Translation of HLA–HIV Associations to the Cellular Level: HIV Adapts To Inflate CD8 T Cell Responses against Nef and HLA-Adapted Variant Epitopes
Year: 2011
Type: article
Study design: Observational Study
Abstract: Strong statistical associations between polymorphisms in HIV-1 population sequences and carriage of HLA class I alleles have been widely used to identify possible sites of CD8 T cell immune selection in vivo. However, there have been few attempts to prospectively and systematically test these genetic hypotheses arising from population-based studies at a cellular, functional level. We assayed CD8 T cell epitope-specific IFN-γ responses in 290 individuals from the same cohort, which gave rise to 874 HLA-HIV associations in genetic analyses, taking into account autologous viral sequences and individual HLA genotypes. We found immunological evidence for 58% of 374 associations tested as sites of primary immune selection and identified up to 50 novel HIV-1 epitopes using this reverse-genomics approach. Many HLA-adapted epitopes elicited equivalent or higher-magnitude IFN-γ responses than did the nonadapted epitopes, particularly in Nef. At a population level, inclusion of all of the immunoreactive variant CD8 T cell epitopes in Gag, Pol, Nef, and Env suggested that HIV adaptation leads to an inflation of Nef-directed immune responses relative to other proteins. We concluded that HLA-HIV associations mark viral epitopes subject to CD8 T cell selection. These results can be used to guide functional studies of specific epitopes and escape mutations, as well as to test, train, and evaluate analytical models of viral escape and fitness. The inflation of Nef and HLA-adapted variant responses may have negative effects on natural and vaccine immunity against HIV and, therefore, has implications for diversity coverage approaches in HIV vaccine design.
Source: The Journal of Immunology
Language: English
Topic: HIV Research and Treatment
Subfield: Virology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: green
Awards: G1033683653, G1068660208, G115468880, The Ohio State University AIDS Clinical Trials Unit, G123932167, G1276011396, University of Cincinnati AIDS Clinical Trials Unit- UC ACTU, WASHINGTON UNIVERSITY AIDS CLINICAL TRIALS UNIT, The Ohio State University AIDS Clinical Trials Unit, New York University HIV/AIDS Clinical Trial Unit, G1346130624, Stanford AIDS Clinical Trials Unit, G154087045, G1586133245, G161582775, UW Clinical HIV Integrated Research Program, WASHINGTON UNIVERSITY AIDS CLINICAL TRIALS UNIT, G1681955143, Chinese Clinical Trials Unit for HIV Research (CCTU), G174905615, U.T. SOUTHWESTERN ADULT AIDS CLINICAL TRIALS UNIT, G185513119, Vanderbilt HIV Clinical Trials Unit, G1939689254, G1944963898, G2027736814, G2069435444, G2135258891, G2199452652, G2245907174, G229144670, G2368841045, G2381598486, G2416365291, Miami HIV/AIDS Clinical Therapeutic and Vaccine Trial Unit, G2682253789, University of North Carolina AIDS Clinical Trials Unit (UNC ACTU), ADULT AIDS CLINICAL TRIALS UNIT, G3116536149, Cornell Clinical Trials Unit, G3277483280, Johns Hopkins AIDS Clinical Trials Unit, HIV-1 adaptation to HLA-restricted immune responses, ADULT AIDS CLINICAL TRIALS UNIT (ACTU), G3525517067, Miami Treatment and Prevention Clinical Trials Unit (CTU), AIDS Clinical Trials Group Network, Alabama-Clinical Trials Unit, G367367271, UCLA AIDS Prevention and Treatment Clinical Trials Unit, UW Clinical HIV Integrated Research Program, G3873853564, G3935416247, Philadelphia IMPAACT Clinical Trials Unit, G3964108010, ADULT AIDS CLINICAL TRIALS UNIT, G420260051, G4205250407, G4316068824, Northwestern University Clinical Trial Unit, Colorado AIDS Clinical Trials Unit, G4614481423, Institute of Human Virology Clinical Trials Unit, Case Clinical Trials Unit, Stanford AIDS Clinical Trials Unit, University of Pittsburgh Clinical Trials Unit, ADULT THERAPEUTIC CLINICAL TRIALS PROGRAM IN AIDS, UCSF HIV Clinical Trials Unit, New York University HIV/AIDS Clinical Trial Unit, ADULT ACTG CENTRAL GROUP, G5588634031, Improving Antiretroviral Management for HIV, G563474107, Statistical and Data Management Center for the AIDS Clinical Trials Group, UCSD Department of Medicine HIV/AIDS Clinical Trials Unit, HIV/AIDS Clinical Trial Unit in NCAIDS, China CDC, Case AIDS Clinical Trials Unit, ADULT AIDS CLINICAL TRIAL UNIT, G6103943158, Philadelphia IMPAACT Clinical Trials Unit, Partners Healthcare Systems/Harvard Medical School/Boston Medical Center AIDS CTU, The Vanderbilt Institute for Clinical and Translational Research (VICTR) UL1, University of Cincinnati AIDS Clinical Trials Unit- UC ACTU, Colorado AIDS Clinical Trials Unit, UCSF HIV Clinical Trials Unit, Partners Healthcare Systems/Harvard Medical School/Boston Medical Center AIDS CTU, G7348756, G7403049968, HAWAII ACTU - ADULT THERAPEUTIC CLINICAL TRIALS PROGRAM, G749807406, HIV/AIDS Clinical Trials Unit, HIV/AIDS Clinical Trials Unit, Institute of Human Virology Clinical Trials Unit, Tennessee Center for AIDS Research (TN-CFAR), UCSD Collaborative Clinical Trials Unit, Weill Cornell Medicine - Rutgers New Jersey Medical School Clinical Trials Unit, Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections, Chicago Clinical Trials Unit, Statistical and Data Management Center (SDMC), Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections (ACTG), Johns Hopkins University Baltimore India Clinical Trail Unit (JHUBI CTU), Pitt-Ohio State Clinical Trials Unit, University of North Carolina Global HIV Prevention and Treatment Clinical Trials Unit, UCLA AIDS Prevention and Treatment Clinical Trials Unit, Vanderbilt HIV Clinical Trials Unit (CTU), A-Z Clinical Trials Unit, G964886957
OpenAlex ID: W2113940664