title: Uncommon pathways of immune escape attenuate HIV-1 integrase replication capacity.
abstract: An attenuation of the HIV-1 replication capacity (RC) has been observed for immune-mediated escape mutations in Gag restricted by protective HLA alleles. However, the extent to which escape mutations affect other viral proteins during natural infection is not well understood. We generated recombinant viruses encoding plasma HIV-1 RNA integrase sequences from antiretroviral-naïve individuals with early (n = 88) and chronic (n = 304) infections and measured the in vitro RC of each. In contrast to data from previous studies of Gag, we observed little evidence that host HLA allele expression was associated with integrase RC. A modest negative correlation was observed between the number of HLA-B-associated integrase polymorphisms and RC in chronic infection (R = -0.2; P = 0.003); however, this effect was not driven by mutations restricted by protective HLA alleles. Notably, the integrase variants S119R, G163E, and I220L, which represent uncommon polymorphisms associated with HLA-C*05, -A*33, and -B*52, respectively, correlated with lower RC (all q < 0.2). We identified a novel C*05-restricted epitope (HTDNGSNF(114-121)) that likely contributes to the selection of the S119R variant, the polymorphism most significantly associated with lower RC in patient sequences. An NL4-3 mutant encoding the S119R polymorphism displayed a ~35%-reduced function that was rescued by a single compensatory mutation of A91E. Together, these data indicate that substantial HLA-driven attenuation of integrase is not a general phenomenon during HIV-1 adaptation to host immunity. However, uncommon polymorphisms selected by HLA alleles that are not conventionally regarded to be protective may be associated with impaired protein function. Vulnerable epitopes in integrase might therefore be considered for future vaccine strategies.
authors.affiliation: Simon Fraser University, Burnaby, Canada.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Brockman
authors.forename: Denis R
authors.initials: DR
authors.lastname: Chopera
authors.forename: Alex
authors.initials: A
authors.lastname: Olvera
authors.forename: Chanson J
authors.initials: CJ
authors.lastname: Brumme
authors.forename: Jennifer
authors.initials: J
authors.lastname: Sela
authors.forename: Tristan J
authors.initials: TJ
authors.lastname: Markle
authors.forename: Eric
authors.initials: E
authors.lastname: Martin
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Carlson
authors.forename: Anh Q
authors.initials: AQ
authors.lastname: Le
authors.forename: Rachel
authors.initials: R
authors.lastname: McGovern
authors.forename: Peter K
authors.initials: PK
authors.lastname: Cheung
authors.forename: Anthony D
authors.initials: AD
authors.lastname: Kelleher
authors.forename: Heiko
authors.initials: H
authors.lastname: Jessen
authors.forename: Martin
authors.initials: M
authors.lastname: Markowitz
authors.forename: Eric
authors.initials: E
authors.lastname: Rosenberg
authors.forename: Nicole
authors.initials: N
authors.lastname: Frahm
authors.forename: Jorge
authors.initials: J
authors.lastname: Sanchez
authors.forename: Simon
authors.initials: S
authors.lastname: Mallal
authors.forename: Mina
authors.initials: M
authors.lastname: John
authors.forename: P Richard
authors.initials: PR
authors.lastname: Harrigan
authors.forename: David
authors.initials: D
authors.lastname: Heckerman
authors.forename: Christian
authors.initials: C
authors.lastname: Brander
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Walker
authors.forename: Zabrina L
authors.initials: ZL
authors.lastname: Brumme
mesh_terms: D015331:Cohort Studies; D015658:HIV Infections / Q000235:genetics / Q000276:immunology* / Q000821:virology; D019427:HIV Integrase / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D015497:HIV-1 / Q000201:enzymology* / Q000235:genetics / Q000276:immunology; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000276:immunology; D006801:Humans; D057131:Immune Evasion; D008969:Molecular Sequence Data; D014779:Virus Replication
chemical_list: D015395:Histocompatibility Antigens Class I; D019427:HIV Integrase; C514801:p31 integrase protein, Human immunodeficiency virus 1