title: Impaired replication capacity of acute/early viruses in persons who become HIV controllers.
abstract: Human immunodeficiency virus type 1 (HIV-1) controllers maintain viremia at <2,000 RNA copies/ml without antiretroviral therapy. Viruses from controllers with chronic infection were shown to exhibit impaired replication capacities, in part associated with escape mutations from cytotoxic-T-lymphocyte (CTL) responses. In contrast, little is known about viruses during acute/early infection in individuals who subsequently become HIV controllers. Here, we examine the viral replication capacities, HLA types, and virus sequences from 18 HIV-1 controllers identified during primary infection. gag-protease chimeric viruses constructed using the earliest postinfection samples displayed significantly lower replication capacities than isolates from persons who failed to control viremia (P = 0.0003). Protective HLA class I alleles were not enriched in these early HIV controllers, but viral sequencing revealed a significantly higher prevalence of drug resistance mutations associated with impaired viral fitness in controllers than in noncontrollers (6/15 [40.0%] versus 10/80 [12.5%], P = 0.018). Moreover, of two HLA-B57-positive (B57(+)) controllers identified, both harbored, at the earliest time point tested, signature escape mutations within Gag that likewise impair viral replication capacity. Only five controllers did not express "protective" alleles or harbor viruses with drug resistance mutations; intriguingly, two of them displayed typical B57 signature mutations (T242N), suggesting the acquisition of attenuated viruses from B57(+) donors. These data indicate that acute/early stage viruses from persons who become controllers have evidence of reduced replication capacity during the initial stages of infection which is likely associated with transmitted or acquired CTL escape mutations or transmitted drug resistance mutations. These data suggest that viral dynamics during acute infection have a major impact on HIV disease outcome.
authors.affiliation: Ragon Institute of MGH, MIT and Harvard, Boston, Massachusetts, USA. miura523@ims.u-tokyo.ac.jp
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Miura
authors.forename: Zabrina L
authors.initials: ZL
authors.lastname: Brumme
authors.forename: Mark A
authors.initials: MA
authors.lastname: Brockman
authors.forename: Pamela
authors.initials: P
authors.lastname: Rosato
authors.forename: Jennifer
authors.initials: J
authors.lastname: Sela
authors.forename: Chanson J
authors.initials: CJ
authors.lastname: Brumme
authors.forename: Florencia
authors.initials: F
authors.lastname: Pereyra
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Kaufmann
authors.forename: Alicja
authors.initials: A
authors.lastname: Trocha
authors.forename: Brian L
authors.initials: BL
authors.lastname: Block
authors.forename: Eric S
authors.initials: ES
authors.lastname: Daar
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Connick
authors.forename: Heiko
authors.initials: H
authors.lastname: Jessen
authors.forename: Anthony D
authors.initials: AD
authors.lastname: Kelleher
authors.forename: Eric
authors.initials: E
authors.lastname: Rosenberg
authors.forename: Martin
authors.initials: M
authors.lastname: Markowitz
authors.forename: Kim
authors.initials: K
authors.lastname: Schafer
authors.forename: Florin
authors.initials: F
authors.lastname: Vaida
authors.forename: Aikichi
authors.initials: A
authors.lastname: Iwamoto
authors.forename: Susan
authors.initials: S
authors.lastname: Little
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Walker
mesh_terms: D024882:Drug Resistance, Viral; D015658:HIV Infections / Q000276:immunology / Q000821:virology*; D020276:HIV Long-Term Survivors; D015497:HIV-1 / Q000254:growth & development / Q000276:immunology / Q000472:pathogenicity / Q000502:physiology*; D015395:Histocompatibility Antigens Class I / Q000235:genetics; D006801:Humans; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D012367:RNA, Viral / Q000235:genetics; D017422:Sequence Analysis, DNA; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D019562:Viral Load; D014766:Viremia; D014779:Virus Replication
chemical_list: D015395:Histocompatibility Antigens Class I; D012367:RNA, Viral