T Cell Turnover in HIV-1 Disease
1997; Cell Press; Volume: 7; Issue: 5 Linguagem: Inglês
10.1016/s1074-7613(00)80379-9
ISSN1097-4180
AutoresMarc K. Hellerstein, Joseph M. McCune,
Tópico(s)T-cell and B-cell Immunology
ResumoA powerful "high turnover" model of human immunodeficiency virus type 1 (HIV-1) immunopathogenesis has been developed over the past several years (8Coffin J.M HIV population dynamics in vivo implications for genetic variation, pathogenesis and therapy.Science. 1995; 267: 483-489Crossref PubMed Scopus (1689) Google Scholar, 18Ho D Neumann A.U Perelson A.S Chen W Leonard J.M Markowitz M Rapid turnover of plasma virions and CD4 lymphocytes in HIV-1 infection.Nature. 1995; 373: 123-126Crossref PubMed Scopus (3789) Google Scholar, 62Wain-Hobson S Virological mayhem.Nature. 1995; 373: 102Crossref PubMed Scopus (62) Google Scholar, 63Wei X Ghosh S.K Taylor M.E Johnson V.A Emini E.A Deutsch P Lifson J.D Bonhoeffer S Nowak M.A Hahn B.H et al.Viral dynamics in human immunodeficiency virus type 1 infection.Nature. 1995; 373: 117-122Crossref PubMed Scopus (2914) Google Scholar, 42Perelson A.S Neumann A.U Markowitz M Leonard J.M Ho D.D HIV-1 dynamics in vivo virion clearance rate, infected cell life-span and viral generation time.Science. 1996; 271: 1582-1586Crossref PubMed Scopus (2813) Google Scholar, 43Perelson A.S Essunger P Cao Y Vesanen M Hurley A Saksela K Markowitz M Ho D Decay characteristics of HIV-1-infected compartments during combination therapy.Nature. 1997; 387: 188-191Crossref PubMed Scopus (1557) Google Scholar). This model differs from previous concepts of HIV-1 disease in its emphasis on the dynamic and quantitative aspects of HIV-1 and lymphocyte behavior. It has deservedly received great attention because it attempts to answer the central paradox of HIV-1 disease: the collapse of the immune system despite an apparently small number of infected target cells. The model also has profound therapeutic implications with respect to strategies by which viral resistance may be avoided, the possible value of early intervention, and the logic of immunostimulants. Here, we review the basic assumptions of this model and its underlying experimental evidence. We discuss aspects of T lymphocyte turnover in HIV-1 disease that are not explained by the model and propose an alternative way to think about them. Finally, we suggest some experiments to refine our exploration of key but unresolved questions about T cell dynamics in HIV-1 disease. The high turnover model of CD4+ T cell depletion has been developed by groups led by Ho (18Ho D Neumann A.U Perelson A.S Chen W Leonard J.M Markowitz M Rapid turnover of plasma virions and CD4 lymphocytes in HIV-1 infection.Nature. 1995; 373: 123-126Crossref PubMed Scopus (3789) Google Scholar, 42Perelson A.S Neumann A.U Markowitz M Leonard J.M Ho D.D HIV-1 dynamics in vivo virion clearance rate, infected cell life-span and viral generation time.Science. 1996; 271: 1582-1586Crossref PubMed Scopus (2813) Google Scholar, 43Perelson A.S Essunger P Cao Y Vesanen M Hurley A Saksela K Markowitz M Ho D Decay characteristics of HIV-1-infected compartments during combination therapy.Nature. 1997; 387: 188-191Crossref PubMed Scopus (1557) Google Scholar) and Shaw (63Wei X Ghosh S.K Taylor M.E Johnson V.A Emini E.A Deutsch P Lifson J.D Bonhoeffer S Nowak M.A Hahn B.H et al.Viral dynamics in human immunodeficiency virus type 1 infection.Nature. 1995; 373: 117-122Crossref PubMed Scopus (2914) Google Scholar) and has been elaborated by 8Coffin J.M HIV population dynamics in vivo implications for genetic variation, pathogenesis and therapy.Science. 1995; 267: 483-489Crossref PubMed Scopus (1689) Google Scholar, 62Wain-Hobson S Virological mayhem.Nature. 1995; 373: 102Crossref PubMed Scopus (62) Google Scholar, and others. Its central assertions are that HIV-1 induces CD4+ T cell destruction at a very high rate (i.e., 1–2 × 109 cells/day) and that the resulting demand on CD4+ T cell proliferation ultimately results in collapse of the immune system. Accordingly, it places virus-induced CD4+ T cell destruction as the central event in HIV-1 immunopathogenesis. This model is based on several lines of evidence, including the following: rates of change in plasma viral concentrations and CD4+ T cell counts after the initiation of highly active antiretroviral therapy (HAART) in advanced HIV-1 disease (18Ho D Neumann A.U Perelson A.S Chen W Leonard J.M Markowitz M Rapid turnover of plasma virions and CD4 lymphocytes in HIV-1 infection.Nature. 1995; 373: 123-126Crossref PubMed Scopus (3789) Google Scholar, 63Wei X Ghosh S.K Taylor M.E Johnson V.A Emini E.A Deutsch P Lifson J.D Bonhoeffer S Nowak M.A Hahn B.H et al.Viral dynamics in human immunodeficiency virus type 1 infection.Nature. 1995; 373: 117-122Crossref PubMed Scopus (2914) Google Scholar, 42Perelson A.S Neumann A.U Markowitz M Leonard J.M Ho D.D HIV-1 dynamics in vivo virion clearance rate, infected cell life-span and viral generation time.Science. 1996; 271: 1582-1586Crossref PubMed Scopus (2813) Google Scholar, 43Perelson A.S Essunger P Cao Y Vesanen M Hurley A Saksela K Markowitz M Ho D Decay characteristics of HIV-1-infected compartments during combination therapy.Nature. 1997; 387: 188-191Crossref PubMed Scopus (1557) Google Scholar); the large number of viral quasispecies present in individuals with HIV-1 infection and the rate of emergence of drug-resistant viral strains during the progression of disease and after the initiation of antiretroviral therapy (7Coffin J Genetic diversity and evolution of retroviruses.Curr. Topics Microbiol. 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The predictions suggested by this model have far-reaching implications for both theoretical views about and therapeutic approaches toward HIV-1 disease. It is posited that absolute CD4+ T cell turnover rates are high early in the course of HIV-1 disease when CD4+ T cell counts are normal and that CD4+ T cell turnover correlates with plasma viral load. It follows that the main impact of HAART will be to slow the rate of cell destruction. Intuitively, this conceptual framework makes sense, but its predictions are based on several assumptions that remain unsupported by direct experimental proof. First, it assumes that changes in circulating CD4+ T cell numbers represent changes in whole-body T cell turnover rather than changes in T cell distribution between blood and tissues. Several workers (11Dimitrov D.S Martin M.A CD4 turnover [letter].Nature. 1995; 375: 194-195Crossref PubMed Scopus (13) Google Scholar, 38Mosier D.E CD4 turnover [letter].Nature. 1995; 375: 193-194Crossref PubMed Scopus (58) Google Scholar, 57Sprent J Tough D CD4 turnover [letter].Nature. 1995; 375: 194Crossref PubMed Scopus (9) Google Scholar) have pointed out that "viral trapping," hormones of stress, or other factors could alter the distribution of lymphocytes between lymphoid organs and the peripheral circulation. If antiviral therapy results in a change in T cell distribution, inferences about turnover would not be justified from measurements of circulating T cell numbers alone. Second, the model assumes that rising CD4+ T cell counts associated with HAART (18Ho D Neumann A.U Perelson A.S Chen W Leonard J.M Markowitz M Rapid turnover of plasma virions and CD4 lymphocytes in HIV-1 infection.Nature. 1995; 373: 123-126Crossref PubMed Scopus (3789) Google Scholar, 63Wei X Ghosh S.K Taylor M.E Johnson V.A Emini E.A Deutsch P Lifson J.D Bonhoeffer S Nowak M.A Hahn B.H et al.Viral dynamics in human immunodeficiency virus type 1 infection.Nature. 1995; 373: 117-122Crossref PubMed Scopus (2914) Google Scholar, 42Perelson A.S Neumann A.U Markowitz M Leonard J.M Ho D.D HIV-1 dynamics in vivo virion clearance rate, infected cell life-span and viral generation time.Science. 1996; 271: 1582-1586Crossref PubMed Scopus (2813) Google Scholar) reflect a decreased rate of cell destruction (lower turnover) rather than an increased rate of cell production. Since HIV-1 infection has adverse effects on central hematopoietic organs (e.g., bone marrow and thymus) (30McCune J.M HIV-1 the infective process in vivo.Cell. 1991; 64: 351-363Abstract Full Text PDF PubMed Scopus (97) Google Scholar, 31McCune, J.M., and Kaneshima, H. (1995). The hematopathology of HIV-1 disease: experimental analysis in vivo. In Human Hematopoiesis in SCID Mice, M.-G. Roncarolo and B. Peault, eds. (Austin, TX: R. G. Landes), pp. 129–156.Google Scholar), the rate of CD4+ T cell production prior to antiretroviral therapy need not be identical to that found after therapy. Indeed, if effective antiretroviral therapy facilitates the production of peripheral CD4+ T cells, the production rate before therapy may be lower. Third, the model assumes that the kinetics of cell and viral turnover observed in late disease can be extrapolated to early disease. However, lymphopenic states have previously been correlated with prolonged survival and a tendency for marked clonal expansion of the remaining lymphocyte pool (48Rocha B Freitas A Coutinho A.A Population dynamics of T lymphocytes, renewal rate and expansion in the peripheral lymphoid organs.J. Immunol. 1983; 131: 2158-2164PubMed Google Scholar, 37Miller R.A Stutman O T cell repopulation from functionally restricted splenic progenitors 10,000-fold expansion documented by using limiting dilution analysis.J. Immunol. 1984; 133: 2925-2932PubMed Google Scholar, 47Rocha B Population kinetics of precursors of IL-2 producing peripheral T lymphocytes evidence for short life-expectancy, continuous renewal and post-thymic expansion.J. Immunol. 1987; 139: 365-372PubMed Google Scholar, 13Freitas A.A Rocha B.B Lymphocyte lifespans homeostasis, selection and competition.Immunol. 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It may therefore be misleading to extrapolate kinetic results about lymphocytes or viral turnover from one end of the disease spectrum to the other. Finally, the high turnover model assumes that normal rates of CD4+ T cell turnover are known, for comparison to rates in HIV infection (36Michie C McLean A Alcock C Beverley P.C.L Lifespan of human lymphocyte subsets defined by CD45 isoforms.Nature. 1992; 360: 264-265Crossref PubMed Scopus (576) Google Scholar, 32McLean A.R Michie C.A In vivo estimates of division and death rates of human T lymphocytes.Proc. Natl. Acad. Sci. USA. 1995; 92: 3707-3711Crossref PubMed Scopus (243) Google Scholar, 28Mackall C.L Hakim F.T Gress R.E T-cell regeneration all repertoires are not created equal.Immunol. 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In sum, there is little or no basis for the conclusion that chronic demand on the T cell production system is greatly elevated above normal levels in HIV-1 infection, thereby taxing the proliferative reserve of the immune system (the "open drain" model18Ho D Neumann A.U Perelson A.S Chen W Leonard J.M Markowitz M Rapid turnover of plasma virions and CD4 lymphocytes in HIV-1 infection.Nature. 1995; 373: 123-126Crossref PubMed Scopus (3789) Google Scholar). In fact, recent studies (64Wolthers K Bea G Wisman G Otto S Husman A.M Scheft N de Wolf K Goudsmit J Coutinho R van der Zee A Meyaard L et al.T cell telomere length in HIV-1 infection no evidence for increased CD4+ T cell turnover.Science. 1996; 274: 1543-1547Crossref PubMed Scopus (238) Google Scholar, 40Palmer L.D Weng N.-P Levine B.L June C.H Lane H.C Hodes R.J Telomere length, telomerase activity, and replicative potential in HIV infection analysis of CD4+ and CD8+ T cells from HIV-discordant monozygotic twins.J. Exp. Med. 1997; 185: 1381-1386Crossref PubMed Scopus (116) Google Scholar) have failed to provide evidence for increased CD4+ T cell turnover during the course of HIV-1 disease. These studies have used an indirect method for assessing cell replication: measurement of telomeric terminal restriction fragment (TRF) length as an index of replicative history. This approach does not provide a definitive answer to the question; if anything, it underscores the current limitations in measuring lymphocyte dynamics in vivo. The TRF method is based on the observation that each round of cell division results in loss of telomeric sequence due to the inability of DNA polymerase to replicate completely the 5′ end of the chromosome. Cells that have progressed through many mitoses exhibit a greater degree of TRF shortening than do those that have divided less often. 64Wolthers K Bea G Wisman G Otto S Husman A.M Scheft N de Wolf K Goudsmit J Coutinho R van der Zee A Meyaard L et al.T cell telomere length in HIV-1 infection no evidence for increased CD4+ T cell turnover.Science. 1996; 274: 1543-1547Crossref PubMed Scopus (238) Google Scholar compared TRF lengths over time in CD4+ and CD8+ T cell populations from HIV-1–seropositive and HIV-1–seronegative subjects, and 40Palmer L.D Weng N.-P Levine B.L June C.H Lane H.C Hodes R.J Telomere length, telomerase activity, and replicative potential in HIV infection analysis of CD4+ and CD8+ T cells from HIV-discordant monozygotic twins.J. Exp. Med. 1997; 185: 1381-1386Crossref PubMed Scopus (116) Google Scholar compared TRF lengths in these cell populations from HIV-1–discordant monozygotic twins. In both studies, TRF lengths in CD4+ T cells from HIV-1–seropositive subjects tended to be longer than in CD8+ T cells from the same individual; in the study by Palmer et al., TRF lengths in CD4+ T cells from HIV-1–seropositive donors were actually longer than those found in HIV-1–seronegative twins. These results clearly document differential population dynamics of CD4+ and CD8+ T cells in HIV-1–infected subjects and could be interpreted to mean that the turnover of CD4+ T cells is equivalent to, or even slower than, that found in HIV-uninfected subjects. The problem with this approach is that it cannot account for T cells that have been destroyed. If proliferating target cells are destroyed (15Gowda S.D Stein B.S Mohagheghpour N Benike C.J Engleman E.G Evidence that T cell activation is required for HIV-1 entry into CD4 lymphocytes.J. 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Indeed, the absence of any TRF shortening in CD4+ T cells from HIV-1–seropositive subjects (64Wolthers K Bea G Wisman G Otto S Husman A.M Scheft N de Wolf K Goudsmit J Coutinho R van der Zee A Meyaard L et al.T cell telomere length in HIV-1 infection no evidence for increased CD4+ T cell turnover.Science. 1996; 274: 1543-1547Crossref PubMed Scopus (238) Google Scholar, 40Palmer L.D Weng N.-P Levine B.L June C.H Lane H.C Hodes R.J Telomere length, telomerase activity, and replicative potential in HIV infection analysis of CD4+ and CD8+ T cells from HIV-discordant monozygotic twins.J. Exp. Med. 1997; 185: 1381-1386Crossref PubMed Scopus (116) Google Scholar) could simply reflect preferential, HIV-1–mediated destruction of proliferating CD4+ T cells. The TRF results thus do not exclude any model of HIV-1 pathogenesis: the absolute rate of CD4+ T cell production in the body could be high, low, or normal. As recently reviewed by 28Mackall C.L Hakim F.T Gress R.E T-cell regeneration all repertoires are not created equal.Immunol. Today. 1997; 18 (a): 245-251Abstract Full Text PDF PubMed Scopus (214) Google Scholar, T cell populations in advanced HIV-1 disease share several characteristics with athymic peripheral expansions found in other settings: depletion of naive relative to memory T cell subsets; restricted diversity of the T cell receptor (TCR) repertoire; a greater proportion of CD8+ compared with CD4+ T cells; low CD4+ T cell number; and reduced functional competence of the T lymphocyte system. Although the high turnover model has focused primarily on changes in total CD4+ T cell numbers, these features of HIV-1–associated T cell pathology require explanation as well. 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Thus, HIV-1 infection may effectively remove or render dysfunctional those signals necessary for the survival of naive cells (e.g., those mediated by major histocompatibility complex class II antigens in the case of naive CD4+ T cells) (60Takeda S Rodewald H.R Arakawa H Bluethmann H Shimiza T MHC class II molecules are not required for survival of newly generated CD4+ T cells, but affect their long-term life-span.Immunity. 1996; 5: 217-228Abstract Full Text Full Text PDF PubMed Scopus (321) Google Scholar, 52Rooke R Waltzinger C Benoist C Mathis D Targeted complementation of MHC class II deficiency by intrathymic delivery of recombinant adenoviruses.Immunity. 1997; 7: 123-134Abstract Full Text Full Text PDF PubMed Scopus (182) Google Scholar). Alternatively, HIV-1–mediated destruction of more mature memory CD4+ T cells may drive accelerated maturation through the naive CD4+ T cell pool. In either scenario, naive T cells would not be destroyed by HIV-1 per se but instead would be lost by attrition or simply by maturation. Another feature of T lymphopoiesis in HIV-1 disease is the marked alterations in various subpopulations of CD8+ T cells, including a late decrease in memory CD8+ T cell number as well as an early depletion of naive CD8+ T cells (35Meyaard L Otto S.A Hooibrink B Miedema F Quantitative analysis of CD4+ T cell function in the course of human immunodeficiency virus infection gradual decline of both naive and memory alloreactive T cells.J. Clin. Invest. 1994; 94: 1947-1952Crossref PubMed Scopus (47) Google Scholar, 45Rabin R.L Roederer M Maldonado Y Petru A Herzenberg L.A Herzenberg L.A Altered representation of naive and memory CD8 T cell subsets in
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