Skip to content
Home
About Us
Resources
Profiles Metrics
Authors Directory
Institutions Directory
Top Authors
Top Institutions
Top Sponsors
AI Digest
Contact Us
Menu
Home
About Us
Resources
Profiles Metrics
Authors Directory
Institutions Directory
Top Authors
Top Institutions
Top Sponsors
AI Digest
Contact Us
Home
About Us
Resources
Profiles Metrics
Authors Directory
Institutions Directory
Top Authors
Top Institutions
Top Sponsors
AI Digest
Contact Us
Menu
Home
About Us
Resources
Profiles Metrics
Authors Directory
Institutions Directory
Top Authors
Top Institutions
Top Sponsors
AI Digest
Contact Us
Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
biochemistry, genetics and molecular biology
Role of Transmitted Gag CTL Polymorphisms in Defining Replicative Capacity and Early HIV-1 Pathogenesis
PLoS Pathogens, Volume 8, No. 11, Article e1003041, Year 2012
Notification
URL copied to clipboard!
Description
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. © 2012 Prince et al.
Available Materials
https://efashare.b-cdn.net/share/pmc/articles/PMC3510241/bin/ppat.1003041.s001.eps
https://efashare.b-cdn.net/share/pmc/articles/PMC3510241/bin/ppat.1003041.s002.eps
https://efashare.b-cdn.net/share/pmc/articles/PMC3510241/bin/ppat.1003041.s003.doc
Authors & Co-Authors
Prince, Jessica L.
United States, Atlanta
Emory University
Claiborne, Daniel T.
United States, Atlanta
Emory University
Carlson, Jonathan M.
United States, Redmond
Microsoft Research
Schaefer, Malinda R.
United States, Atlanta
Emory University
Yu, Tianwei
United States, Atlanta
Emory University
Lahki, Shabir
Zambia, Lusaka
Zambia-emory Hiv Research Project
Prentice, Heather A.
United States, Birmingham
The University of Alabama at Birmingham
Yue, Ling
United States, Atlanta
Emory University
Vishwanathan, Sundaram A.
United States, Atlanta
Emory University
United States, Atlanta
National Center for Hiv, Viral Hepatitis, Std, and tb Prevention
Kilembe, William
Zambia, Lusaka
Zambia-emory Hiv Research Project
Goepfert, Paul A.
United States, Birmingham
The University of Alabama at Birmingham
Price, Matt A.
United States, San Francisco
International Aids Vaccine Initiative
Gilmour, Jill W.
United States, New York
International Aids Vaccine Initiative
Mulenga, Joseph
Zambia, Lusaka
Zambia-emory Hiv Research Project
Farmer, Paul K.
United States, Atlanta
Emory University
Derdeyn, Cynthia A.
United States, Atlanta
Emory University
Tang, Jiaming
United States, Birmingham
The University of Alabama at Birmingham
Heckerman, David E.
United States, Redmond
Microsoft Research
Kaslow, Richard A.
United States, Birmingham
The University of Alabama at Birmingham
Allen, Susan A.
Zambia, Lusaka
Zambia-emory Hiv Research Project
United States, Atlanta
Emory University
United States, Atlanta
Rollins School of Public Health
Hunter, Eric
United States, Atlanta
Emory University
Statistics
Citations: 95
Authors: 21
Affiliations: 8
Identifiers
Doi:
10.1371/journal.ppat.1003041
ISSN:
15537366
e-ISSN:
15537374
Research Areas
Infectious Diseases
Study Design
Cohort Study
Study Locations
Zambia