title: Dual pressure from antiretroviral therapy and cell-mediated immune response on the human immunodeficiency virus type 1 protease gene.
abstract: Human immunodeficiency virus (HIV)-specific CD8(+) T-lymphocyte pressure can lead to the development of viral escape mutants, with consequent loss of immune control. Antiretroviral drugs also exert selection pressures on HIV, leading to the emergence of drug resistance mutations and increased levels of viral replication. We have determined a minimal epitope of HIV protease, amino acids 76 to 84, towards which a CD8(+) T-lymphocyte response is directed. This epitope, which is HLA-A2 restricted, includes two amino acids that commonly mutate (V82A and I84V) in the face of protease inhibitor therapy. Among 29 HIV-infected patients who were treated with protease inhibitors and who had developed resistance to these drugs, we show that the wild-type PR82V(76-84) epitope is commonly recognized by cytotoxic T lymphocytes (CTL) in HLA-A2-positive patients and that the CTL directed to this epitope are of high avidity. In contrast, the mutant PR82A(76-84) epitope is generally not recognized by wild-type-specific CTL, or when recognized it is of low to moderate avidity, suggesting that the protease inhibitor-selected V82A mutation acts both as a CTL and protease inhibitor escape mutant. Paradoxically, the absence of a mutation at position 82 was associated with the presence of a high-avidity CD8(+) T-cell response to the wild-type virus sequence. Our results indicate that both HIV type 1-specific CD8(+) T cells and antiretroviral drugs provide complex pressures on the same amino acid sequence of the HIV protease gene and, thus, can influence viral sequence evolution.
authors.affiliation: Gladstone Institute of Virology and Immunology, University of California, San Francisco, California 94141, USA. akarlsson@gladstone.ucsf.edu
authors.forename: Annika C
authors.initials: AC
authors.lastname: Karlsson
authors.forename: Steven G
authors.initials: SG
authors.lastname: Deeks
authors.forename: Jason D
authors.initials: JD
authors.lastname: Barbour
authors.forename: Brandon D
authors.initials: BD
authors.lastname: Heiken
authors.forename: Sophie R
authors.initials: SR
authors.lastname: Younger
authors.forename: Rebecca
authors.initials: R
authors.lastname: Hoh
authors.forename: Meghan
authors.initials: M
authors.lastname: Lane
authors.forename: Matti
authors.initials: M
authors.lastname: Sällberg
authors.forename: Gabriel M
authors.initials: GM
authors.lastname: Ortiz
authors.forename: James F
authors.initials: JF
authors.lastname: Demarest
authors.forename: Teri
authors.initials: T
authors.lastname: Liegler
authors.forename: Robert M
authors.initials: RM
authors.lastname: Grant
authors.forename: Jeffrey N
authors.initials: JN
authors.lastname: Martin
authors.forename: Douglas F
authors.initials: DF
authors.lastname: Nixon
mesh_terms: D023241:Antiretroviral Therapy, Highly Active; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D024882:Drug Resistance, Viral; D018984:Epitopes, T-Lymphocyte; D015658:HIV Infections / Q000188:drug therapy* / Q000276:immunology / Q000821:virology; D016333:HIV Protease / Q000187:drug effects* / Q000235:genetics; D017320:HIV Protease Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology / Q000235:genetics; D015789:HLA-A2 Antigen / Q000378:metabolism; D006801:Humans; D009154:Mutation
chemical_list: D018984:Epitopes, T-Lymphocyte; D017320:HIV Protease Inhibitors; D015789:HLA-A2 Antigen; D016333:HIV Protease