Interactive selective pressures of HLA-restricted immune responses and antiretroviral drugs on HIV-1.
HIV-specific cytotoxic T lymphocyte (CTL) responses mediated by human leukocyte antigen (HLA) recognition and antiretroviral drugs exert selection pressure on HIV-1 in vivo. The selection of CTL escape mutations strongly underpins the failure of CTL control in most untreated infections whilst drug-resistance mutations predict failure of drug control. These two evolutionary forces share common target residues in HIV-1 at which their selection effects could be synergistic or antagonistic, such that the propensity to develop drug resistance and virological treatment failure may be influenced by HLA type. We examined HIV-1 reverse transcriptase (RT) and protease sequences in a large clinical observational cohort of 487 HIV-infected individuals and found evidence of site-specific interactions between specific antiretroviral drug exposures, HLA alleles and HIV sequence diversity at population level. Such interactions may have general and specific implications for explaining in vivo/in vitro discordance of drug resistance, host-specific susceptibility to drug resistance, individualization of therapy and therapeutic vaccine design.
John
Mina
M
Centre for Clinical Immunology and Biomedical Statistics, Royal Perth Hospital and Murdoch University, Perth, WA, Australia.
Moore
Corey B
CB
James
Ian R
IR
Mallal
Simon A
SA
D019380:Anti-HIV Agents / Q000494:pharmacology*; D024882:Drug Resistance, Viral / Q000235:genetics*; D014644:Genetic Variation; D015658:HIV Infections / Q000188:drug therapy / Q000276:immunology / Q000821:virology; D016333:HIV Protease / Q000235:genetics; D054303:HIV Reverse Transcriptase / Q000235:genetics; D015497:HIV-1 / Q000187:drug effects / Q000235:genetics* / Q000276:immunology; D006680:HLA Antigens; D006801:Humans; D009154:Mutation; D012641:Selection, Genetic; D013602:T-Lymphocytes, Cytotoxic
D019380:Anti-HIV Agents; D006680:HLA Antigens; D054303:HIV Reverse Transcriptase; D016333:HIV Protease