Subscribe to RSS
Please copy the URL and add it into your RSS Feed Reader.
https://www.thieme-connect.de/rss/thieme/en/10.1055-s-00000069.xml
Download PDF
Semin Liver Dis 2003; 23(2): 115-124
DOI: 10.1055/s-2003-39942
DOI: 10.1055/s-2003-39942
Natural History and Pathogenesis of Human Immunodeficiency Virus Infection
Further Information
Publication History
Publication Date:
11 June 2003 (online)
ABSTRACT
In this article, we discuss how human immunodeficiency virus (HIV) infection of activated CD4+ cells, expressing the chemokine receptors CCR5 or CXCR4, results in severe immunosuppression while evading the immune response. We describe how infection through mucosal surfaces or via the parenteral route results in rapid spread of the virus throughout the body prior to a vigorous CD8+ cytolytic T cell response, resulting in establishment of a viral set point. Data is examined that suggests the half-life of HIV virions in circulation is less than 6 hours and possibly as short as 30 minutes, whereas that of infected CD4 T cells is on average 1 to 1.5 days. We also explain how the rate of viral replication dictates the rate at which HIV evades the immune response and the rapidity with which resistance to antiviral medications may develop. Lastly, we show how anatomic and cellular reservoirs of latent viral pools have made the long-term goal of complete virus eradication difficult despite enormous advances in our therapeutic armamentarium.
KEYWORDS
HIV pathogenesis - antiviral immunity - viral kinetics - reservoirs
REFERENCES
- 1 Hogg R, Cahn P, Katabira E T. et al . Time to act: global apathy towards HIV/AIDS is a crime against humanity. Lancet . 2002; 360 1710-1711
- 2 Dalgleish A G, Beverley P C, Clapham P R. et al . The CD4 (T4) antigen is an essential component of the receptor for the AIDS retrovirus. Nature . 1984; 312 763-767
- 3 Klatzmann D, Champagne E, Chamaret S. et al . T-lymphocyte T4 molecule behaves as the receptor for human retrovirus LAV. Nature . 1984; 312 767-768
- 4 Klatzmann D, Barre-Sinoussi F, Nugeyre M T. et al . Selective tropism of lymphadenopathy associated virus (LAV) for helper-inducer T lymphocytes. Science . 1984; 225 59-63
- 5 Maddon P J, Dalgleish A G, McDougal J S. et al . The T4 gene encodes the AIDS virus receptor and is expressed in the immune system and the brain. Cell . 1986; 47 333-348
- 6 Alkhatib G, Liao F, Berger E A, Farber J M, Peden K W. A new SIV co-receptor, STRL33. Nature . 1997; 388 238
- 7 Liao F, Alkhatib G, Peden K W. et al . STRL33, a novel chemokine receptor-like protein, functions as a fusion cofactor for both macrophage-tropic and T cell line-tropic HIV-1. J Exp Med . 1997; 185 2015-2023
- 8 Rucker J, Edinger A L, Sharron M. et al . Utilization of chemokine receptors, orphan receptors, and herpesvirus-encoded receptors by diverse human and simian immunodeficiency viruses. J Virol . 1997; 71 8999-9007
- 9 Hill C M, Deng H, Unutmaz D. et al . Envelope glycoproteins from human immunodeficiency virus types 1 and 2 and simian immunodeficiency virus can use human CCR5 as a coreceptor for viral entry and make direct CD4-dependent interactions with this chemokine receptor. J Virol . 1997; 71 6296-6304
- 10 Trkola A, Dragic T, Arthos J. et al . CD4-dependent, antibody-sensitive interactions between HIV-1 and its co-receptor CCR-5. Nature . 1996; 384 184-187
- 11 Wu L, Gerard N P, Wyatt R. et al . CD4-induced interaction of primary HIV-1 gp120 glycoproteins with the chemokine receptor CCR-5. Nature . 1996; 384 179-183
- 12 Lapham C K, Ouyang J, Chandrasekhar B. et al . Evidence for cell-surface association between fusin and the CD4-gp120 complex in human cell lines. Science . 1996; 274 602-605
- 13 Spira A I, Marx P A, Patterson B K. et al . Cellular targets of infection and route of viral dissemination after an intravaginal inoculation of simian immunodeficiency virus into rhesus macaques. J Exp Med . 1996; 183 215-225
- 14 Geijtenbeek T B, Kwon D S, Torensma R. et al . DC-SIGN, a dendritic cell-specific HIV-1-binding protein that enhances trans-infection of T cells. Cell . 2000; 100 587-597
- 15 Embretson J, Zupancic M, Ribas J L. et al . Massive covert infection of helper T lymphocytes and macrophages by HIV during the incubation period of AIDS. Nature . 1993; 362 359-362
- 16 Chakrabarti L, Isola P, Cumont M C. et al . Early stages of simian immunodeficiency virus infection in lymph nodes. Evidence for high viral load and successive populations of target cells. Am J Pathol . 1994; 144 1226-1237
- 17 Reimann K A, Tenner-Racz K, Racz P. et al . Immunopathogenic events in acute infection of rhesus monkeys with simian immunodeficiency virus of macaques. J Virol . 1994; 68 2362-2370
- 18 Daar E S, Moudgil T, Meyer R D, Ho D D. Transient high levels of viremia in patients with primary human immunodeficiency virus type 1 infection. N Engl J Med . 1991; 324 961-964
- 19 Lyles R H, Munoz A, Yamashita T E. et al . Natural history of human immunodeficiency virus type 1 viremia after seroconversion and proximal to AIDS in a large cohort of homosexual men. Multicenter AIDS Cohort Study. J Infect Dis . 2000; 181 872-880
- 20 Mellors J W, Kingsley L A, Rinaldo Jr R C. et al . Quantitation of HIV-1 RNA in plasma predicts outcome after seroconversion. Ann Intern Med . 1995; 122 573-579
- 21 Pantaleo G, Graziosi C, Demarest J F. et al . HIV infection is active and progressive in lymphoid tissue during the clinically latent stage of disease. Nature . 1993; 362 355-358
- 22 Pantaleo G, Graziosi C, Butini L. et al . Lymphoid organs function as major reservoirs for human immunodeficiency virus. Proc Natl Acad Sci USA . 1991; 88 9838-9842
- 23 Perelson 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 1582-1586
- 24 Wei X, Ghosh S K, Taylor M E. et al . Viral dynamics in human immunodeficiency virus type 1 infection. Nature . 1995; 373 117-122
- 25 Ho D D, Neumann A U, Perelson A S. et al . Rapid turnover of plasma virions and CD4 lymphocytes in HIV-1 infection. Nature . 1995; 373 123-126
- 26 Lifson A R, Rutherford G W, Jaffe H W. The natural history of human immunodeficiency virus infection. J Infect Dis . 1988; 158 1360-1367
- 27 Munoz A, Wang M C, Bass S. et al . Acquired immunodeficiency syndrome (AIDS)-free time after human immunodeficiency virus type 1 (HIV-1) seroconversion in homosexual men. Multicenter AIDS Cohort Study Group. Am J Epidemiol . 1989; 130 530-539
- 28 Jason J, Lui K J, Ragni M V, Hessol N A, Darrow W W. Risk of developing AIDS in HIV-infected cohorts of hemophilic and homosexual men. JAMA . 1989; 261 725-727
- 29 Buchbinder S P, Katz M H, Hessol N A, O'Malley P M, Holmberg S D. Long-term HIV-1 infection without immunologic progression. AIDS . 1994; 8 1123-1128
- 30 Cao Y, Qin L, Zhang L, Safrit J, Ho D D. Virologic and immunologic characterization of long-term survivors of human immunodeficiency virus type 1 infection. N Engl J Med . 1995; 332 201-208
- 31 Pantaleo G, Menzo S, Vaccarezza M. et al . Studies in subjects with long-term nonprogressive human immunodeficiency virus infection. N Engl J Med . 1995; 332 209-216
- 32 Koup R A, Safrit J T, Cao Y. et al . Temporal association of cellular immune responses with the initial control of viremia in primary human immunodeficiency virus type 1 syndrome. J Virol . 1994; 68 4650-4655
- 33 Borrow P, Lewicki H, Hahn B H, Shaw G M, Oldstone M B. Virus-specific CD8+ cytotoxic T-lymphocyte activity associated with control of viremia in primary human immunodeficiency virus type 1 infection. J Virol . 1994; 68 6103-6110
- 34 Wilson J D, Ogg G S, Allen R L. et al . Direct visualization of HIV-1-specific cytotoxic T lymphocytes during primary infection. AIDS . 2000; 14 225-233
- 35 McMichael A J, Rowland-Jones S L. Cellular immune responses to HIV. Nature . 2001; 410 980-987
- 36 Ogg G S, Jin X, Bonhoeffer S. et al . Quantitation of HIV-1-specific cytotoxic T lymphocytes and plasma load of viral RNA. Science . 1998; 279 2103-2106
- 37 Klein M R, van Baalen A C, Holwerda A M. et al . Kinetics of Gag-specific cytotoxic T lymphocyte responses during the clinical course of HIV-1 infection: a longitudinal analysis of rapid progressors and long-term asymptomatics. J Exp Med . 1995; 181 1365-1372
- 38 Rinaldo C, Huang X L, Fan Z F. et al . High levels of anti-human immunodeficiency virus type 1 (HIV-1) memory cytotoxic T-lymphocyte activity and low viral load are associated with lack of disease in HIV-1-infected long-term nonprogressors. J Virol . 1995; 69 5838-5842
- 39 Brodie S J, Patterson B K, Lewinsohn D A. et al . HIV-specific cytotoxic T lymphocytes traffic to lymph nodes and localize at sites of HIV replication and cell death. J Clin Invest . 2000; 105 1407-1417
- 40 Schmitz J E, Kuroda M J, Santra S. et al . Control of viremia in simian immunodeficiency virus infection by CD8+ lymphocytes. Science . 1999; 283 857-860
- 41 Jin X, Bauer D E, Tuttleton S E. et al . Dramatic rise in plasma viremia after CD8(+) T cell depletion in simian immunodeficiency virus-infected macaques. J Exp Med . 1999; 189 991-998
- 42 Cocchi F, DeVico A L, Garzino-Demo A. et al . Identification of RANTES, MIP-1 alpha, and MIP-1 beta as the major HIV-suppressive factors produced by CD8+ T cells. Science . 1995; 270 1811-1815
- 43 Wagner L, Yang O O, Garcia-Zepeda E A. et al . Beta-chemokines are released from HIV-1-specific cytolytic T-cell granules complexed to proteoglycans. Nature . 1998; 391 908-911
- 44 Samson M, Labbe O, Mollereau C, Vassart G, Parmentier M. Molecular cloning and functional expression of a new human CC-chemokine receptor gene. Biochemistry . 1996; 35 3362-3367
- 45 Combadiere C, Ahuja S K, Tiffany H L, Murphy P M. Cloning and functional expression of CC CKR5, a human monocyte CC chemokine receptor selective for MIP-1(alpha), MIP-1(beta), and RANTES. J Leukoc Biol . 1996; 60 147-152
- 46 Hadida F, Vieillard V, Autran B. et al . HIV-specific T cell cytotoxicity mediated by RANTES via the chemokine receptor CCR3. J Exp Med . 1998; 188 609-614
- 47 Zhang L, Yu W, He T. et al . Contribution of human alpha-defensin 1, 2, and 3 to the anti-HIV-1 activity of CD8 antiviral factor. Science . 2002; 298 995-1000
- 48 Matloubian M, Concepcion R J, Ahmed R. CD4+ T cells are required to sustain CD8+ cytotoxic T-cell responses during chronic viral infection. J Virol . 1994; 68 8056-8063
- 49 Zajac A J, Blattman J N, Murali-Krishna K. et al . Viral immune evasion due to persistence of activated T cells without effector function. J Exp Med . 1998; 188 2205-2213
- 50 Clerici M, Stocks N I, Zajac R A. et al . Detection of three distinct patterns of T helper cell dysfunction in asymptomatic, human immunodeficiency virus-seropositive patients. Independence of CD4+ cell numbers and clinical staging. J Clin Invest . 1989; 84 1892-1899
- 51 Rosenberg E S, Billingsley J M, Caliendo A M. et al . Vigorous HIV-1-specific CD4+ T cell responses associated with control of viremia. Science . 1997; 278 1447-1450
- 52 Schwartz D, Sharma U, Busch M. et al . Absence of recoverable infectious virus and unique immune responses in an asymptomatic HIV+ long-term survivor. AIDS Res Hum Retroviruses . 1994; 10 1703-1711
- 53 Rosenberg E S, Altfeld M, Poon S H. et al . Immune control of HIV-1 after early treatment of acute infection. Nature . 2000; 407 523-526
- 54 Autran B, Carcelain G, Li T S. et al . Positive effects of combined antiretroviral therapy on CD4+ T cell homeostasis and function in advanced HIV disease. Science . 1997; 277 112-116
- 55 Kelleher A D, Carr A, Zaunders J, Cooper D A. Alterations in the immune response of human immunodeficiency virus (HIV)-infected subjects treated with an HIV-specific protease inhibitor, ritonavir. J Infect Dis . 1996; 173 321-329
- 56 Mascola J R, Stiegler G, Van Cott C T. et al . Protection of macaques against vaginal transmission of a pathogenic HIV-1/SIV chimeric virus by passive infusion of neutralizing antibodies. Nat Med . 2000; 6 207-210
- 57 Baba T W, Liska V, Hofmann-Lehmann R. et al . Human neutralizing monoclonal antibodies of the IgG1 subtype protect against mucosal simian-human immunodeficiency virus infection. Nat Med . 2000; 6 200-206
- 58 Lifson A R, Buchbinder S P, Sheppard H W. et al . Long-term human immunodeficiency virus infection in asymptomatic homosexual and bisexual men with normal CD4+ lymphocyte counts: immunologic and virologic characteristics. J Infect Dis . 1991; 163 959-965
- 59 Barker E, Mackewicz C E, Reyes-Teran G. et al . Virological and immunological features of long-term human immunodeficiency virus-infected individuals who have remained asymptomatic compared with those who have progressed to acquired immunodeficiency syndrome. Blood . 1998; 92 3105-3114
- 60 Gandhi R T, Walker B D. Immunologic control of HIV-1. Annu Rev Med . 2002; 53 149-172
- 61 Moore J P, Parren P W, Burton D R. Genetic subtypes, humoral immunity, and human immunodeficiency virus type 1 vaccine development. J Virol . 2001; 75 5721-5729
- 62 Wyatt R, Sodroski J. The HIV-1 envelope glycoproteins: fusogens, antigens, and immunogens. Science . 1998; 280 1884-1888
- 63 Goulder P J, Phillips R E, Colbert R A. et al . Late escape from an immunodominant cytotoxic T-lymphocyte response associated with progression to AIDS. Nat Med . 1997; 3 212-217
- 64 Price D A, Goulder P J, Klenerman P. et al . Positive selection of HIV-1 cytotoxic T lymphocyte escape variants during primary infection. Proc Natl Acad Sci USA . 1997; 94 1890-1895
- 65 Borrow P, Lewicki H, Wei X. et al . Antiviral pressure exerted by HIV-1-specific cytotoxic T lymphocytes (CTLs) during primary infection demonstrated by rapid selection of CTL escape virus. Nat Med . 1997; 3 205-211
- 66 Evans D T, O'Connor D H, Jing P. et al . Virus-specific cytotoxic T-lymphocyte responses select for amino-acid variation in simian immunodeficiency virus Env and Nef. Nat Med . 1999; 5 1270-1276
- 67 Roberts J D, Bebenek K, Kunkel T A. The accuracy of reverse transcriptase from HIV-1. Science . 1988; 242 1171-1173
- 68 Preston B D, Poiesz B J, Loeb L A. Fidelity of HIV-1 reverse transcriptase. Science . 1988; 242 1168-1171
- 69 Coffin J M. HIV population dynamics in vivo: implications for genetic variation, pathogenesis, and therapy. Science . 1995; 267 483-489
- 70 Goulder P J, Brander C, Tang Y. et al . Evolution and transmission of stable CTL escape mutations in HIV infection. Nature . 2001; 412 334-338
- 71 Wong J K, Hezareh M, Gunthard H F. et al . Recovery of replication-competent HIV despite prolonged suppression of plasma viremia. Science . 1997; 278 1291-1295
- 72 Collins K L, Chen B K, Kalams S A, Walker B D, Baltimore D. HIV-1 Nef protein protects infected primary cells against killing by cytotoxic T lymphocytes. Nature . 1998; 391 397-401
- 73 Pantaleo G, Soudeyns H, Demarest J F. et al . Evidence for rapid disappearance of initially expanded HIV-specific CD8+ T cell clones during primary HIV infection. Proc Natl Acad Sci USA . 1997; 94 9848-9853
- 74 McKinney D M, Lewinsohn D A, Riddell S R, Greenberg P D, Mosier D E. The antiviral activity of HIV-specific CD8+ CTL clones is limited by elimination due to encounter with HIV-infected targets. J Immunol . 1999; 163 861-867
- 75 Finzi D, Hermankova M, Pierson T. et al . Identification of a reservoir for HIV-1 in patients on highly active antiretroviral therapy. Science . 1997; 278 1295-1300
- 76 Perelson A S, Essunger P, Cao Y. et al . Decay characteristics of HIV-1-infected compartments during combination therapy. Nature . 1997; 387 188-191
- 77 Chun T W, Finzi D, Margolick J. et al . In vivo fate of HIV-1-infected T cells: quantitative analysis of the transition to stable latency. Nat Med . 1995; 1 1284-1290
- 78 Chun T W, Carruth L, Finzi D. et al . Quantification of latent tissue reservoirs and total body viral load in HIV-1 infection. Nature . 1997; 387 183-188
- 79 Ahmed R, Gray D. Immunological memory and protective immunity: understanding their relation. Science . 1996; 272 54-60
- 80 Zhang Z, Schuler T, Zupancic M. et al . Sexual transmission and propagation of SIV and HIV in resting and activated CD4+ T cells. Science . 1999; 286 1353-1357
- 81 Finzi D, Blankson J, Siliciano J D. et al . Latent infection of CD4+ T cells provides a mechanism for lifelong persistence of HIV-1, even in patients on effective combination therapy. Nat Med . 1999; 5 512-517
- 82 Chun T W, Engel D, Berrey M M. et al . Early establishment of a pool of latently infected, resting CD4(+) T cells during primary HIV-1 infection. Proc Natl Acad Sci USA . 1998; 95 8869-8873
- 83 Davey Jr T R, Bhat N, Yoder C. et al . HIV-1 and T cell dynamics after interruption of highly active antiretroviral therapy (HAART) in patients with a history of sustained viral suppression. Proc Natl Acad Sci USA . 1999; 96 15109-15114
- 84 Zhang L, Chung C, Hu B S. et al . Genetic characterization of rebounding HIV-1 after cessation of highly active antiretroviral therapy. J Clin Invest . 2000; 106 839-845
- 85 Chun T W, Davey Jr T R, Ostrowski M. et al . Relationship between pre-existing viral reservoirs and the re-emergence of plasma viremia after discontinuation of highly active anti-retroviral therapy. Nat Med . 2000; 6 757-761
- 86 Ho D D, Rota T R, Hirsch M S. Infection of monocyte/macrophages by human T lymphotropic virus type III. J Clin Invest . 1986; 77 1712-1715
- 87 van Furth R. Origin and turnover of monocytes and macrophages. Curr Top Pathol . 1989; 79 125-150
- 88 McIlroy D, Autran B, Cheynier R. et al . Low infection frequency of macrophages in the spleens of HIV+ patients. Res Virol . 1996; 147 115-121
- 89 Orenstein J M, Fox C, Wahl S M. Macrophages as a source of HIV during opportunistic infections. Science . 1997; 276 1857-1861
- 90 Fox C H, Tenner-Racz K, Racz P. et al . Lymphoid germinal centers are reservoirs of human immunodeficiency virus type 1 RNA. J Infect Dis . 1991; 164 1051-1057
- 91 Reinhart T A, Rogan M J, Viglianti G A. et al . A new approach to investigating the relationship between productive infection and cytopathicity in vivo. Nat Med . 1997; 3 218-221
- 92 Cavert W, Notermans D W, Staskus K. et al . Kinetics of response in lymphoid tissues to antiretroviral therapy of HIV-1 infection. Science . 1997; 276 960-964
- 93 Heath S L, Tew J G, Szakal A K, Burton G F. Follicular dendritic cells and human immunodeficiency virus infectivity. Nature . 1995; 377 740-744
- 94 Smith B A, Gartner S, Liu Y. et al . Persistence of infectious HIV on follicular dendritic cells. J Immunol . 2001; 166 690-696
- 95 Palella Jr J F, Delaney K M, Moorman A C. et al . Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. HIV Outpatient Study Investigators. N Engl J Med . 1998; 338 853-860
- 96 Gulick R M, Mellors J W, Havlir D. et al . Treatment with indinavir, zidovudine, and lamivudine in adults with human immunodeficiency virus infection and prior antiretroviral therapy. N Engl J Med . 1997; 337 734-739
- 97 Hammer S M, Squires K E, Hughes M D. et al . A controlled trial of two nucleoside analogues plus indinavir in persons with human immunodeficiency virus infection and CD4 cell counts of 200 per cubic millimeter or less. AIDS Clinical Trials Group 320 Study Team. N Engl J Med . 1997; 337 725-733
- 98 Justice A, Chang C H, Fusco J. et al .Extrapolating long-term HIV/AIDS survival in the post-HAART era. Presented at the Interscience Conference on Antimicrobal Agents and Chemotherapy.
September 26-29, 1999; San Francisco, CA. Abstract 1158
MissingFormLabel
- 99 Bica I, McGovern B, Dhar R. et al . Increasing mortality due to end-stage liver disease in patients with human immunodeficiency virus infection. Clin Infect Dis . 2001; 32 492-497