HIV-Induced Immunopathogenesis
1998; Cell Press; Volume: 9; Issue: 5 Linguagem: Inglês
10.1016/s1074-7613(00)80656-1
ISSN1097-4180
Autores Tópico(s)HIV/AIDS drug development and treatment
ResumoFrom the time of the discovery of the acquired immune deficiency syndrome (AIDS) in 1981, it was realized that the condition involved a critical loss of immune competence that was reflected in susceptibility to opportunistic infections previously seen primarily among immune-compromised patients. Laboratory immunologic parameters that describe this severely impaired immune system include reduced T cell proliferative responses to soluble antigens and mitogens as well as impaired delayed type hypersensitivity reactions. The hallmark of this condition, recognized in the first patients, was the depletion of CD4+ T cells (reviewed in 25Gottlieb M.S. Groopman J.E. Weinstein W.M. Fahey J.L. Detels R. The acquired immunodeficiency syndrome.Ann. Intern. Med. 1983; 99: 208-220Crossref PubMed Scopus (254) Google Scholar). Within three years of the first reported AIDS cases, human immunodeficiency virus type-1 (HIV) had been isolated and identified (reviewed in 32Levy J.A. Pathogenesis of human immunodeficiency virus infection.Microbiol. Rev. 1993; 57: 183-289Crossref PubMed Google Scholar). The logical interpretation of the immunologic consequences of AIDS is that HIV infects and kills CD4+ T cells, resulting in the depletion of the CD4+ T cell subset. Although infection with HIV is responsible for AIDS development, it is important to know to what extent the pathogenesis is the result of immune-mediated mechanisms, in contrast to a direct killing of CD4+ T cells by infection. It is clear that there is an initial strong immune response to HIV similar to and possibly stronger than that against other viral infections. Although HIV is cytopathic to in vitro infected CD4+ T cells (reviewed in 32Levy J.A. Pathogenesis of human immunodeficiency virus infection.Microbiol. Rev. 1993; 57: 183-289Crossref PubMed Google Scholar), it can be questioned whether the percentage of infected T cells detected at any point in time can account for the extensive CD4 depletion observed in AIDS patients. The loss of helper cell (Th) function is observed relatively soon after infection, even before CD4+ T cell decline. In addition, both immune activation (2Ascher M.S. Sheppard H.W. AIDS as immune system activation a model for pathogenesis.Clin. Exp. Immunol. 1988; 73: 165-167PubMed Google Scholar) and loss of immune function are seen simultaneously. These two observations suggest that part of the T cell functional loss occurs independently of both direct HIV infection of CD4+ T cells and of CD4 numbers. This in turn suggests immune dysregulation rather than exclusively immune deficiency (reviewed in 53Shearer G.M. Clerici M. Type 1 and type 2 responses in HIV infection and exposure.in: Gupta S. Immunology of HIV Infection. Plenum Press, New York1996Google Scholar). Numerous abnormalities in the cells that comprise the immune system have been identified in the developing syndrome, including polyclonal B cell activation and the production of autoantibodies, decreased cytolytic activity of natural killer (NK) and antigen-specific cytolytic T lymphocytes (CTL), reduced Th function to multiple T cell stimuli, impaired or aberrant antigen-presenting cell (APC) activity, and disruption of immunoregulatory cytokine expression and production (reviewed in 33Levy J.A. HIV and the Pathogenesis of AIDS, Second Edition. American Society of Microbiology, Washington, DC1998Google Scholar). Cellular defects in the peripheral blood mononuclear cells (PBMC) of asymptomatic HIV-infected (HIV+) individuals and AIDS patients can be demonstrated in CTL, Th, and APC. Deficiencies of in vitro CTL responses of AIDS patients can be corrected by addition of interleukin 2 (IL-2) to the cultures (49Rook A.H. Mazur H. Lane L.C. Frederick W. Kasahara T. Macher A.M. Djeu J.Y. Manischewitz J.F. Jackson L. Fauci A.S. Quinnan Jr., G.V. Interleukin-2 enhances the depressed natural killer and cytomegalovirus-specific cytotoxic activity of lymphocytes from patients with the acquired immunodeficiency syndrome.J. Clin. Invest. 1983; 72: 398-403Crossref PubMed Scopus (304) Google Scholar), indicating that the primary immunologic defect resides upstream of CD8+ T effector (Te) function. CD4 Th function is impaired in asymptomatic HIV+ individuals (reviewed in 53Shearer G.M. Clerici M. Type 1 and type 2 responses in HIV infection and exposure.in: Gupta S. Immunology of HIV Infection. Plenum Press, New York1996Google Scholar). In fact, loss of in vitro Th function as well as loss of in vivo DTH responses are key elements in the progression of HIV disease, because both are predictive of disease progression and time to death (38Miedema F. Meyaard L. Koot M. Klein M.R. Roos M.Th.L. Groenink M. Fouchier R.A.M. Vant Wout A.B. Tersmette M. Schellekens P.Th.A. Schuitemaker H. Changing virus-host interactions in the course of HIV-1 infection.Immunol. Rev. 1994; 140: 35-72Crossref PubMed Scopus (136) Google Scholar, 17Dolan M.J. Clerici M. Blatt S.P. Hendrix C.W. Melcher G.P. Boswell R.N. Shearer G.M. A functional and phenotypic assessment of T-helper cells in HIV-1 infected patients offers independent prognostic information for survival.J. Infect. Dis. 1995; 172: 79-87Crossref PubMed Scopus (127) Google Scholar). This conclusion is supported by the recent demonstration of an inverse relation between HIV-specific Th activity and HIV viremia (50Rosenberg E.S. Billingsley J.M. Caliendo A.M. Boswell S.L. Sax P.E. Kalams S.A. Walker B.D. Vigorous HIV-1-specific CD4+ T cell responses associated with control of viremia.Science. 1997; 278: 1447-1450Crossref PubMed Scopus (1645) Google Scholar). Abnormalities in Th integrity span a range of parameters that include reduced IL-2 receptor expression (45Prince H.E. Kermani-Arab B. Fahey J.L. Depressed interleukin-2 receptor expression in acquired immune deficiency and lymphadenopathy syndromes.J. Immunol. 1984; 133: 1313-1317PubMed Google Scholar), preferential loss of the naive T cell subset (47Roederer M. Dubs J.G. Anderson M.T. Raju P.A. Herzenberg L.A. Herzenberg L.A. CD8 naive T cell counts decrease progressively in HIV-infected adults.J. Clin. Invest. 1995; 95: 2061-2066Crossref PubMed Scopus (388) Google Scholar), disturbance of the T cell Vβ repertoire (30Imberti L. Sottini A. Bettinardi A. Puoti M. Primi D. Selective depletion in HIV infection of T cells that bear specific T cell receptor Vβ sequences.Science. 1991; 254: 860-862Crossref PubMed Scopus (307) Google Scholar), and reduced expression of signal transduction and activators of transcription or STATs (43Pericle F. Pinto L.A. Hicks S. Kirken R.A. Sconocchia G. Rusnak J. Dolan M.J. Shearer G.M. Segal D. HIV-1 infection induces a selective reduction in STAT5 protein expression.J. Immunol. 1998; 160: 28-31PubMed Google Scholar). Although much attention is focused on the CD4+ Th, helper cell abnormalities may be secondary to aberrant signaling by HIV-infected APC (37Meyaard L. Schuitemaker H. Miedema F. T-cell dysfunction in HIV-infection - anergy due to defective antigen-presenting cell-function.Immunol. Today. 1993; 14: 161-164Abstract Full Text PDF PubMed Scopus (164) Google Scholar). It is clear that cytokines participate in the immune dysregulation of the syndrome. In vitro stimulation of blood leukocytes from HIV-infected (HIV+) patients results in decreased production of IL-2, interferon-γ (IFNγ), and IL-12 but increased production of IL-4 and IL-10 (reviewed in 53Shearer G.M. Clerici M. Type 1 and type 2 responses in HIV infection and exposure.in: Gupta S. Immunology of HIV Infection. Plenum Press, New York1996Google Scholar). Consistent with the murine (40Mosmann T.R. Coffman R.L. Th1 and Th2 cells different patterns of lymphokine secretion lead to different functional properties.Annu. Rev. Immunol. 1989; 7: 145-173Crossref PubMed Scopus (6662) Google Scholar) and human (48Romagnani S. Human TH1 and TH2 subsets doubt no more.Immunol. Today. 1991; 12: 256-258Abstract Full Text PDF PubMed Scopus (975) Google Scholar) Th1/Th2 models of cytokine-mediated immune regulation, the suggestion was made that HIV-induced immune dysregulation involves a Th1-to-Th2 cytokine shift (8Clerici M. Shearer G.M. TH1 → TH2 switch is a critical step in the etiology of HIV infection.Immunol. Today. 1993; 14: 107-111Abstract Full Text PDF PubMed Scopus (1230) Google Scholar). It is now known that HIV infection results in methylation of the IFNγ promoter, resulting in downregulation of IFNγ production (39Mikovits J.A. Young H.A. Vertino P. Issa J.-P.J. Pitha P.M. Turcoski-Corrales S. Taub D.D. Petrow C.L. Baylin S.B. Ruscetti F.W. Infection with human immunodeficiency virus type 1 upregulates DNA methyltransferase, resulting in de novo methylation of the gamma interferon (IFN-γ) promoter and subsequent downregulation of IFN-γ production.Mol. Cell. Biol. 1998; 18: 5166-5177Crossref PubMed Google Scholar). The nomenclature was changed to type 1 and type 2 cytokines because immunoregulatory cytokines other than IFNγ and IL-4 (the benchmark Th1 and Th2 cytokines) have been discovered, and because AIDS patients are more complex than clones of CD4+ T cells (9Clerici M. Shearer G.M. The Th1-Th2 hypothesis of HIV infection new insights.Immunol. Today. 1994; 15: 575-581Abstract Full Text PDF PubMed Scopus (639) Google Scholar). Type 1 cytokines predominantly upregulate cellular (Th1-like) responses and include IFNγ, IL-2, IL-12, IL-15, and IL-18. Type 2 cytokines mainly (but not exclusively) enhance (Th2-like) B cell responses such as allergy and hypereosinophilia and include IL-4, IL-5, IL-6, IL-10, and IL-13 (9Clerici M. Shearer G.M. The Th1-Th2 hypothesis of HIV infection new insights.Immunol. Today. 1994; 15: 575-581Abstract Full Text PDF PubMed Scopus (639) Google Scholar). The type 1/type 2 concept is based on immune function rather than on two cytokines produced by CD4+ T cell clones that define the Th1/Th2 model. The pathogenesis of HIV/AIDS can be divided into two broad categories: a direct infectious cytopathic effect of HIV infection of CD4+ T cells (viral pathogenesis) and indirect effects, in which immunopathogenesis is a major driving force (Figure 1) (reviewed in 32Levy J.A. Pathogenesis of human immunodeficiency virus infection.Microbiol. Rev. 1993; 57: 183-289Crossref PubMed Google Scholar, 42Pantaleo G. Fauci A.S. New concepts in the immunopathogenesis of HIV infection.Annu. Rev. Immunol. 1995; 13: 487-512Crossref PubMed Scopus (264) Google Scholar). Direct viral pathogenesis can occur by infection of the CD4+ T cells themselves or via an infected APC intermediate that passes the virus on to the T cells. Infection of CD4+ T cells can also occur via follicular dendritic cells that bind infectious HIV/anti-HIV complexes (27Heath S.L. Tew J.G. Tew J.G. Szakal A.K. Burton G.F. Follicular dendritic cells and human immunodeficiency virus infectivity.Nature. 1995; 377: 740-744Crossref PubMed Scopus (246) Google Scholar). Suggested immunopathogenic models include (1) HIV-specific CD8+ CTL that can kill HIV-infected CD4+ cells (59Zinkernagel R.M. Hengartner H. T-cell mediated immunopathology versus direct cytolysis by virus implications for HIV and AIDS.Immunol. Today. 1994; 15: 262-268Abstract Full Text PDF PubMed Scopus (197) Google Scholar); (2) autoimmune reactions, including autoantibodies that destroy the immune system (reviewed in 42Pantaleo G. Fauci A.S. New concepts in the immunopathogenesis of HIV infection.Annu. Rev. Immunol. 1995; 13: 487-512Crossref PubMed Scopus (264) Google Scholar); (3) immune suppression induced by HIV proteins such as gp120, Tat, or Nef (reviewed in 33Levy J.A. HIV and the Pathogenesis of AIDS, Second Edition. American Society of Microbiology, Washington, DC1998Google Scholar); (4) activation of APC and/or T cells, a characteristic of HIV disease (23Fuchs D. Hausen A. Reibnegger G. Werner E.R. Dierich M.P. Wachter H. Neopterin as a marker for activated cell-mediated immunity application in HIV infection.Immunol. Today. 1988; 9: 150-155Abstract Full Text PDF PubMed Scopus (579) Google Scholar, 29Ho H.-N. Hultin L.E. Mitsuyasu R.T. Matud J.L. Hausner M.A. Bockstoce D Chou C.-C. O'Rourke S. Taylor J.M.G. Giorgi J.V. Circulating HIV-specific CD8+ cytotoxic T cells express CD38 and HLA-DR antigens.J. Immunol. 1993; 150: 3070-3079PubMed Google Scholar); and (5) apoptotic T cell death (ATCD), suggested to contribute to the pathology of HIV disease (1Ameisen J.-C. Capron A. Cell dysfunction and depletion in AIDS the programmed cell death hypotheses.Immunol. Today. 1991; 12: 102-105Abstract Full Text PDF PubMed Scopus (483) Google Scholar; and reviewed in 21Finkel T.H. Banda N.K. Indirect mechanisms of HIV pathogenesis how does HIV kill T cells?.Curr. Opin. Immunol. 1994; 6: 605-615Crossref PubMed Scopus (103) Google Scholar, 41Oyaizu N. Pahwa S. Role of apoptosis in HIV disease pathogenesis.J. Clin. Immunol. 1995; 15: 217-231Crossref PubMed Scopus (76) Google Scholar). That activation of APC occurs in AIDS is supported by increased neopterin and IFNγ levels in patients' sera (reviewed in 23Fuchs D. Hausen A. Reibnegger G. Werner E.R. Dierich M.P. Wachter H. Neopterin as a marker for activated cell-mediated immunity application in HIV infection.Immunol. Today. 1988; 9: 150-155Abstract Full Text PDF PubMed Scopus (579) Google Scholar) as well as increased expression of CD40 on monocytes in HIV+ patients (7Chougnet C. Thomas E. Landay A.L. Kessler H.A. Buchbinder S. Scheer S. Shearer G.M. CD40 ligand and IFN-γ synergistically restore IL-12 production in HIV-infected patients.Eur. J. Immunol. 1998; 28: 646-656Crossref PubMed Scopus (44) Google Scholar). Furthermore, T cells, particularly the CD8+ subset, exhibit increased HLA-DR and CD38 expression (29Ho H.-N. Hultin L.E. Mitsuyasu R.T. Matud J.L. Hausner M.A. Bockstoce D Chou C.-C. O'Rourke S. Taylor J.M.G. Giorgi J.V. Circulating HIV-specific CD8+ cytotoxic T cells express CD38 and HLA-DR antigens.J. Immunol. 1993; 150: 3070-3079PubMed Google Scholar), also reflecting T cell activation. Elevated levels of CD38+CD8+ T cells are associated with reduced CD4+ T cell counts (24Giorgi J.V. Liu Z. Hultin L.E. Cumberland W.G. Hennessey K. Detels R. Elevated levels of CD38+CD8+ T cells in HIV infection add to the prognostic value of low CD4+ T cell levels results of 6 years of follow-up.J. Acq. Imm. Def. Syn. 1993; 6: 904-912Google Scholar), suggesting a connection between activation and disease progression. The mechanism(s) responsible for T cell activation in HIV+ patients remains to be elucidated. One suggestion is that some HIV peptides have superantigen-like properties (reviewed in 57Westby M. Manca F. Dalgleish A.G. The role of host immune responses in determining the outcome of HIV infection.Immunol. Today. 1996; 17: 120-126Abstract Full Text PDF PubMed Scopus (46) Google Scholar). Alternatively, HIV particles carry HLA-DR molecules, and these DR-bearing virions can interact with bacterial superantigens to activate T cells (51Rossio J.L. Bess Jr., J. Henderson L.E. Creswell P. Arthur L.O. HLA class II on HIV particles is functional in superantigen presentation to human T cells implications for HIV pathogenesis.AIDS Res. Hum. Retrov. 1995; 11: 1433-1439Crossref PubMed Scopus (59) Google Scholar). It is also possible that HIV proteins such as Tat, Nef, gp120, or gp120–anti-gp120 complexes, previously shown to induce immune suppression or cytokine dysregulation (reviewed in 33Levy J.A. HIV and the Pathogenesis of AIDS, Second Edition. American Society of Microbiology, Washington, DC1998Google Scholar), activate T cells. These signals could prime the T cells for ATCD in HIV+ patients. Increased T cell apoptosis is observed in unstimulated cultures of PBMC from HIV+ patients and is further increased by stimulation via the T cell receptor (TCR) with anti-CD3 or with specific antigens (reviewed in 21Finkel T.H. Banda N.K. Indirect mechanisms of HIV pathogenesis how does HIV kill T cells?.Curr. Opin. Immunol. 1994; 6: 605-615Crossref PubMed Scopus (103) Google Scholar, 41Oyaizu N. Pahwa S. Role of apoptosis in HIV disease pathogenesis.J. Clin. Immunol. 1995; 15: 217-231Crossref PubMed Scopus (76) Google Scholar). Stimulation through the TCR with pan–T cell activators induces death of both the CD4+ and CD8+ subsets in PBMC from infected patients. However, HIV-induced ATCD is more selective for the CD4+ subset when T cell activation is induced by recall antigens or through monocytes/macrophages (13Clerici M. Sarin A. Berzofsky J.A. Landay A.L. Kessler H.A. Hashemi F. Hendrix C.W. Blatt S.P. Rusnak J. Dolan M.J. et al.Antigen-stimulated apoptotic T cell death in HIV infection is selective for CD4+ T cells, modulated by cytokines and effected by lymphotoxin.AIDS. 1996; 10 (b): 603-611Crossref PubMed Scopus (65) Google Scholar, 4Badley A.D. Dockrell D. Simpson M. Schut R. Lynch D.H. Leibson P. Paya C.V. Macrophage-dependent apoptosis of CD4+ T lymphocytes from HIV-infected individuals is mediated by FasL and tumor necrosis factor.J. Exp. Med. 1997; 185: 55-64Crossref PubMed Scopus (214) Google Scholar). Thus, the involvement of APC in HIV-induced ATCD may be more selective for the CD4+ Th subset than is panactivation via the TCR. Characteristics of HIV-associated ATCD that suggest its contribution to the immunopathogenesis in HIV disease include the following: (1) type 1 but not type 2 cytokines protect against ATCD; (2) ATCD is seen mainly in uninfected rather than infected T cells; (3) gp120–anti-gp120 complexes can induce ATCD; (4) ATCD correlates with viral burden and inversely correlates with CD4 T cell levels; (5) increased expression of the Fas and FasL in HIV+ patients is associated with increased apoptotic death; (6) serum levels of lymphotoxin (TNFβ) and Fas are predictive for progression to AIDS; and (7) ATCD is not a characteristic of HIV-infected chimpanzees, a species that can be infected with HIV but rarely develops AIDS symptoms (reviewed in 14Clerici M. Sarin A. Henkart P.A. Shearer G.M. Apoptotic cell death and cytokine dysregulation in human immunodeficiency virus infection pivotal factors in disease progression.Cell Death Differ. 1997; 4: 699-706Crossref PubMed Scopus (13) Google Scholar). In vitro infection of monocytes/macrophages results in loss of accessory or APC function for stimulating T cell responses (20Ennen J. Seipp I. Norley S.G. Kurth R. Decreased accessory cell function of macrophages after infection with human immunodeficiency virus type 1 in vitro.Eur. J. Immunol. 1990; 20: 2451-2456Crossref PubMed Scopus (30) Google Scholar, 58Yoo J. Chen H. Kraus D. Hirsch D. Polyak S. George I. Sperber K. Altered cytokine production and accessory cell function after HIV-1 infection.J. Immunol. 1996; 157: 1313-1320PubMed Google Scholar) as well as in reduced expression of MHC class II (44Polyak S. Chen H. Hirsch D. George I. Hershberg R. Sperber K. Impaired class II expression and antigen uptake in monocytic cells after HIV-1 infection.J. Immunol. 1997; 159: 2177-2188PubMed Google Scholar) and decreased IL-12 and increased IL-10 expression/production (6Chougnet C. Clerici M. Shearer G.M. Role of IL-12 in HIV disease/AIDS.Res. Immunol. 1996; 147: 615-622Google Scholar). Monocytes from HIV+ patients exhibit decreased expression of MHC class II (11Clerici M. Landay A. Kessler H.A. Zajac R.A. Boswell R.N. Muluk S.C. Shearer G.M. Multiple patterns of alloantigen presenting/stimulating cell dysfunction in patients with AIDS.J. Immunol. 1991; 146: 2207-2213PubMed Google Scholar, 60Zwilling B.S. Salkowitz J. Laufman H. Pearl D. Differences in the expression of histocompatibility antigen-DR and in anti-mycobacterial activity of monocytes from HIV-infected individuals.AIDS. 1991; 5: 1327-1332Crossref PubMed Scopus (7) Google Scholar) as well as of the B7 costimulatory molecules CD80/86 (18Dudhane A. Conti B. Orlikowsky T. Wang Z.Q. Mangla N. Gupta A. Wormser G.P. Hoffmann M.K. Monocytes in HIV type-1 infected individuals lose expression of costimulatory B7 molecules and acquire cytotoxic activity.AIDS Res. Hum. Retro. 1996; 12 (a): 885-892Crossref PubMed Scopus (47) Google Scholar) and IL-12, but they exhibit increased expression of IL-10 (6Chougnet C. Clerici M. Shearer G.M. Role of IL-12 in HIV disease/AIDS.Res. Immunol. 1996; 147: 615-622Google Scholar). Thus, it is likely that the decreased expression of class II, CD80/86, and IL-12 and increased expression of IL-10 contribute to HIV-induced immune dysregulation through aberrant T cell signaling. Monocyte/macrophages that express reduced levels of MHC class II and CD80/86 can destroy CD4+ Th by antibody-dependent cellular cytotoxicity and may contribute to CD4+ T cell depletion in HIV disease by a gp120/anti-gp120 antigen/antibody complex–mediated mechanism (19Dudhane A. Wang Z.Q. Orlikowsky T. Gupta A. Wormser G.P. Horowitz H. Kufer P. Hoffmann M.K. AIDS patient monocytes target CD4 T cells for cellular conjugate formation and deletion through the membrane expression of HIV-1 envelope molecules.AIDS Res. Hum. Retro. 1996; 12 (b): 893-899Crossref PubMed Scopus (17) Google Scholar). Increased expression of Fas and the de novo appearance of FasL are also observed upon HIV infection of monocytic cells (3Badley A.D. McElhinny J.A. Leibson P.J. Lynch D.H. Alderson M.R. Paya C.V. Upregulation of Fas ligand expression by human immunodeficiency virus in human macrophages mediates apoptosis of uninfected T lymphocytes.J. Virol. 1996; 70: 199-206Crossref PubMed Google Scholar), and FasL expression is upregulated in HIV-infected differentiated macrophages (16Dockrell D.H. Badley A.D. Vallacian J.S. Heppelmann C.J. Algeciras A. Ziesmer S. Yagita H. Lynch D.H. Roche P.C. Leibson P.J. Paya C.V. The expression of Fas Ligand by macrophages and its upregulation by human immunodeficiency virus infection.J. Clin. Invest. 1998; 101: 2394-2405Crossref PubMed Scopus (104) Google Scholar). These observations indicate that the HIV-modified APC has an increased potential for Fas- and FasL-mediated apoptotic death. ATCD in HIV infection is dependent on monocytes/macrophages (4Badley A.D. Dockrell D. Simpson M. Schut R. Lynch D.H. Leibson P. Paya C.V. Macrophage-dependent apoptosis of CD4+ T lymphocytes from HIV-infected individuals is mediated by FasL and tumor necrosis factor.J. Exp. Med. 1997; 185: 55-64Crossref PubMed Scopus (214) Google Scholar) and involves a two-step mechanism that is gp120 dependent (15Cottrez F. Manca F. Dalgleish A.G. Arenzana-Seisdedos F. Capron A. Groux H. Priming of human CD4+ antigen-specific T cells to undergo apoptosis by HIV-infected monocytes. A two-step mechanism involving the gp120 molecule.J. Clin. Invest. 1997; 99: 257-266Crossref PubMed Scopus (79) Google Scholar). Thus, APC exhibiting a combination of the characteristics noted above would likely be efficient inducers of aberrant T cell signaling and increased T cell apoptosis. Such an APC is shown in the indirect immunopathogenic pathway in Figure 1. This modified APC might also be capable of contributing to the direct viral pathogenesis by infection as shown. The increased expression of FasL in lymphoid tissue of HIV+ patients appears not to be decreased after highly active antiretroviral therapy (HAART) (5Badley A.D. Dockrell D.H. Algeciras A. Ziesmer S. Landay A. Lederman M.M. Connick E. Kessler H. Kuritzkes D. Lynch D.H. et al.In vivo analysis of Fas/FasL interactions in HIV-infected patients.J. Clin. Invest. 1998; 102: 79-87Crossref PubMed Scopus (130) Google Scholar). This observation raises the possibility that antiviral therapy will be ineffective in reversing this APC abnormality and will have little or no long-term beneficial effect on APC-induced immunopathogenesis. Th1 and Th2 cells may be differentially susceptible to HIV-induced pathogenesis by different mechanisms (9Clerici M. Shearer G.M. The Th1-Th2 hypothesis of HIV infection new insights.Immunol. Today. 1994; 15: 575-581Abstract Full Text PDF PubMed Scopus (639) Google Scholar). Th1 cells are reported to be more susceptible to apoptosis than Th2 cells (46Ramsdell F. Seaman M.S. Miller R.E. Picha K.S. Kennedy M.K. Lynch D.H. Differential ability of Th1 and Th2 T cells to express Fas ligand and to undergo activation-induced cell death.Int. Immunol. 1994; 10: 1545-1553Crossref Scopus (315) Google Scholar, 55Varadhachary A.S. Perdow S.N. Hu C. Ramanarayanan M. Salgame P. Differential ability of T cell subsets to undergo activation-induced cell death.Proc. Natl. Acad. Sci. USA. 1997; 94: 5778-5783Crossref PubMed Scopus (168) Google Scholar), whereas Th2 cells appear to be more susceptible to HIV infection (34Maggi E. Mazzetti M. Ravina A. Annunziato F. de Carli M. Piccinni M.P. Manetti R. Carbonari M. Pesce A.M. del Prete G. Romagnani S. Ability of HIV to promote a Th1 to Th0 shift and to replicate preferentially in Th2 and Th0 cells.Science. 1994; 265: 244-248Crossref PubMed Scopus (442) Google Scholar, 56Vyakarnam A. Matear P.M. Martin S.J. Wagstaff M. Th1 cells specific for HIV-1 gag p24 are less efficient than Th0 cells in supporting HIV replication, and inhibit virus replication in Th0 cells.Immunology. 1995; 86: 85-96PubMed Google Scholar). These observations suggest that the two subsets of CD4+ Th are differentially susceptible to death by the direct and indirect mechanisms of HIV pathogenesis (Figure 2). The proportional representation of Th1-like and Th2-like function might change, depending on the balance of the direct and indirect pathogenic mechanisms of T cell death. This model raises the possibility that a cytokine shift favoring one Th subset may be due less to expansion of that subset than to accelerated death of the opposing subset. One of the more surprising and impressive aspects of the immunologic activity associated with HIV disease is the speed and strength with which HIV-specific cellular responses develop during acute HIV infection. Within days of documented introduction of the virus, T cells in the PBMC of acutely infected individuals can generate potent CD4-mediated Th activity and CD8-mediated CTL to HIV antigens (31Koup R.A. Safrit J.T. Cao Y. Andrews C.A. McLeod G. Borkowsky W. Farthing C. Ho D. Temporal association of cellular immune responses with the initial control of viremia in primary human immunodeficiency virus type 1 syndrome.J. Virol. 1994; 68: 4650-4655Crossref PubMed Google Scholar, 50Rosenberg E.S. Billingsley J.M. Caliendo A.M. Boswell S.L. Sax P.E. Kalams S.A. Walker B.D. Vigorous HIV-1-specific CD4+ T cell responses associated with control of viremia.Science. 1997; 278: 1447-1450Crossref PubMed Scopus (1645) Google Scholar). The CTL activity peak is coincident with the dramatic (frequently 103 to 104) drop in plasma virus titers, both of which occur weeks before the appearance of neutralizing serum antibodies (31Koup R.A. Safrit J.T. Cao Y. Andrews C.A. McLeod G. Borkowsky W. Farthing C. Ho D. Temporal association of cellular immune responses with the initial control of viremia in primary human immunodeficiency virus type 1 syndrome.J. Virol. 1994; 68: 4650-4655Crossref PubMed Google Scholar, 42Pantaleo G. Fauci A.S. New concepts in the immunopathogenesis of HIV infection.Annu. Rev. Immunol. 1995; 13: 487-512Crossref PubMed Scopus (264) Google Scholar). This kinetic pattern suggests that cellular immunity plays an important role in controlling the virus once infection has occurred. A question that is often asked is if HIV-specific cellular responses appear so rapidly and contribute to the dramatic reduction in plasma viremia, why does the immune system ultimately fail to control the infection? Several nonmutually exclusive possibilities have been suggested, including (1) retention of infectious virus particles sufficient to maintain a low level of infection, despite the dramatic decline in plasma viremia; (2) sequestration of HIV from immune surveillance; (3) a decline in the HIV-specific cellular response due to reduced HIV antigen expression that parallels the drop in plasma virus titer; (4) selective activation of HIV-specific T cells that are rendered more susceptible to HIV infection and viral pathogenesis; and (5) integration of HIV proviral DNA into infected host CD4+ cells that reappears as infectious virus after HIV-specific T cell immune function wanes or has been compromised (reviewed in 33Levy J.A. HIV and the Pathogenesis of AIDS, Second Edition. American Society of Microbiology, Washington, DC1998Google Scholar). Another possibility is the appearance of viral mutations that are not recognized by protective HIV-specific CTL (reviewed in 36McMichael A.J. Phillips R.E. Escape of human immunodeficiency virus from immune control.Annu. Rev. Immunol. 1997; 15: 271-296Crossref PubMed Scopus (281) Google Scholar). The HIV-specific Th response appears to be the first T cell response to be lost after HIV infection (10Clerici M. Stocks N.I. Zajac R.A. Boswell R.N. Bernstein D.C. Mann D.L. Shearer G.M. Berzofsky J.A. Interleukin-2 production used to detect antigenic peptide recognition by T-helper lymphocytes from asymptomatic HIV-seropositive individuals.Nature. 1989; 339: 383-385Crossref PubMed Scopus (190) Google Scholar, 38Miedema F. Meyaard L. Koot M. Klein M.R. Roos M.Th.L. Groenink M. Fouchier R.A.M. Vant Wout A.B. Tersmette M. Schellekens P.Th.A. Schuitemaker H. Changing virus-host interactions in the course of HIV-1 infection.Immunol. Rev. 1994; 140: 35-72Crossref PubMed Scopus (136) Google Scholar, 50Rosenberg E.S. Billingsley J.M. Caliendo A.M. Boswell S.L. Sax P.E. Kalams S.A. Walker B.D. Vigorous HIV-1-specific CD4+ T cell responses associated with control of viremia.Science. 1997; 278: 1447-1450Crossref PubMed Scopus (1645) Google Scholar). This event could be initiated by HIV-infected APC that exhibit the altered APC phenotype and present HIV antigens to virus-specific CD4+ Th (Figure 3). It is suggested that the signals transmitted from these modified APC to the HIV-specific Th clones, via reduced class II and/or CD80/86 expression as well as increased Fas and FasL expression, should result in their selective ATCD. This HIV-specific deletion of CD4+ Th cells could occur soon after HIV infection and before an appreciable proportion of T cells of other specificities become activated for ATCD. The effect would be an initial selective crippling of Th immunity to HIV antigens. After the early depletion of HIV-specific Th, repeated exposure to a spectrum of different antigens could gradually deplete CD4+ Th of these specificities over an extended period of time, similar to the mechanism shown for HIV in Figure 3. It is also known that HIV-associated ATCD can occur as a "bystander" phenomenon, killing uninfected T cells (22Finkel T.H. Tudor-Williams G. Banda N.K. Cotton M.F. Curiel T. Monks C. Baba T.W. Ruprecht R.M. Kupfer A. Apoptosis occurs predominantly in bystander cells and not in productively infected cells of HIV- and SIV-infected lymph nodes.Nat. Med. 1995; 1: 129-134Crossref PubMed Scopus (781) Google Scholar), and that monocytes/macrophages from infected patients can induce the death of uninfected, activated T cells (13Clerici M. Sarin A. Berzofsky J.A. Landay A.L. Kessler H.A. Hashemi F. Hendrix C.W. Blatt S.P. Rusnak J. 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With the current world-wide rate of HIV infection estimated to be 16,000 per day and more than 30 million individuals currently infected, two priorities of AIDS immunology are to determine the optimal conditions for generating an effective AIDS vaccine and establish protocols of immune-based therapy. The objective of a prophylactic vaccine is to prevent HIV infection. The goal of immune-based therapy is to enhance and/or redirect the immune systems of HIV+ individuals in whom successful viral infection has been established. Although these two priorities are sometimes discussed together, the optimal strategies to attain these goals may differ appreciably. Immunization intended to redirect the immune system while simultaneously interfering with immune activation and immunopathogenesis will likely require a different strategy than immunization of an uninfected population. AIDS researchers are seeking correlates of immune protection in both HIV+ and uninfected individuals to determine whether protective immunity can be developed against HIV. Analyses of the immune responses of individuals who appear to have prevented or controlled the infection might yield information that would be important for designing AIDS vaccines and developing immune-based therapy. These studies have concentrated on the immunologic profiles of three categories of individuals: (1) patients whose immune systems appear to reduce the virus titer during the acute phase of infection (31Koup R.A. Safrit J.T. Cao Y. Andrews C.A. McLeod G. Borkowsky W. Farthing C. Ho D. Temporal association of cellular immune responses with the initial control of viremia in primary human immunodeficiency virus type 1 syndrome.J. Virol. 1994; 68: 4650-4655Crossref PubMed Google Scholar, 50Rosenberg E.S. Billingsley J.M. Caliendo A.M. Boswell S.L. Sax P.E. Kalams S.A. Walker B.D. Vigorous HIV-1-specific CD4+ T cell responses associated with control of viremia.Science. 1997; 278: 1447-1450Crossref PubMed Scopus (1645) Google Scholar), (2) long-term nonprogressors who are HIV+ but remain without symptoms for more than 10 years (reviewed in 12Clerici M. Balotta C. Meroni L. Ferrario E. Riva C. Trabattoni D. Ridolfo A. Villa M. Shearer G.M. Moroni M. Galli M. Type 1 cytokine production and low prevalence of viral isolation correlate with long-term nonprogression in HIV infection.AIDS Res. Hum. Retro. 1996; 12 (a): 1053-1061Crossref PubMed Scopus (91) Google Scholar, 33Levy J.A. HIV and the Pathogenesis of AIDS, Second Edition. American Society of Microbiology, Washington, DC1998Google Scholar), and (3) exposed seronegative individuals who have had repeated parenteral exposure to HIV but have remained seronegative (reviewed in 52Rowland-Jones S.L. McMichael A. Immune responses in HIV-exposed seronegatives have they repelled the virus?.Curr. Opin. Immunol. 1995; 7: 448-455Crossref PubMed Scopus (165) Google Scholar, 54Shearer G.M. Clerici M. Protective immunity against HIV infection has nature done the experiment for us?.Immunol. Today. 1996; 17 (b): 21-24Abstract Full Text PDF PubMed Scopus (175) Google Scholar). A common immunologic denominator shared by all three cohorts is strong HIV-specific Th1-like immunity, as well as CD8-mediated HIV-specific CTL and anti-viral activity, in the absence of serum IgM or IgG antibodies to HIV. It is now known that HIV seronegative female sexual partners of HIV+ men not only have HIV-specific cellular responses to HIV but also can exhibit neutralizing vaginal and cervical IgA antibodies to HIV (35Mazzoli S. Trabattoni D. Lo Caputo S. Piconi S. Ble C. Meacci F. Ruzzante S. Salvi A. Semplici F. Longhi R. et al.HIV-specific mucosal and cellular immunity in HIV-seronegative partners of HIV-seropositive individuals.Nat. Med. 1997; 3: 1250-1257Crossref PubMed Scopus (375) Google Scholar). Taken together, such "experiments of nature" raise the possibility that an AIDS vaccine strategy that induces strong systemic cellular immunity, including T helper, T effector responses and mucosal IgA, can be protective against HIV infection and AIDS progression without inducing adverse immunologic outcomes. The 1996 International AIDS Conference in Vancouver, British Columbia, Canada, was filled with optimism that the anti-viral approaches of new drugs (protease inhibitors) and more drugs (HAART) would finally eliminate the virus and solve the AIDS problem. The 1998 International AIDS Conference in Geneva, Switzerland, projected a more somber atmosphere. Although therapy with combination antiretroviral drugs has recently resulted in dramatic improvement in the course of HIV disease (26Gulick R.M. Mellors J.W. Havlir D. Eron J.J. Gonzalez C. McMahon D. Richman D.D. Valentine F.T. Jonas L. Meibohm A. et al.Treatment with indinavir, zidovudine, and lamivudine in adults with human immunodeficiency virus infection and prior antiretroviral therapy.N. Engl. J. Med. 1997; 337: 734-739Crossref PubMed Scopus (1656) Google Scholar), several problems remain. These include high costs, side effects, complex dosing schedules, viral mutation, and marginal T cell responses to HIV antigens. Furthermore, despite President Clinton's directive of 1 year ago for the NIH to build an AIDS vaccine, the reality of an effective vaccine appears to be distant. It remains to be seen whether there will be a move among AIDS researchers toward immunology and whether there will be a move among experienced and insightful immunologists to become actively involved in HIV immunopathogenesis, immune-based therapy, and vaccine strategies. Without their expertise, erroneous immunologic decisions likely will be made, and the impressive achievements of basic immunology during the past quarter century will not be fully realized in the HIV disease setting. From an immunologist's perspective, AIDS can be viewed as a virus-initiated, viral product–induced, immune-mediated syndrome. Therefore, the "AIDS" acronym could be used as easily to describe A ctivated I mmune D ysregulatory S yndrome as A cquired I mmune D eficiency S yndrome. The author thanks Ms. Susan Payne for preparing and editing the manuscript; Drs. Claire Chougnet, Keith Fowke, Barbara Mittleman (National Institutes of Health), and Alan Landay (Rush Medical College, Chicago, Illinois) for reviewing the manuscript; and Dr. Michael Hoffmann (New York Medical College, Valhalla, New York) for helpful discussions.
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