Functional Cure of SIVagm Infection in Rhesus Macaques Results in Complete Recovery of CD4+ T Cells and Is Reverted by CD8+ Cell Depletion

PLoS Pathogens

Rajeev Gautam¹  David Montefiori¹  Thaidra Gaufin²  Ruy M. Ribeiro³  Ivona Pandrea⁴  Jan Kristoff⁵  Daniel Mandell⁵  Brandon F. Keele⁵  Cristian Apetrei⁶  Ronald S. Veazey⁷ 

[1] Center for Vaccine Research, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America;Department of Pathology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America;Department of Surgery, Duke University, Durham, North Carolina, United States of America;Division of Comparative Pathology, Tulane National Primate Research Center, Covington, Louisiana, United States of America;Division of Microbiology, Tulane National Primate Research Center, Covington, Louisiana, United States of America;Los Alamos National Laboratory, Los Alamos New Mexico, United States of America;SAIC Frederick, Inc, NCI, NIH, Frederick, Maryland, United States of America

关键词: Viral replication;    T cells;    Infectious disease control;    Animal models of infection;    Apoptosis;    Gastrointestinal tract;    Immune activation;    SIV;   

DOI  :  10.1371/journal.ppat.1002170

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

Understanding the mechanism of infection control in elite controllers (EC) may shed light on the correlates of control of disease progression in HIV infection. However, limitations have prevented a clear understanding of the mechanisms of elite controlled infection, as these studies can only be performed at randomly selected late time points in infection, after control is achieved, and the access to tissues is limited. We report that SIVagm infection is elite-controlled in rhesus macaques (RMs) and therefore can be used as an animal model for EC HIV infection. A robust acute infection, with high levels of viral replication and dramatic mucosal CD4+ T cell depletion, similar to pathogenic HIV-1/SIV infections of humans and RMs, was followed by complete and durable control of SIVagm replication, defined as: undetectable VLs in blood and tissues beginning 72 to 90 days postinoculation (pi) and continuing at least 4 years; seroreversion; progressive recovery of mucosal CD4+ T cells, with complete recovery by 4 years pi; normal levels of T cell immune activation, proliferation, and apoptosis; and no disease progression. This “functional cure” of SIVagm infection in RMs could be reverted after 4 years of control of infection by depleting CD8 cells, which resulted in transient rebounds of VLs, thus suggesting that control may be at least in part immune mediated. Viral control was independent of MHC, partial APOBEC restriction was not involved in SIVagm control in RMs and Trim5 genotypes did not impact viral replication. This new animal model of EC lentiviral infection, in which complete control can be predicted in all cases, permits research on the early events of infection in blood and tissues, before the defining characteristics of EC are evident and when host factors are actively driving the infection towards the EC status.

【 授权许可】

CC BY