The Expression of Functional Vpx during Pathogenic SIVmac Infections of Rhesus Macaques Suppresses SAMHD1 in CD4+ Memory T Cells

PLoS Pathogens

Masashi Shingai¹  Malcolm A. Martin¹  Jason M. Brenchley¹  Ronald J. Plishka¹  Eri Miyagi¹  Yoshiaki Nishimura¹  Alicia Buckler-White¹  Sarah Welbourn¹  Klaus Strebel¹  Priyamvada Acharya²  Peter D. Kwong² 

[1] Laboratory of Molecular Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America;Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America

关键词: Macaque;    T cells;    Memory T cells;    SIV;    Viral replication;    Rhesus monkeys;    Monkeys;    Immunoblotting;   

DOI  :  10.1371/journal.ppat.1004928

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

For nearly 20 years, the principal biological function of the HIV-2/SIV Vpx gene has been thought to be required for optimal virus replication in myeloid cells. Mechanistically, this Vpx activity was recently reported to involve the degradation of Sterile Alpha Motif and HD domain-containing protein 1 (SAMHD1) in this cell lineage. Here we show that when macaques were inoculated with either the T cell tropic SIVmac239 or the macrophage tropic SIVmac316 carrying a Vpx point mutation that abrogates the recruitment of DCAF1 and the ensuing degradation of endogenous SAMHD1 in cultured CD4+ T cells, virus acquisition, progeny virion production in memory CD4+ T cells during acute infection, and the maintenance of set-point viremia were greatly attenuated. Revertant viruses emerging in two animals exhibited an augmented replication phenotype in memory CD4+ T lymphocytes both in vitro and in vivo, which was associated with reduced levels of endogenous SAMHD1. These results indicate that a critical role of Vpx in vivo is to promote the degradation of SAMHD1 in memory CD4+ T lymphocytes, thereby generating high levels of plasma viremia and the induction of immunodeficiency.

【 授权许可】

CC BY