title: HLA-associated alterations in replication capacity of chimeric NL4-3 viruses carrying gag-protease from elite controllers of human immunodeficiency virus type 1.
abstract: Human immunodeficiency virus type 1 (HIV-1)-infected persons who maintain plasma viral loads of <50 copies RNA/ml without treatment have been termed elite controllers (EC). Factors contributing to durable control of HIV in EC are unknown, but an HLA-dependent mechanism is suggested by overrepresentation of "protective" class I alleles, such as B*27, B*51, and B*57. Here we investigated the relative replication capacity of viruses (VRC) obtained from EC (n = 54) compared to those from chronic progressors (CP; n = 41) by constructing chimeric viruses using patient-derived gag-protease sequences amplified from plasma HIV RNA and inserted into an NL4-3 backbone. The chimeric viruses generated from EC displayed lower VRC than did viruses from CP (P < 0.0001). HLA-B*57 was associated with lower VRC (P = 0.0002) than were other alleles in both EC and CP groups. Chimeric viruses from B*57(+) EC (n = 18) demonstrated lower VRC than did viruses from B*57(+) CP (n = 8, P = 0.0245). Differences in VRC between EC and CP were also observed for viruses obtained from individuals expressing no described "protective" alleles (P = 0.0065). Intriguingly, two common HLA alleles, A*02 and B*07, were associated with higher VRC (P = 0.0140 and 0.0097, respectively), and there was no difference in VRC between EC and CP sharing these common HLA alleles. These findings indicate that cytotoxic T-lymphocyte (CTL) selection pressure on gag-protease alters VRC, and HIV-specific CTLs inducing escape mutations with fitness costs in this region may be important for strict viremia control in EC of HIV.
authors.affiliation: Partners AIDS Research Center, Massachusetts General Hospital, 149 13th St., Room 5212, Charlestown, MA 02129, USA.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Miura
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: Florencia
authors.initials: F
authors.lastname: Pereyra
authors.forename: Alicja
authors.initials: A
authors.lastname: Trocha
authors.forename: Brian L
authors.initials: BL
authors.lastname: Block
authors.forename: Arne
authors.initials: A
authors.lastname: Schneidewind
authors.forename: Todd M
authors.initials: TM
authors.lastname: Allen
authors.forename: David
authors.initials: D
authors.lastname: Heckerman
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Walker
mesh_terms: D015497:HIV-1 / Q000276:immunology / Q000502:physiology*; D006680:HLA Antigens / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D010802:Phylogeny; D012367:RNA, Viral / Q000235:genetics; D011995:Recombination, Genetic; D012641:Selection, Genetic; D017422:Sequence Analysis, DNA; D017385:Sequence Homology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014779:Virus Replication; D054301:gag Gene Products, Human Immunodeficiency Virus / Q000235:genetics* / Q000378:metabolism
chemical_list: D006680:HLA Antigens; D012367:RNA, Viral; D054301:gag Gene Products, Human Immunodeficiency Virus