Journal article
Role of Transmitted Gag CTL Polymorphisms in Defining Replicative Capacity and Early HIV-1 Pathogenesis
PLoS pathogens, Vol.8(11), pp.e1003041-e1003041
11/01/2012
DOI: 10.1371/journal.ppat.1003041
PMCID: PMC3510241
PMID: 23209412
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.
Details
- Title: Subtitle
- Role of Transmitted Gag CTL Polymorphisms in Defining Replicative Capacity and Early HIV-1 Pathogenesis
- Creators
- Jessica L. Prince - Emory UniversityDaniel T. Claiborne - Emory UniversityJonathan M. Carlson - MicrosoftMalinda Schaefer - Emory UniversityTianwei Yu - Emory UniversityShabir Lahki - Emory and Henry CollegeHeather A. Prentice - University of Alabama at BirminghamLing Yue - Emory UniversitySundaram A. Vishwanathan - Emory UniversityWilliam Kilembe - Emory and Henry CollegePaul Goepfert - University of Alabama at BirminghamMatthew A. Price - International AIDS Vaccine InitiativeJill Gilmour - International AIDS Vaccine InitiativeJoseph Mulenga - Emory and Henry CollegePaul Farmer - Emory UniversityCynthia A. Derdeyn - Emory UniversityJiaming Tang - University of Alabama at BirminghamDavid Heckerman - MicrosoftRichard A. Kaslow - University of Alabama at BirminghamSusan A. Allen - Emory UniversityEric Hunter - Emory University
- Resource Type
- Journal article
- Publication Details
- PLoS pathogens, Vol.8(11), pp.e1003041-e1003041
- Publisher
- Public Library Science
- DOI
- 10.1371/journal.ppat.1003041
- PMID
- 23209412
- PMCID
- PMC3510241
- ISSN
- 1553-7366
- eISSN
- 1553-7374
- Number of pages
- 15
- Grant note
- P51RR165 / National Center for Research Resources; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Center for Research Resources (NCRR) P51OD011132 / OFFICE OF THE DIRECTOR, NATIONAL INSTITUTES OF HEALTH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA International AIDS Vaccine Initiative 2P51RR000165-51 / Yerkes National Primate Research Center base grant P30 AI050409 / Virology Core at the Emory Center for AIDS Research R01AI064060 / NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Allergy & Infectious Diseases (NIAID) P51RR000165 / NATIONAL CENTER FOR RESEARCH RESOURCES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Center for Research Resources (NCRR) OD P51OD11132 / Office of Research Infrastructure Programs Action Cycling Fellowships
- Language
- English
- Date published
- 11/01/2012
- Academic Unit
- Obstetrics and Gynecology
- Record Identifier
- 9984697043502771
Metrics
1 Record Views