Role of Transmitted Gag CTL Polymorphisms in Defining Replicative Capacity and Early HIV-1 Pathogenesis

PLoS Pathogens

Tianwei Yu¹  Heather A. Prentice²  Susan A. Allen²  Paul Goepfert³  David Heckerman³  Jiaming Tang⁴  Paul Farmer⁵  Sundaram A. Vishwanathan⁵  Ling Yue⁵  Cynthia A. Derdeyn⁵  Daniel T. Claiborne⁵  Jessica L. Prince⁵  Malinda Schaefer⁵  Jill Gilmour⁶  Matthew A. Price⁷  Jonathan M. Carlson⁸  Richard A. Kaslow⁸  Joseph Mulenga⁹  Shabir Lahki⁹  William Kilembe⁹  Eric Hunter⁹ 

[1] Department of Biostatistics and Bioinformatics, Emory University, Atlanta, Georgia, United States of America;Department of Epidemiology, University of Alabama, Birmingham, Alabama, United States of America;Department of Medicine, University of Alabama, Birmingham, Alabama, United States of America;Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia, United States of America;Emory Vaccine Center at Yerkes National Primate Research Center, Emory University, Atlanta, Georgia, United States of America;International AIDS Vaccine Initiative, London, England;International AIDS Vaccine Initiative, San Francisco, California, United States of America;Microsoft Research, Los Angeles, California, United States of America;Zambia-Emory HIV Research Project, Lusaka, Zambia

关键词: Viral replication;    HIV-1;    T cells;    Microbial mutation;    Sequence analysis;    Amino acid sequence analysis;    Pathogenesis;    Viral load;   

DOI  :  10.1371/journal.ppat.1003041

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY