Cytotoxic T lymphocytes (CTLs) lyse virally infected cells that display viral peptide epitopes in association with major histocompatibility complex (MHC) class I molecules on the cell surface. However, despite a strong CTL response directed against viral epitopes, untreated people infected with the human immunodeficiency virus (HIV-1) develop AIDS. To resolve this enigma, we have examined the ability of CTLs to recognize and kill infected primary T lymphocytes. We found that CTLs inefficiently lysed primary cells infected with HIV-1 if the viral nef gene product was expressed. Resistance of infected cells to CTL killing correlated with nef-mediated downregulation of MHC class I (ref. 1) and could be overcome by adding an excess of the relevant HIV-1 epitope as soluble peptide. Thus, Nef protected infected cells by reducing the epitope density on their surface. This effect of nef may allow evasion of CTL lysis by HIV-1-infected cells.
Access optionsAccess options
Subscribe to Journal
Get full journal access for 1 year
only $3.90 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Schwartz, O., Marechal, V., Le Gall, S., Lemonnier, F. & Heard, J. Endocytosis of major histocompatibility complex class I molecules is induced by the HIV-1 Nef protein. Nature Med. 2, 338–342 (1996).
O'Brien, M. C. & Bolton, W. E. Comparison of cell viability probes compatible with fixation and permeabilization for combined surface and intracellular staining in flow cytometry. Cytometry 19, 243–255 (1995).
Philpott, N. J.et al. The use of 7-amino actinomycin D in identifying apoptosis: simplicity of use and broad spectrum of application compared with other techniques. Blood 87, 2244–2251 (1996).
Walter, J.et al. Stimulation of human cytotoxic T cells with HIV-1-derived peptides presented by recombinant HLA-A2 peptide complexes. Int. Immunol. 9, 451–459 (1997).
Johnson, R.et al. HIV-1 gag specific cytotoxic T lymphocytes recognize multiple highly conserved epitopes. Fine specificity of the gag-specific response defined by using unstimulated peripheral blood mononuclear cells and cloned effector cells. J. Immunol. 147, 1512–1521 (1991).
Walker, B.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).
Tsomides, T.et al. Naturally processed viral peptides recognized by cytotoxic T lymphocytes on cells chronically infected by human immunodeficiency virus type 1. J. Exp. Med. 180, 1283–1293 (1994).
Yang, O.et al. Efficient lysis of human immunodeficiency virus type 1-infected cells by cytotoxic T lymphocytes. J. Virol. 70, 5799–5806 (1996).
Pelletier, J. & Sonenberg, N. Internal initiation of translation of eukaryotic mRNA directed by a sequence derived from poliovirus RNA. Nature 334, 320–325 (1988).
Ghattas, I., Sanes, J. & Majors, J. The encephalomycocarditis virus internal ribosome entry site allows efficient coexpression of two genes from a recombinant provirus in cultured cells and in embryos. Mol. Cell Biol. 11, 5848–5859 (1991).
Chen, B., Gandhi, R. & Baltimore, D. CD4 down-modulation during infection of human T cells with human immunodeficiency virus type 1 involves independent activities of vpu, env, and nef. J. Virol. 70, 6044–6053 (1996).
Xu, X.et al. Evasion of CTL responses by Nef-dependent induction of fas ligand (CD95L) expression on simian immunodeficiency virus-infected cells. J. Exp. Med. 186, 1–10 (1997).
Philips, R.et al. Human immunodeficiency virus genetic variation that can escape cytotoxic T-cell recognition. Nature 354, 453–459 (1991).
Borrow, P.et al. Antiviral pressure exerted by HIV-1-specific cytotoxic T lymphocytes (CTLs) during primary infection demonstrated by rapid selection of CTL escape virus. Nature Med. 3, 205–211 (1997).
Goulder, P.et al. Late escape from an immunodominant cytotoxic T-lymphocyte response associated with progression to AIDS. Nature Med. 3, 212–217 (1997).
Kerkau, T., Schmitt-Landgraf, R., Schimpl, A. & Wecker, E. Downregulation of HLA class I antigens in HIV-1-infected cells. AIDS Res. Hum. Retrovir. 5, 613–620 (1989).
Scheppler, J., Nicholson, J., Swan, D., Ahmed-Ansari, A. & McDougal, J. Down-modulation of MHC-I in a CD4+ T cell line, CEM-E5, after HIV-1 infection. J. Immunol. 143, 2858–2866 (1989).
Howcroft, T., Strebel, K., Martin, M. & Singer, D. Repression of MHC class I gene promoter activity by two-exon Tat of HIV. Science 260, 1320–1322 (1993).
Kerkau, T.et al. The human immunodeficiency virus type 1 (HIV-1) Vpu protein interferes with an early step in the biosynthesis of major histocompatibility complex (MHC) class I molecules. J. Exp. Med. 185, 1295–1305 (1997).
Hill, A.et al. Class I major histocompatibility complex-restricted cytotoxic T lymphocytes specific for Epstein-Barr virus (EBV) nuclear antigens fail to lyse the EBV-transformed B lymphoblastoid cell lines against which they were raised. J. Exp.Med. 181, 2221–2228 (1995).
Jondal, M., Schirmbeck, R. & Reimann, J. MHC class I-restricted CTL responses to exogenous antigens. Immunity 5, 295–302 (1996).
O'Brien, T. R.et al. Serum HIV-1 RNA levels and time to develop of AIDS in the multicenter hemophila cohort study. J. Am. Chem. Assoc. 276, 105–110 (1996).
Mellors, J. W.et al. Prognosis in HIV-1 infection predicted by the quantity of virus in plasma. Science 72, 1167–1170 (1996).
Pantaleo, G.et al. The qualitative nature of the primary immune response to HIV infection is a prognosticator of disease progression independent of the initial level of plasma viremia. Proc. Natl Acad. Sci. USA 94, 254–258 (1997).
Adachi, A.et al. Production of acquired immunodeficiency syndrome-associated retrovirus in human and nonhuman cells transfected with an infectious molecular clone. J. Virol. 59, 284–291 (1986).
Ausubel, F.et al. Current Protocols in Molecular Biology 1-9.11.1-9.11.18 (Wiley, New York, 1996).
Tsomides, T., Walker, B. & Eisen, H. An optimal viral peptide recognized by CD8+ T cells binds very tightly to the restricting class I major histocompatibility complex protein on intact cells but not to the purified class I protein. Proc. Natl Acad. Sci. USA 88, 11276–11280 (1991).
We thank H. Eisen, H. Ploegh, D. Camerini and members of D.B.'s laboratory; and A. K. Trocha, O. O. Yang, N. Jones and E. Rosenberg for help with culturing CTL clones, for chromium-release assays and for human lymphocytes. K.C. was the recipient of a Howard Hughes fellowship award for physicians. B.K.C. was supported by a Medical Scientist Training Program Award. D.B. is an American Cancer Society Research Professor. Supported at M.I.T. by funds from the Ivan R. Cottrell Chair and at M.G.H. by grants from the N.I.H.
About this article
Lovastatin Inhibits HIV-1-Induced MHC-I Downregulation by Targeting Nef–AP-1 Complex Formation: A New Strategy to Boost Immune Eradication of HIV-1 Infected Cells
Frontiers in Immunology (2019)
Molecular Immunology (2019)
Future Virology (2019)
JAIDS Journal of Acquired Immune Deficiency Syndromes (2019)
Journal of Clinical Virology (2019)