Abstract
The capacity of HIV-1 to establish latent infection of CD4+ T cells may allow viral persistence despite immune responses and antiretroviral therapy. Measurements of infectious virus1,2 and viral RNA3,4 in plasma and of infectious virus1, viral DNA5–10 and viral messenger RNA species11–14 in infected cells all suggest that HIV-1 replication continues throughout the course of infection. Uncertainty remains over what fraction of CD4+ T cells are infected and whether there are latent reservoirs for the virus. We show here that during the asymptomatic phase of infection there is an extremely low total body load of latently infected resting CD4+ T cells with replication-competent integrated pro virus (<107 cells). The most prevalent form of HIV-1 DNA in resting and activated CD4+ T cells is a full-length, linear, unintegrated form that is not replication competent. The infection progresses even though at any given time in the lymphoid tissues integrated HIV-1 DNA is present in only a minute fraction of the susceptible populations, including resting and activated CD4+ T cells and macrophages.
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References
1. Ho, D. D., Moudgil, T. & Alam, M. Quantitation of human immunodeficiency virus type 1 in the blood of infected persons. N. Engl. J. Med. 321, 1621-1625 (1989). Coombs, R. W. et al. Plasma viremia in human immunodeficiency virus infection. N. Engl. J. Med. 2. 3. 321, 1626-1631 (1989). Piatak, M. Jr. et al. High levels of HIV-1 in plasma during all stages of infection determined by competitive PCR. Science 259, 1749-1754 (1993). 4. Mellors, J. W. et al. Prognosis in HIV- 1 infection predicted by the quantity of virus in plasma. Science 272, 1167-1170(1986). 5. Schnittman, S. M. et al. The reservoir for HIV-1 in human peripheral blood is a T cell that maintains expression of CD4. Science 245, 305-308 (1989). 6. Bukrinsky, M. L, Stanwick, T. L., Dempsey, M. P. & Stevenson, M. Quiescent T lymphocytes as an inducible virus reservoir in HIV-1 infection. Science 254, 423-427 (1991). 7. Bagasra, O., Hauptman, S. P., Lischner, H. W., Sachs, M. & Pomerantz, R. J. Detection of human immunodeficiency virus type 1 provirus in mononuclear cells by in situ polymerase chain reaction. N. Engl. J. Med. 326, 1385-1391 (1992). 8. Patterson, B. K. et al. Detection of HIV- 1 DNA and messenger RNA in individual cells by PCR-driven in situ hybridization and flow cytometry. Science 260, 976-979 (1993). 9. 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). 1 0. 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). 11. Harper, M. E., Marselle, L. M., Gallo, R. C. & Wong-Staal, R Detection of lymphocytes expressing human T-lymphotropic virus type III in lymph nodes and peripheral blood from infected individuals by in situ hybridization. Proc. Natl Acad. Sci. USA 83, 772-776 (1986). 12. Seshamma, T., Bagasra, O., Trono, D., Baltimore, D. & Pomerantz, R. J. Blocked early-stage latency in the peripheral blood cells of certain individuals infected with human immunodeficiency virus type 1. Proc. Natl Acad. Sci. USA 89, 10663-10667 (1992). 13. Adams, M. et al. Cellular latency in human immunodeficiency virus-infected individuals with high CD4 levels can be detected by the presence of promoter-proximal transcripts. Proc. Natl Acad. Sci. USA 91, 3862-3866(1994). 14. Haase, A. T. et al. Quantitative image analysis of HIV-1 infection in lymphoid tissue. Science 274, 985-989 (1996). 15. Ho, D. D. et al. Rapid turnover of plasma virions and CD4 lymphocytes in HIV-1 infection. Nature 373, 123-126 (1995). 16. Wei, X. et al. Viral dynamics in human immunodeficiency virus type 1 infection. Nature 373,117-122 (1995). 17. 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, viral generation time. Science 271, 1582-1586 (1986). 18. Coffin, J. M. HIV population dynamics in vivo: Implications for genetic variation, pathogenesis, and therapy. Science 267, 483-489 (1995). 19. Zack, J. A. et al. HIV-1 entry into quiescent primary lymphocytes: molecular analysis reveals a labile, latent viral structure. Cell 61, 213-222 (1990). 20. Bukrinsky, M. I. etal. Active nuclear import of human immunodeficiency virus type 1 preintegration complexes. Proc. Natl Acad. Sci. USA 89, 6580-6584 (1992). 21. Chun, T.-W. et al. Fate of HIV-1-infected T cells in vivo: Rates of transition to stable latency. Nature Med. 1, 1284-1290 (1995). 22. Pauza, C. D. Two bases are deleted from the termini of HIV-1 linear DNA during integrative recombination. Virology 179, 886-889 (1990). 23. Brown, P. O., Bowerman, B., Varmus, H. E. & Bishop, J. M. Retroviral integration: Structure of the initial covalent product and its precursor, and a role for the viral IN protein. Proc. Natl Acad. Sci. USA 86,2525-2529(1989). 24. Dimitrov, D. S. et al. Quantitation of human immunodeficiency virus type 1 infection kinetics. /. Virol. 67,2182-2190(1993). 25. Gartner, S. et al. The role of mononuclear phagocytes in HTLV-III/LAV infection. Science 233, 215-219 (1986). 26. Dickover, R. E. et al. Decreases in unintegrated HIV DNA are associated with antiretroviral therapy in AIDS patients. /. Acq. Imm. Def. Syndr. 5, 31-36 (1992). 27. Michie, C. A., McLean, A., Alcock, C. & Beverley, P. C. Lifespan of human lymphocyte subsets defined by CD45 isoforms. Nature 360, 264-265 (1992). 28. Patel, S. S., Duby, A. D., Tiele, D. L. & Lipsky, P. E. Phenotypic and functional characterization of human T cell clones. /. Immunol. 141, 3726-3736 (1988). 29. Myers, L. A., McQuay, L. J. & Hollinger, F. B. Dilution assay statistics. /. Clin. Microbiol. 32, 732-739 (1994). 30. Perelson, A. S. et al. Decay characteristics of HIV-1-infected compartments during combination therapy. Nature 387, 188-191 (1997).
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Chun, TW., Carruth, L., Finzi, D. et al. Quantification of latent tissue reservoirs and total body viral load in HIV-1 infection. Nature 387, 183–188 (1997). https://doi.org/10.1038/387183a0
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DOI: https://doi.org/10.1038/387183a0
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