HIV-1 Vpr Accelerates Viral Replication during Acute Infection by Exploitation of Proliferating CD4+ T Cells In Vivo

PLoS Pathogens

Naoko Misawa¹  Dong Sung An²  Yorifumi Satou³  Kazuyuki Aihara⁴  Yoshio Koyanagi⁵  Mamoru Ito⁶  Yukihito Ishizaka⁶  Shingo Iwami⁷  Kei Sato⁷  Masao Matsuoka⁸ 

[1] Center for Emerging Virus Research, Institute for Virus Research, Kyoto University, Kyoto, Kyoto, Japan;Central Institute for Experimental Animals, Kawasaki, Kanagawa, Japan;Department of Biology, Faculty of Sciences, Kyushu University, Fukuoka, Fukuoka, Japan;Department of Intractable Diseases, National Center for Global Health and Medicine, Shinjuku-ku, Tokyo, Japan;Institute of Industrial Science, The University of Tokyo, Meguro-ku, Tokyo, Japan;Laboratory of Viral Control, Institute for Virus Research, Kyoto University, Kyoto, Kyoto, Japan;Laboratory of Virus Pathogenesis, Institute for Virus Research, Kyoto University, Kyoto, Kyoto, Japan;Precursory Research for Embryonic Science and Technology (PRESTO), Japan Science and Technology Agency (JST), Kawaguchi, Saitama, Japan

关键词: HIV-1;    Mouse models;    Regulatory T cells;    T cells;    Immune activation;    Cytotoxic T cells;    Flow cytometry;    Apoptosis;   

DOI  :  10.1371/journal.ppat.1003812

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

The precise role of viral protein R (Vpr), an HIV-1-encoded protein, during HIV-1 infection and its contribution to the development of AIDS remain unclear. Previous reports have shown that Vpr has the ability to cause G2 cell cycle arrest and apoptosis in HIV-1-infected cells in vitro. In addition, vpr is highly conserved in transmitted/founder HIV-1s and in all primate lentiviruses, which are evolutionarily related to HIV-1. Although these findings suggest an important role of Vpr in HIV-1 pathogenesis, its direct evidence in vivo has not been shown. Here, by using a human hematopoietic stem cell-transplanted humanized mouse model, we demonstrated that Vpr causes G2 cell cycle arrest and apoptosis predominantly in proliferating CCR5+ CD4+ T cells, which mainly consist of regulatory CD4+ T cells (Tregs), resulting in Treg depletion and enhanced virus production during acute infection. The Vpr-dependent enhancement of virus replication and Treg depletion is observed in CCR5-tropic but not CXCR4-tropic HIV-1-infected mice, suggesting that these effects are dependent on the coreceptor usage by HIV-1. Immune activation was observed in CCR5-tropic wild-type but not in vpr-deficient HIV-1-infected humanized mice. When humanized mice were treated with denileukin diftitox (DD), to deplete Tregs, DD-treated humanized mice showed massive activation/proliferation of memory T cells compared to the untreated group. This activation/proliferation enhanced CCR5 expression in memory CD4+ T cells and rendered them more susceptible to CCR5-tropic wild-type HIV-1 infection than to vpr-deficient virus. Taken together, these results suggest that Vpr takes advantage of proliferating CCR5+ CD4+ T cells for enhancing viremia of CCR5-tropic HIV-1. Because Tregs exist in a higher cycling state than other T cell subsets, Tregs appear to be more vulnerable to exploitation by Vpr during acute HIV-1 infection.

【 授权许可】

CC BY