title: Role of transmitted Gag CTL polymorphisms in defining replicative capacity and early HIV-1 pathogenesis.
abstract: Initial studies of 88 transmission pairs in the Zambia Emory HIV Research Project cohort demonstrated that the number of transmitted HLA-B associated polymorphisms in Gag, but not Nef, was negatively correlated to set point viral load (VL) in the newly infected partners. These results suggested that accumulation of CTL escape mutations in Gag might attenuate viral replication and provide a clinical benefit during early stages of infection. Using a novel approach, we have cloned gag sequences isolated from the earliest seroconversion plasma sample from the acutely infected recipient of 149 epidemiologically linked Zambian transmission pairs into a primary isolate, subtype C proviral vector, MJ4. We determined the replicative capacity (RC) of these Gag-MJ4 chimeras by infecting the GXR25 cell line and quantifying virion production in supernatants via a radiolabeled reverse transcriptase assay. We observed a statistically significant positive correlation between RC conferred by the transmitted Gag sequence and set point VL in newly infected individuals (p = 0.02). Furthermore, the RC of Gag-MJ4 chimeras also correlated with the VL of chronically infected donors near the estimated date of infection (p = 0.01), demonstrating that virus replication contributes to VL in both acute and chronic infection. These studies also allowed for the elucidation of novel sites in Gag associated with changes in RC, where rare mutations had the greatest effect on fitness. Although we observed both advantageous and deleterious rare mutations, the latter could point to vulnerable targets in the HIV-1 genome. Importantly, RC correlated significantly (p = 0.029) with the rate of CD4+ T cell decline over the first 3 years of infection in a manner that is partially independent of VL, suggesting that the replication capacity of HIV-1 during the earliest stages of infection is a determinant of pathogenesis beyond what might be expected based on set point VL alone.
authors.affiliation: Emory Vaccine Center at Yerkes National Primate Research Center, Emory University, Atlanta, Georgia, United States of America.
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Prince
authors.forename: Daniel T
authors.initials: DT
authors.lastname: Claiborne
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Carlson
authors.forename: Malinda
authors.initials: M
authors.lastname: Schaefer
authors.forename: Tianwei
authors.initials: T
authors.lastname: Yu
authors.forename: Shabir
authors.initials: S
authors.lastname: Lahki
authors.forename: Heather A
authors.initials: HA
authors.lastname: Prentice
authors.forename: Ling
authors.initials: L
authors.lastname: Yue
authors.forename: Sundaram A
authors.initials: SA
authors.lastname: Vishwanathan
authors.forename: William
authors.initials: W
authors.lastname: Kilembe
authors.forename: Paul
authors.initials: P
authors.lastname: Goepfert
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Price
authors.forename: Jill
authors.initials: J
authors.lastname: Gilmour
authors.forename: Joseph
authors.initials: J
authors.lastname: Mulenga
authors.forename: Paul
authors.initials: P
authors.lastname: Farmer
authors.forename: Cynthia A
authors.initials: CA
authors.lastname: Derdeyn
authors.forename: Jiaming
authors.initials: J
authors.lastname: Tang
authors.forename: David
authors.initials: D
authors.lastname: Heckerman
authors.forename: Richard A
authors.initials: RA
authors.lastname: Kaslow
authors.forename: Susan A
authors.initials: SA
authors.lastname: Allen
authors.forename: Eric
authors.initials: E
authors.lastname: Hunter
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000821:virology; D002460:Cell Line; D005260:Female; D005500:Follow-Up Studies; D016679:Genome, Viral / Q000235:genetics / Q000276:immunology; D015658:HIV Infections / Q000453:epidemiology / Q000235:genetics / Q000276:immunology*; D015497:HIV-1 / Q000472:pathogenicity / Q000502:physiology; D006801:Humans; D008297:Male; D009154:Mutation; D011110:Polymorphism, Genetic; D014779:Virus Replication / Q000235:genetics / Q000276:immunology*; D015024:Zambia / Q000453:epidemiology; D054301:gag Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000276:immunology*
chemical_list: D054301:gag Gene Products, Human Immunodeficiency Virus