title: Early selection in Gag by protective HLA alleles contributes to reduced HIV-1 replication capacity that may be largely compensated for in chronic infection.
abstract: Mutations that allow escape from CD8 T-cell responses are common in HIV-1 and may attenuate pathogenesis by reducing viral fitness. While this has been demonstrated for individual cases, a systematic investigation of the consequence of HLA class I-mediated selection on HIV-1 in vitro replication capacity (RC) has not been undertaken. We examined this question by generating recombinant viruses expressing plasma HIV-1 RNA-derived Gag-Protease sequences from 66 acute/early and 803 chronic untreated subtype B-infected individuals in an NL4-3 background and measuring their RCs using a green fluorescent protein (GFP) reporter CD4 T-cell assay. In acute/early infection, viruses derived from individuals expressing the protective alleles HLA-B*57, -B*5801, and/or -B*13 displayed significantly lower RCs than did viruses from individuals lacking these alleles (P < 0.05). Furthermore, acute/early RC inversely correlated with the presence of HLA-B-associated Gag polymorphisms (R = -0.27; P = 0.03), suggesting a cumulative effect of primary escape mutations on fitness during the first months of infection. At the chronic stage of infection, no strong correlations were observed between RC and protective HLA-B alleles or with the presence of HLA-B-associated polymorphisms restricted by protective alleles despite increased statistical power to detect these associations. However, RC correlated positively with the presence of known compensatory mutations in chronic viruses from B*57-expressing individuals harboring the Gag T242N mutation (n = 50; R = 0.36; P = 0.01), suggesting that the rescue of fitness defects occurred through mutations at secondary sites. Additional mutations in Gag that may modulate the impact of the T242N mutation on RC were identified. A modest inverse correlation was observed between RC and CD4 cell count in chronic infection (R = -0.17; P < 0.0001), suggesting that Gag-Protease RC could increase over the disease course. Notably, this association was stronger for individuals who expressed B*57, B*58, or B*13 (R = -0.27; P = 0.004). Taken together, these data indicate that certain protective HLA alleles contribute to early defects in HIV-1 fitness through the selection of detrimental mutations in Gag; however, these effects wane as compensatory mutations accumulate in chronic infection. The long-term control of HIV-1 in some persons who express protective alleles suggests that early fitness hits may provide lasting benefits.
authors.affiliation: Simon Fraser University, Molecular Biology and Biochemistry, British Columbia V5A 1S6, Canada. mark_brockman@sfu.ca
authors.forename: Mark A
authors.initials: MA
authors.lastname: Brockman
authors.forename: Zabrina L
authors.initials: ZL
authors.lastname: Brumme
authors.forename: Chanson J
authors.initials: CJ
authors.lastname: Brumme
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Miura
authors.forename: Jennifer
authors.initials: J
authors.lastname: Sela
authors.forename: Pamela C
authors.initials: PC
authors.lastname: Rosato
authors.forename: Carl M
authors.initials: CM
authors.lastname: Kadie
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Carlson
authors.forename: Tristan J
authors.initials: TJ
authors.lastname: Markle
authors.forename: Hendrik
authors.initials: H
authors.lastname: Streeck
authors.forename: Anthony D
authors.initials: AD
authors.lastname: Kelleher
authors.forename: Martin
authors.initials: M
authors.lastname: Markowitz
authors.forename: Heiko
authors.initials: H
authors.lastname: Jessen
authors.forename: Eric
authors.initials: E
authors.lastname: Rosenberg
authors.forename: Marcus
authors.initials: M
authors.lastname: Altfeld
authors.forename: P Richard
authors.initials: PR
authors.lastname: Harrigan
authors.forename: David
authors.initials: D
authors.lastname: Heckerman
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Walker
authors.forename: Todd M
authors.initials: TM
authors.lastname: Allen
mesh_terms: D000483:Alleles; D018791:CD4 Lymphocyte Count; D002908:Chronic Disease; D015331:Cohort Studies; D015658:HIV Infections / Q000235:genetics* / Q000276:immunology / Q000821:virology; D015497:HIV-1 / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D015235:HLA-B Antigens / Q000235:genetics* / Q000276:immunology; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D014779:Virus Replication; D054301:gag Gene Products, Human Immunodeficiency Virus / Q000235:genetics* / Q000276:immunology
chemical_list: D015235:HLA-B Antigens; D054301:gag Gene Products, Human Immunodeficiency Virus; C083868:gag protein p1, Human immunodeficiency virus
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