1 infection, Gag-specific CTL responses have been inversely associated with HIV-1 load [26]. Virus-specific CTL activity appears to be critically important in containment of viral replication, beginning in acute HIV-1 infection. During untreated acute HIV-1 infection, virus-specific CTL activity is associated with the initial decrease of plasma viremia [27,28]. Furthermore, in vitro studies have demonstrated potent inhibition of viral replication by CTLs, mediated by both lytic and non-lytic mechanisms [29]. In addition, animalmodel data have shown that CD8+ T cell depletion is associated with a dramatic increase in viral load [30•,31•] in SIV-infected macaques. Despite the dramatic antiviral effect of CD8+ T cells in vitro and in vivo, the majority of infected persons have persistent uncontrolled viremia and progressive HIV-1 disease. Although the hallmark of progressive HIV-1 infection is a decline in the number of CD4+ T helper cells, qualitative impairment of CD4+ lymphocyte function occurs very early in the course of infection prior to quantitative decreases in CD4+ T helper cell numbers [32–34]. Activated CD4+ T helper cells are the main target of HIV-1 and are killed by infection [35] and HIV-1-induced apoptosis [36,37]. Early
T helper cells in the cytotoxic T lymphocyte response to HIV-1 Altfeld and Rosenberg
studies looking at the T helper cell proliferative responses to HIV-1 have shown these responses to be weak or undetectable [38–40], leading to the conclusion that the virus was not capable of inducing strong virus-specific CD4+ T helper cell responses. Most of these studies were performed in persons with progressive disease in which a decline of virus-specific CTL responses has also been described [41,42]. A recent study using tetramers of peptide with MHC class I showed that HIV-1-specific CTLs could persist for prolonged periods in the absence of circulating, peripheral, virus-specific CD4+ T cells [43•]. The ability of these CTLs to produce IFN-γ to specific stimulation was, however, impaired — suggesting a lack of direct effector activity of these cells [16]. These observations are consistent with previous findings in other human and animal viral infection supporting the idea that maintenance of effective virus-specific CTL responses is not possible in the absence of CD4+ T cell help. The most notable exception to the above observation — of absent HIV-1-specific CD4+ T helper cell function and subsequent loss of virus-specific CTL activity — is in a small subset of chronically infected individuals with long-term nonprogressive HIV-1 infection. These persons remain clinically asymptomatic and maintain a low or undetectable HIV-1 virus load in the absence of antiretroviral therapy despite infection, in some cases for more than 20 years. In these subjects persistently low viral loads have been associated with strong CTL responses [41,42,44,45] (Figure 1b). What do we know about HIV-1-specific CD4+ T cell activity in these subjects? An early report [46] in a long-term nonprogressor demonstrated for the first time the ability of HIV-1 to induce virus-specific T helper cell responses under certain conditions. Additionally, robust, Th1-like, p24-specific CD4+ T helper cell responses were observed in a small cohort of HIV-1-infected long-term nonprogressors [3] (Figure 1b). The presence of strong HIV-1-specific T helper cells in individuals controlling viral replication raised the question of whether a relationship exists between T helper cell responses to HIV-1 antigen and viral load. Analyzing untreated individuals who had chronic HIV-1 infection and a wide range of plasma HIV-1 viral loads, a highly significant negative correlation between lymphoproliferative responses to HIV-1 p24 and viral load was observed [3]. Individuals with the strongest gag-specific CD4+ T cell responses had the lowest viral loads and, conversely, those with higher HIV-1 viral load had markedly diminished ability to respond to HIV-1 antigen. Furthermore, recent data indicate an association between robust HIV-1-specific CTLs and strong T helper cell responses [4•,47], providing additional evidence that these two effector mechanisms of the immune system are linked in HIV-1 infection. Further support for the linkage between HIV-1-specific CD4+ T cells and CTL activity derives from a recent cross-sectional study using a sensitive flow cytometric assay to analyze antigen-specific IFN-γ
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production by CD4+ T cells [48••]. Upon stimulation with p55 (Gag), significant levels of IFN-γ were detected in subjects with long-term nonprogressive HIV-1 infection. Furthermore, in chronically infected individuals, a decline in HIV-1-specific IFN-γ-producing CD4+ T cells was observed with prolonged viral suppression under highly active antiretroviral therapy (HAART). These data are consistent with the observation of declining HIV-1-specific CTL responses after initiation of effective antiretroviral treatment in chronically infected individuals [49,50], providing additional support for the hypothesis that T helper cells may mediate their antiviral effect through facilitation of CTL responses. In addition, HIV-1-specific IFN-γ-producing CD4+ T cells were shown to persist in subjects with chronic untreated HIV-1 infection with varying viral loads [48••]. However, the functionality of these cells is unknown. Recent, preliminary data demonstrate that HIV1-specific CD4+ T cells, measured by antigen-specific IFN-γ production, are maintained in untreated patients with and without proliferative responses to HIV-1. These IFN-γ-producing cells did not differ significantly between a cohort of long-term nonprogressors with strong lymphoproliferative responses to HIV-1 antigen and a cohort of untreated patients with similar CD4+ T cell counts but without lymphoproliferative responses (AC McNeil, abstract 187, 7th Conference on Retroviruses and Opportunistic Infections 2000, San Francisco, January 30th to February 2nd, 2000). Although deletion of antigen-specific CD4+ T helper cells may occur early in the course of infection, it appears that populations of antigen-specific T helper cells remain but may have impaired proliferative function due to other mechanisms. The recent arrival of HLA class II tetramers [51•] will be used to further explore the functional role of T helper cells in HIV-1 infection [52]. The observations described above lead to the hypothesis that very early initiation of effective antiretroviral treatment may prevent the loss of HIV-1-specific CD4+ T cell activity and allow for sufficient T cell help to maintain a functional effective CTL response to HIV-1 [53]. Subjects treated effectively with HAART prior to or around the time of HIV-1 seroconversion generate strong virusspecific CD4+ T cell responses [3,54]. In contrast to the increased T helper cell responses in treated acute infection, HIV-1-specific CTL responses were of low magnitude and narrowly directed against a few epitopes [55] (M Altfeld, ES Rosenberg, PJR Goulder, BD Walker, unpublished data). However, CTL responses persisted in these individuals with strong virus-specific CD4+ T helper cell function during the first year of treatment with HAART (M Altfeld, ES Rosenberg, PJR Goulder, BD Walker, unpublished data) and were not lost, as described in treated chronically infected individuals [56,57]. In two recent reports [58•,59•] both virus-specific CD4+ T helper cell and CTL responses were enhanced during re-exposure to HIV-1 following treatment interruptions (Figure 1c); this may ultimately translate into improved immunological control of HIV-1
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replication. These recent findings underscore the important role of virus-specific CD4+ T cell help for the induction and maintenance of CTL responses to HIV-1.
Conclusions It has been shown that virus-specific CD4+ T helper cell responses are critical for the maintenance of effective immunity to chronic viral infections. However, HIV-1 infection presents a unique challenge to the cellular immune system because it impairs HIV-1-specific T helper function very early in the course of disease. Recent reports indicate that HIV-1-specific cellular immune responses are functionally relevant and can be augmented in infected individuals. These observations underscore the rationale for further investigation of immunotherapeutic approaches and shed insight into relevant immune responses that may be critical for vaccine development.
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Acknowledgements We are indebted to Bruce D Walker for thoughtful and critical review of this manuscript.
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58. Ortiz GM, Nixon DF, Trkola A, Binley J, Jin X, Bonhoeffer S, Kuebler PJ, • Donahoe SM, Demoitie MA, Kakimoto WM et al.: HIV-1-specific immune responses in subjects who temporarily contain virus replication after discontinuation of highly active antiretroviral therapy. J Clin Invest 1999, 104:R13-R18. See annotation to [59•].
59. Lisziewicz J, Rosenberg E, Lieberman J, Jessen H, Lopalco L, • Siliciano R, Walker B, Lori F: Control of HIV despite the discontinuation of antiretroviral therapy. N Engl J Med 1999, 340:1683-1684. These reports [58•,59•] describe HIV-1-infected individuals who were treated early after primary infection and who interrupted antiretroviral treatment. Re-exposure to HIV-1 during treatment interruption increased virus-specific cellular immune responses in these individuals and was associated in some individuals with spontaneous control of HIV-1 viremia without any treatment. These reports are interesting but are limited by the small number of subjects and retrospective analysis of data. 60. Goulder PJR: Treat acute HIV at an early stage. HIV & AIDS Current Trends 1999, 5:6-8.