Abstract
The HIV-1-specific cytotoxic T lymphocyte (CTL) response is temporally associated with the decline in viremia during primary HIV-1 infection, but definitive evidence that it is of importance in virus containment has been lacking. Here we show that in a patient whose early CTL response was focused on a highly immunodominant epitope in gp160, there was rapid elimination of the transmitted virus strain and selection for a virus population bearing amino acid changes at a single residue within this epitope, which conferred escape from recognition by epitope-specific CTL. The magnitude (> 100-fold), kinetics (30–72 days from onset of symptoms) and genetic pathways of virus escape from CTL pressure were comparable to virus escape from antiretroviral therapy, indicating the biological significance of the CTL response in vivo. One aim of HIV-1 vaccines should thus be to elicit strong CTL responses against multiple codominant viral epitopes.
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Koup, R.A. et al. Temporal association of cellular immune responses with the initial control of viremia in primary human immunodeficiency virus type 1 syndrome. J. Virol. 68, 4650–4655 (1994).
Borrow, P., Lewicki, H., Hahn, B.H., Shaw, G.M. & Oldstone, M.B.A. Virus-specific CD8+ cytotoxic T-lymphocyte activity associated with control of viremia in primary human immunodeficiency virus type 1 infection. J. Virol. 68, 6103–6110 (1994).
Gallimore, A. et al. Early suppression of SIV replication by CD8+nef-specific cytotoxic T cells in vaccinated macaques. Nature Med. 1, 1167–1173 (1995).
Flynn, J.N. et al. Env-specific CTL predominate in cats protected from feline immunodeficiency virus infection by vaccination. J. Immunol. 157, 3658–3665 (1996).
Rowland-Jones, S. et al. HIV-specific cytotoxic T-cells in HIV-exposed but uninfected Gambian women. Nature Med. 1, 59–64 (1995).
Pinto, L.A. et al. ENV-specific cytotoxic T lymphocyte responses in HIV seronegative health care workers occupationally exposed to HIV-contaminated body fluids. J. Clin. Invest. 96, 867–876 (1995).
Paxton, W.A. et al. Relative resistance to HIV-1 infection of CD4 lymphocytes from persons who remain uninfected despite multiple high-risk sexual exposures. Nature Med. 2, 412–417 (1996).
Klein, M.R. 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. 181, 1365–1372 (1995).
Rinaldo, C. 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. 69, 5838–5842 (1995).
Carmichael, A., Jin, X., Sissons, P. & Borysiewicz, L., Quantitative analysis of the human immunodeficiency virus type 1 (HIV-1)-specific cytotoxic T lymphocyte (CTL) response at different stages of HIV-1 infection: Differential CTL responses to HIV-1 and Epstein-Barr virus in late disease. J. Exp. Med. 177, 249–256 (1993).
Hoffenbach, A. et al. Unusually high frequencies of HIV-specific cytotoxic T lymphocytes in humans. J. Immunol. 142, 452–462 (1989).
Phillips, A.M. Reduction of HIV concentration during acute infection: Independence from a specific immune response. Science 271, 497–499 (1996).
Clark, S.J. et al. High titers of cytopathic virus in plasma of patients with symptomatic primary HIV-1 infection. N. Engl. J. Med. 324, 954–960 (1991).
Pantaleo, G. et al. Major expansion of CD8+ T cells with a predominant Vβ usage during the primary immune response to HIV. Nature 370, 463–467 (1994).
Lau, L.L., Jamieson, B.D., Somasundaram, T. & Ahmed, R. Cytotoxic T-Cell memory without antigen. Nature 369, 648–652 (1994).
Pircher, H. et al. Viral escape by selection of cytotoxic T cell-resistant virus variants in vivo. Nature 346, 629–633 (1990).
Rammensee, H.-G., Friede, T. & Stevanovic, S. MHC ligands and peptide motifs: First listing. Immunogenetics 41, 178–228 (1995).
Wei, X. et al. Viral dynamics in human immunodeficiency virus type 1 infection. Nature 373, 117–122 (1995).
Ho, D.D. et al. Rapid turnover of plasma virions and CD4 lymphocytes in HIV-1 infection. Nature 373, 123–126 (1995).
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 271, 1582–1586 (1996).
Phillips, R.E. et al. Human immunodeficiency virus genetic variation that can escape cytotoxic T cell recognition. Nature 354, 453–459 (1991).
Couillin, I. et al. Impaired cytotoxic T lymphocyte recognition due to genetic variations in the main immunogenic region of the human immunodeficiency virus 1 NEF protein. J. Exp. Med. 180, 1129–1134 (1994).
Nowak, M.A. et al. Antigenic oscillations and shifting immunodominance in HIV-1 infections. Nature 375, 606–611 (1995).
Safrit, J.T., Andrews, C.A., Zhu, T., Ho, D.D. & Koup, R.A. Characterization of human immunodeficiency virus type 1-specific cytotoxic T lymphocyte clones isolated during acute seroconversion: Recognition of autologous virus sequences within a conserved immunodominant epitope. J. Exp. Med. 179, 463–472 (1994).
Harrer, T. et al. Cytotoxic T lymphocytes in asymptomatic long-term nonprogressing HIV-1 infection. J. Immunol. 156, 2616–2623 (1996).
Lewicki, H. et al. CTL escape viral variants. I. Generation and molecular characterization. Virology 210, 29–40 (1995).
Moskophidis, D. & Zinkernagel, R.M. Immunobiology of cytotoxic T-Cell escape mutants of lymphocytic choriomeningitis virus. J. Virol. 69, 2187–2193 (1995).
Klenerman, P. et al. Cytotoxic T-cell activity antagonized by naturally occurring HIV-1 gag variants. Nature 369, 403–407 (1994).
Selin, L.K., Vergilis, K., Welsh, R.M. & Nahill, S.R. Reduction of otherwise remarkably stable virus-specific cytotoxic T lymphocyte memory by heterologous viral infections. J. Exp. Med. 183, 2489–2499 (1996).
Selin, L.K., Nahill, S.R. & Welsh, R.M. Cross-reactivities in memory cytotoxic T lymphocyte recognition of heterologous viruses. J. Exp. Med. 179, 1933–1943 (1994).
Piatak, M.J. et al. High levels of HIV-1 in plasma during all stages of infection determined by competitive PCR. Science 259, 1749–1754 (1993).
Mellors, J.W. et al. Prognosis in HIV-1 infection predicted by the quantity of virus in plasma. Science 272, 1167–1170 (1996).
Koup, R.A. et al. Limiting dilution analysis of cytotoxic T lymphocytes to human immunodeficiency virus gag antigens in infected persons: In vitro quantitation of effector cell populations with p17 and p24 specificities. J. Exp. Med. 174, 1593–1600 (1991).
Whitton, J.L., Southern, P.J. & Oldstone, M.B.A. Analyses of the cytotoxic T lymphocyte responses to glycoprotein and nucleoprotein components of lymphocytic choriomeningitis virus. Virology 162, 321–327 (1988).
Korber, B.T.M. et al. HIV Molecular Immunology Database 1995 (Los Alamos National Laboratory, Los Alamos, NM, 1995).
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).
Gairin, J.E. Mazarguil, H., Hundrisier, D. & Oldstone, M.B.A. Optimal lymphocytic choriomeningitis virus sequences restricted by H-2Db major histocompatibility complex class I molecules and presented to cytotoxic T lymphocytes. J. Virol. 69, 2297–2305 (1995).
De St Groth, S.F. The evaluation of limiting dilution assays. J. Immunol. Methods 49, 11–23 (1982).
Myers, G. et al. Human Retroviruses and AIDS 1995: A Compilation and Analysis of Nucleic Acid and Amino Acid Sequences (Los Alamos National Laboratory, Los Alamos, NM, 1995).
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Borrow, P., Lewicki, H., Wei, X. et al. Antiviral pressure exerted by HIV-l-specific cytotoxic T lymphocytes (CTLs) during primary infection demonstrated by rapid selection of CTL escape virus. Nat Med 3, 205–211 (1997). https://doi.org/10.1038/nm0297-205
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DOI: https://doi.org/10.1038/nm0297-205
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