title: HIV-1 Vpr accelerates viral replication during acute infection by exploitation of proliferating CD4+ T cells in vivo.
abstract: 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.
authors: Laboratory of Virus Pathogenesis, Institute for Virus Research, Kyoto University, Kyoto, Kyoto, Japan ; Center for Emerging Virus Research, Institute for Virus Research, Kyoto University, Kyoto, Kyoto, Japan.
authors: Kei
authors: K
authors: Sato
authors: Naoko
authors: N
authors: Misawa
authors: Shingo
authors: S
authors: Iwami
authors: Yorifumi
authors: Y
authors: Satou
authors: Masao
authors: M
authors: Matsuoka
authors: Yukihito
authors: Y
authors: Ishizaka
authors: Mamoru
authors: M
authors: Ito
authors: Kazuyuki
authors: K
authors: Aihara
authors: Dong Sung
authors: DS
authors: An
authors: Yoshio
authors: Y
authors: Koyanagi
mesh_terms: D000208:Acute Disease; D000818:Animals; D000831:Animals, Newborn; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000821:virology*; D049109:Cell Proliferation; D002478:Cells, Cultured; D015658:HIV Infections / Q000276:immunology* / Q000821:virology*; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008822:Mice, Transgenic; D014766:Viremia / Q000276:immunology; D014779:Virus Replication; D054325:vpr Gene Products, Human Immunodeficiency Virus / Q000502:physiology*
chemical_list: D054325:vpr Gene Products, Human Immunodeficiency Virus; C514912:vpr protein, Human immunodeficiency virus 1