Abstract
We and others have postulated that a constant number of T lymphocytes is normally maintained without regard to CD4+ or CD8+ phenotype (‘blind’ T-cell homeostasis). Here we confirm essentially constant T-cell levels (despite marked decline in CD4+ T cells and increase in CD8+ T cells) in homosexual men with incident human immunodeficiency virus, type 1 (HIV-1), infection who remained free of acquired immunodeficiency syndrome (AIDS) for up to eight years after seroconversion. In contrast, seroconverters who developed AIDS exhibited rapidly declining T cells (both CD4+ and CD8+) for approximately two years before AIDS, independent of the time between seroconversion and AIDS, suggesting that homeostasis failure is an important landmark in HIV disease progression. Given the high rate of T-cell turnover in HIV-1 infection, blind T-cell homeostasis may contribute to HIV pathogenesis through a CD8+ T lymphocytosis that interferes with regeneration of lost CD4+ T cells.
Similar content being viewed by others
Article PDF
References
Margolick, J.B. et al. Changes in T and non-T lymphocyte subsets following seroconversion to HIV-1: Stable CD3+ and declining CD3− populations suggest regulatory responses linked to loss of CD4 lymphocytes. J. AIDS 6, 153–161 (1993).
Adleman, L.M. & Wofsy, D. T-cell homeostasis: Implications in HIV infection. J. AIDS 6, 144–152 (1993).
Adleman, L.M. & Wofsy, D. Blind homeostasis in CD4 knockout mice. First natn. Conference on Human Retroviruses and Related Infections (12–16 December 1993, Washington, DC, Abstr. 280 (Am. Soc. Microbiol., Washington, DC, 1993).
Ho, D.D. et al. Rapid turnover of plasma virions and CD4 lymphocytes in HIV-1 infection. Nature 373, 123–126 (1995).
Wei, X. et al. Viral dynamics in human immunodeficiency virus type 1 infection. Nature 373, 117–122 (1995).
Zolla-Pazner, S. et al. Nonrandom development of immunologic abnormalities after infection with human immunodeficiency virus: Implications for immunologic classification of the disease. Proc. natn. Acad. Sci. U.S.A. 84, 5404–5408 (1987).
Hoover, D.R. et al. The progression of untreated HIV-1 infection prior to AIDS. Am. J. Public Hlth 82, 1538–1541 (1992).
Galai, N. et al. Tracking of markers and onset of disease among HIV-1 serocon-verters. Statist. Med. 12, 2133–2145 (1993).
Margolick, J.B., Donnenberg, A. & Muñoz, A. T lymphocyte homeostasis after HIV seroconversion. J. acquit. Immun. Defic. Syndr. 8, 415–416 1994.
Ascher, M.S. & Sheppard, H.W. AIDS as immune system activation.II. The panergic imnesia hypothesis. J. acquit. Immun. Defic. Syndr. 3, 177–91 (1990).
Meuer, S.C. et al. Cellular origin of interleukin 2 in man: Evidence for stimulus restricted IL2 production by T4+ and T8+ lymphocytes. J. Immun. 129, 1076–1079 (1982).
Walker, B.D. et al. HIV-specific cytotoxic T lymphocytes in seropositive individuals. Nature 328, 345–348 (1987).
Koenig, S. et al. Group-specific, major histocompatibility complex class I-restricted cytotoxic responses to human immunodeficiency virus 1 (HIV-1) envelope proteins by cloned peripheral blood T cells from an HIV-1-infected individual. Proc. natn. Acad. Sci. U.S.A. 85, 8638–8642 (1988).
Ho, H.-N. et al. Circulating HIV-specific CD8+ cytotoxic T cells express CD38 and HLA-DR antigens. J. Immun. 150, 3070–3079 (1993).
Mackewicz, C.E., Ortega, H.W. & Levy, J.A. CD8+ cell anti-HIV activity correlates with the clinical state of the infected individual. J. clin. Invest. 87, 1462–1466 (1991).
Hausner, M.A., Giorgi, J.V. & Plaeger-Marshall, S. A reproducible method to detect CD8 T cell mediated inhibition of HIV production from naturally infected CD4 cells. J. immunol. Methods 157, 181–187 (1993).
Pantaleo, G., Graziosi, C. & Fauci, A. The immunopathogenesis of human immunodeficiency virus infection. New Engl. J. Med. 328, 327–335 (1993).
Gougeon, M.L. & Montagnier, L. Apoptosis in AIDS. Science 260, 1269–1270 (1993).
Donnenberg, A.D., Margolick, J.B., Beltz, L.A., Donnenberg, V.S. & Rinaldo, C.R. Apoptosis parallels lymphopoiesis in bone marrow transplantation and HIV disease. Res. Immun. 146, 11–21 (1995).
Lang, W. et al. Patterns of T lymphocyte changes with human immunodeficiency virus infection: From seroconversion to the development of AIDS. J. acquit. Immun. Defic. Syndr. 2, 63–69 (1989).
Koot, M. et al. Prognostic value of HIV-1 syncytium-inducing phenotype for rate of CD4+ cell depletion and progression to AIDS. Ann. intern. Med. 118, 681–688 (1993).
Pantaleo, G. et al. HIV infection is active and progressive in lymphoid tissue during the clinically latent stage of disease. Nature 362, 355–358 (1993).
Embretson, J. et al. Massive covert infection of helper T lymphocytes and macrophages by HIV during the incubation period of AIDS. Nature 362, 359–362 (1993).
Giorgi, J.V. & Janossy, G. Flow cytometry studies in HIV disease: Relevance to AIDS vaccine development. AIDS 8 (suppl. 1), S183–S193 (1994).
Donnenberg, A.D., Margolick, J.B. & Donnenberg, V.S. poiesis, apoptosis, and immune amnesia. Ann. N.Y. Acad. Sci. (in the press).
Centers for Disease Control. Revision of the CDC surveillance case definition for acquired immunodeficiency syndrome. Morbid. Mortal Weekly Rep. 36, 3S–15S (1987).
Hoffman, R.A., Kung, P.C., Hansen, W.P. & Goldstein, G. Simple and rapid measurement of human T lymphocytes and their subclasses in peripheral blood. Proc. natn. Acad Sci 77, 4914–4917 (1980).
Giorgi, J.V. et al. Quality control in the flow cytometric measurement of T-lymphocyte subsets: the Multicenter Aids Cohort study (MACS) experience. Clin. Immun. Immunopathol 55, 173–186 (1990).
Schenker, E.L. et al. Evaluation of a dual-color flow cytometry immunophenotyping panel in multicenter quality assurance program. Cytometry 14, 307–317 (1993).
Author information
Authors and Affiliations
Consortia
Rights and permissions
About this article
Cite this article
Margolick, J., Muñoz, A., Donnenberg, A. et al. Failure of T-cell homeostasis preceding AIDS in HIV-1 infection. Nat Med 1, 674–680 (1995). https://doi.org/10.1038/nm0795-674
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/nm0795-674
This article is cited by
-
Modifications of CD4 T cells, CD4/CD8 ratio and serum levels of soluble CD14 in HIV-HCV-coinfected patients after sustained HCV response induced by direct-acting antiviral agents: influence of liver cirrhosis
European Journal of Clinical Microbiology & Infectious Diseases (2021)
-
Impact of antigen specificity on CD4+T cell activation in chronic HIV-1 infection
BMC Infectious Diseases (2013)
-
Seventeen-colour flow cytometry: unravelling the immune system
Nature Reviews Immunology (2004)
-
AIDS pathogenesis: what have two decades of HIV research taught us?
Nature Reviews Immunology (2003)
-
A new entry route for HIV
Nature Medicine (2001)