title: Influence of Gag-protease-mediated replication capacity on disease progression in individuals recently infected with HIV-1 subtype C.
abstract: HLA class I-mediated selection of immune escape mutations in functionally important Gag epitopes may partly explain slower disease progression in HIV-1-infected individuals with protective HLA alleles. To investigate the impact of Gag function on disease progression, the replication capacities of viruses encoding Gag-protease from 60 individuals in early HIV-1 subtype C infection were assayed in an HIV-1-inducible green fluorescent protein reporter cell line and were correlated with subsequent disease progression. Replication capacities did not correlate with viral load set points (P = 0.37) but were significantly lower in individuals with below-median viral load set points (P = 0.03), and there was a trend of correlation between lower replication capacities and lower rates of CD4 decline (P = 0.09). Overall, the proportion of host HLA-specific Gag polymorphisms in or adjacent to epitopes was negatively associated with replication capacities (P = 0.04), but host HLA-B-specific polymorphisms were associated with higher viral load set points (P = 0.01). Further, polymorphisms associated with host-specific protective HLA alleles were linked with higher viral load set points (P = 0.03). These data suggest that transmission or early HLA-driven selection of Gag polymorphisms results in reduced early cytotoxic T-lymphocyte (CTL) responses and higher viral load set points. In support of the former, 46% of individuals with nonprotective alleles harbored a Gag polymorphism exclusively associated with a protective HLA allele, indicating a high rate of their transmission in sub-Saharan Africa. Overall, HIV disease progression is likely to be affected by the ability to mount effective Gag CTL responses as well as the replication capacity of the transmitted virus.
authors.affiliation: HIV Pathogenesis Programme, University of KwaZulu-Natal, 719 Umbilo Road, Durban, 4013, South Africa.
authors.forename: Jaclyn K
authors.initials: JK
authors.lastname: Wright
authors.forename: Vladimir
authors.initials: V
authors.lastname: Novitsky
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: Jonathan M
authors.initials: JM
authors.lastname: Carlson
authors.forename: David
authors.initials: D
authors.lastname: Heckerman
authors.forename: Bingxia
authors.initials: B
authors.lastname: Wang
authors.forename: Elena
authors.initials: E
authors.lastname: Losina
authors.forename: Mopo
authors.initials: M
authors.lastname: Leshwedi
authors.forename: Mary
authors.initials: M
authors.lastname: van der Stok
authors.forename: Lungile
authors.initials: L
authors.lastname: Maphumulo
authors.forename: Nompumelelo
authors.initials: N
authors.lastname: Mkhwanazi
authors.forename: Fundisiwe
authors.initials: F
authors.lastname: Chonco
authors.forename: Philip J R
authors.initials: PJ
authors.lastname: Goulder
authors.forename: Max
authors.initials: M
authors.lastname: Essex
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Walker
authors.forename: Thumbi
authors.initials: T
authors.lastname: Ndung'u
mesh_terms: D000328:Adult; D018450:Disease Progression; D005260:Female; D015658:HIV Infections / Q000821:virology*; D016333:HIV Protease / Q000378:metabolism*; D015497:HIV-1 / Q000302:isolation & purification / Q000472:pathogenicity*; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D011110:Polymorphism, Genetic; D012367:RNA, Viral / Q000235:genetics; D017422:Sequence Analysis, DNA; D019562:Viral Load; D014774:Virulence; D014779:Virus Replication; D054301:gag Gene Products, Human Immunodeficiency Virus / Q000378:metabolism*
chemical_list: D012367:RNA, Viral; D054301:gag Gene Products, Human Immunodeficiency Virus; D016333:HIV Protease