Abstract
Variable viruses, such as human immunodeficiency virus (HIV) and hepatitis C virus (HCV), persist despite host immune responses directed against them. Numerous lines of evidence have suggested that antiviral CD8+ T-cell responses are key among these immune responses, but these vary widely in their ability to contain virus. We propose that only a proportion of responses may exert significant antiviral pressure ('driver' responses), leading to control over viral replication (protection) and/or, ultimately, selection of escape mutants. Another set of responses may exert only weak pressure on the virus ('passenger' responses): these neither protect nor select. To examine this we have analysed (using established databases of HIV and HCV sequences and cytotoxic T-lymphocyte (CTL) epitopes, and published experimental datasets) two important features--predicted binding of the epitope to major histocompatibility complex molecule and observed variability of the epitope--that might distinguish such responses. We find that a high predicted binding estimate could only explain a limited set of 'driver' responses associated with protection or selection. There is statistical evidence that readily defined (and non-protective) CTL responses target regions associated with lower levels of viral variability. Taken together, this suggests that a large number of well-documented responses may represent 'passengers' and we propose a mechanism that might explain their presence.
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Selected References
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- Altfeld Marcus, Allen Todd M., Yu Xu G., Johnston Mary N., Agrawal Deepak, Korber Bette T., Montefiori David C., O'Connor David H., Davis Ben T., Lee Paul K. HIV-1 superinfection despite broad CD8+ T-cell responses containing replication of the primary virus. Nature. 2002 Nov 28;420(6914):434–439. doi: 10.1038/nature01200. [DOI] [PubMed] [Google Scholar]
- Carbone F. R., Bevan M. J. Class I-restricted processing and presentation of exogenous cell-associated antigen in vivo. J Exp Med. 1990 Feb 1;171(2):377–387. doi: 10.1084/jem.171.2.377. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Carrington Mary, O'Brien Stephen J. The influence of HLA genotype on AIDS. Annu Rev Med. 2001 Dec 3;54:535–551. doi: 10.1146/annurev.med.54.101601.152346. [DOI] [PubMed] [Google Scholar]
- Collins K. L., Chen B. K., Kalams S. A., Walker B. D., Baltimore D. HIV-1 Nef protein protects infected primary cells against killing by cytotoxic T lymphocytes. Nature. 1998 Jan 22;391(6665):397–401. doi: 10.1038/34929. [DOI] [PubMed] [Google Scholar]
- Goulder P. J., Phillips R. E., Colbert R. A., McAdam S., Ogg G., Nowak M. A., Giangrande P., Luzzi G., Morgan B., Edwards A. Late escape from an immunodominant cytotoxic T-lymphocyte response associated with progression to AIDS. Nat Med. 1997 Feb;3(2):212–217. doi: 10.1038/nm0297-212. [DOI] [PubMed] [Google Scholar]
- Klenerman Paul, Wu Ying, Phillips Rodney. HIV: current opinion in escapology. Curr Opin Microbiol. 2002 Aug;5(4):408–413. doi: 10.1016/s1369-5274(02)00339-9. [DOI] [PubMed] [Google Scholar]
- McMichael A. J., Ogg G., Wilson J., Callan M., Hambleton S., Appay V., Kelleher T., Rowland-Jones S. Memory CD8+ T cells in HIV infection. Philos Trans R Soc Lond B Biol Sci. 2000 Mar 29;355(1395):363–367. doi: 10.1098/rstb.2000.0575. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Moore Corey B., John Mina, James Ian R., Christiansen Frank T., Witt Campbell S., Mallal Simon A. Evidence of HIV-1 adaptation to HLA-restricted immune responses at a population level. Science. 2002 May 24;296(5572):1439–1443. doi: 10.1126/science.1069660. [DOI] [PubMed] [Google Scholar]
- Ward S., Lauer G., Isba R., Walker B., Klenerman P. Cellular immune responses against hepatitis C virus: the evidence base 2002. Clin Exp Immunol. 2002 May;128(2):195–203. doi: 10.1046/j.1365-2249.2002.01840.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Willberg C., Barnes E., Klenerman P. HCV immunology--death and the maiden T cell. Cell Death Differ. 2003 Jan;10 (Suppl 1):S39–S47. doi: 10.1038/sj.cdd.4401122. [DOI] [PubMed] [Google Scholar]
- Yusim Karina, Kesmir Can, Gaschen Brian, Addo Marylyn M., Altfeld Marcus, Brunak Søren, Chigaev Alexandre, Detours Vincent, Korber Bette T. Clustering patterns of cytotoxic T-lymphocyte epitopes in human immunodeficiency virus type 1 (HIV-1) proteins reveal imprints of immune evasion on HIV-1 global variation. J Virol. 2002 Sep;76(17):8757–8768. doi: 10.1128/JVI.76.17.8757-8768.2002. [DOI] [PMC free article] [PubMed] [Google Scholar]
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