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

• DOI: 10.1371/journal.ppat.1003812
• Publication Date: 2013-12-05T22:03:05Z
• Authors: Kei Sato; Naoko Misawa; Shingo Iwami; Yorifumi Satou; Masao Matsuoka; Yukihito Ishizaka; Mamoru Ito; Kazuyuki Aihara; Dong Sung An; Yoshio Koyanagi
• Keywords: CD4-Positive T-Lymphocytes; 0303 health sciences; QH301-705.5; HIV Infections; Mice, Transgenic; Mice, SCID; vpr Gene Products, Human Immunodeficiency Virus; RC581-607; Virus Replication; 3. Good health; Mice; 03 medical and health sciences; Animals, Newborn; Mice, Inbred NOD; Acute Disease; HIV-1; Animals; Humans; Viremia; Immunologic diseases. Allergy; Biology (General); Cells, Cultured; Research Article; Cell Proliferation

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.