Virus-specific T-helper cells are considered critical for the control of chronic viral infections1,2. Successful treatment of acute HIV-1 infection leads to augmentation of these responses3,4,5, but whether this enhances immune control has not been determined. We administered one or two supervised treatment interruptions to eight subjects with treated acute infection, with the plan to restart therapy if viral load exceeded 5,000 copies of HIV-1 RNA per millilitre of plasma (the level at which therapy has been typically recommended) for three consecutive weeks, or 50,000 RNA copies per ml at one time. Here we show that, despite rebound in viraemia, all subjects were able to achieve at least a transient steady state off therapy with viral load below 5,000 RNA copies per ml. At present, five out of eight subjects remain off therapy with viral loads of less than 500 RNA copies per ml plasma after a median 6.5 months (range 5–8.7 months). We observed increased virus-specific cytotoxic T lymphocytes and maintained T-helper-cell responses in all. Our data indicate that functional immune responses can be augmented in a chronic viral infection, and provide rationale for immunotherapy in HIV-1 infection.
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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. 68, 8056–8063 (1994).
Battegay, M. et al. Enhanced establishment of a virus carrier state in adult CD4+ T-cell-deficient mice. J. Virol. 68, 4700–4704 (1994).
Rosenberg, E. S. et al. Vigorous HIV-1-specific CD4+ T cell responses associated with control of viremia. Science 278, 1447–1450 (1997).
Oxenius, A. et al. Early highly active antiretroviral therapy for acute HIV-1 infection preserves immune function of CD8+ and CD4+ T lymphocytes. Proc. Natl Acad. Sci. USA 97, 3382–3387 (2000).
Malhotra, U. et al. Effect of combination antiretroviral therapy on T-cell immunity in acute human immunodeficiency virus type 1 infection. J. Infect. Dis. 181, 121–131 ( 2000).
Kalams, S. A. & Walker, B. D. The critical need for CD4 help in maintaining effective cytotoxic T lymphocyte responses. J. Exp. Med. 188, 2199–2204 ( 1998).
von Herrath, M. G., Yokoyama, M., Dockter, J., Oldstone, M. B. & Whitton, J. L. CD4-deficient mice have reduced levels of memory cytotoxic T lymphocytes after immunization and show diminished resistance to subsequent virus challenge. J. Virol. 70, 1072–1079 (1996).
Zajac, A. J. et al. Viral immune evasion due to persistence of activated T cells without effector function. J. Exp. Med. 188, 2205–2213 (1998).
Kalams, S. A. et al. Association between virus-specific cytotoxic T-lymphocyte and helper responses in human immunodeficiency virus type 1 infection. J. Virol. 73, 6715–6720 (1999).
Gerlach, J. T. et al. Recurrence of hepatitis C virus after loss of virus-specific CD4(+) T- cell response in acute hepatitis C. Gastroenterology 117, 933–941 ( 1999).
Lechner, F. et al. Analysis of successful immune responses in persons infected with hepatitis C virus. J. Exp. Med. 191, 1499–1512 (2000).
Lisziewicz, J. et al. Control of HIV despite the discontinuation of antiretroviral therapy. N. Engl. J. Med. 340, 1683– 1684 (1999).
Ortiz, G. M. et al. HIV-1-specific immune responses in subjects who temporarily contain virus replication after discontinuation of highly active antiretroviral therapy. J. Clin. Invest. 104, R13– R18 (1999).
Kahn, J. O. & Walker, B. D. Acute human immunodeficiency virus type 1 infection. N. Engl. J. Med. 339, 33–39 (1998).
Lori, F. et al. Treatment of human immunodeficiency virus infection with hydroxyurea, didanosine, and a protease inhibitor before seroconversion is associated with normalized immune parameters and limited viral reservoir. J. Infect. Dis. 180, 1827–1832 ( 1999).
Carpenter, C. C. et al. Antiretroviral therapy for HIV infection in 1997. Updated recommendations of the International AIDS Society/USA panel. J. Am. Med. Assoc. 277, 1962–1969 (1997).
Lyles, R. H. 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. 181, 872–880 (2000).
Pantaleo, G. et al. Major expansion of CD8+ T cells with a predominant V beta usage during the primary immune response to HIV. Nature 370, 463–467 ( 1994).
Autran, B. et al. Positive effects of combined antiretroviral therapy on CD4+ T cell homeostasis and function in advanced HIV disease. Science 277, 112–116 ( 1997).
Evans, D. T. et al. Virus-specific cytotoxic T-lymphocyte responses select for amino-acid variation in simian immunodeficiency virus Env and Nef. Nature Med. 5, 1270–1276 (1999).
Dhodapkar, M. V. et al. Rapid generation of broad T-cell immunity in humans after a single injection of mature dendritic cells. J. Clin. Invest. 104, 173–180 ( 1999).
Davey, R. T. Jr 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 96, 15109–15114 (1999).
Janssen, R. S. et al. New testing strategy to detect early HIV-1 infection for use in incidence estimates and for clinical and prevention purposes. J. Am. Med. Assoc. 280, 42–48 (1998).
Little, S. J. et al. Reduced antiretroviral drug susceptibility among patients with primary HIV infection. J. Am. Med. Assoc. 282, 1142–1149 (1999).
Brander, C. & Walker, B. D. in Molecular Immunology Data Base (eds Korber, B. T. et al.) IV-50–IV-60 (Los Alamos National Laboratory, Los Alamos, New Mexico, 1997).
Goulder, P. J. et al. Differential narrow focusing of immunodominant human immunodeficiency virus gag-specific cytotoxic T-lymphocyte responses in infected African and caucasoid adults and children. J. Virol. 74, 5679–5690 (2000).
Walker, B. D. et al. Long-term culture and fine specificity of human cytotoxic T-lymphocyte clones reactive with human immunodeficiency virus type 1. Proc. Natl Acad. Sci. USA 86, 9514– 9518 (1989).
Martinez-Picado, J., Sutton, L., De Pasquale, M. P., Savara, A. V. & D'Aquila, R. T. Human immunodeficiency virus type 1 cloning vectors for antiretroviral resistance testing. J. Clin. Microbiol. 37, 2943–2951 (1999).
Kalams, S. A. et al. Levels of human immunodeficiency virus type 1-specific cytotoxic T- lymphocyte effector and memory responses decline after suppression of viremia with highly active antiretroviral therapy. J. Virol. 73, 6721–6728 (1999).
This work was supported by the Doris Duke Charitable Foundation (B.D.W., E.S.R.), the NIH (E.S.R., R.D., B.D.W.), the Elizabeth Glaser Pediatric AIDS Foundation (P.J.R.G.), the Deutscher Akademischer Austauschdienst (M.A.), the UK Medical Research Council (P.J.R.G.) and several private donors. We thank A. Munoz for conducting the analysis comparing our data with the MACS data. We also thank the subjects who participated in these trials, M. S. Hirsch and D. T. Scadden for comments on the manuscript; B. Dale for supplying kits for viral load testing; P. Sax and B. Davis for help in recruiting study subjects; M. J. Ferraro, J. Eversley and S. Masci, for technical support; and B. Rawal for performing modified HIV-1 ELISA assays. P.J.R.G. is an Elizabeth Glaser Scientist and B.D.W. is a Doris Duke Distinguished Clinical Science Professor.
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Rosenberg, E., Altfeld, M., Poon, S. et al. Immune control of HIV-1 after early treatment of acute infection. Nature 407, 523–526 (2000). https://doi.org/10.1038/35035103
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