Vpr Overcomes Macrophage-Specific Restriction of HIV-1 Env Expression and Virion Production

Michael Mashiba, David R. Collins, Valeri H. Terry, and Kathleen L. Collins1

Cell Host & Microbe. (2014) 16, 722–735

Speaker: Hsin-Hsin Chen (陳亲亲)                              Time: 15:10~16:00, May. 13, 2015

Commentator: Dr. Shainn-Wei Wang (王憲威 老師)  Place: Room 601

Abstract:

The primate lentiviruses, including HIV-1, HIV-2, encode a group of accessory proteins, Vif, Vpr, Vpx, Vpu, and Nef, whose function is to promote immune evasion by modulating intrinsic antiviral factors [1]. Recent studies demonstrated that Vpr utilizes DCAF1 and the Rbx1/Cullin4A E3 ubiquitin ligase complex to activate the structure- specific endonuclease (SSE) regulator SLX4 complex that leads to evade the innate immune sensing [2]. The interaction of Vpr and DCAF1 can enhance HIV infection in primary macrophage. However, the underlying mechanisms yet to be uncovered. Initially, authors constructed a Vpr-null mutant of the 89.6 molecular clone (89.6vpr^-), which was isolated from the blood of an HIV-1-infected person with AIDS. 89.6vpr^- is defective in infection of primary human monocyte-derived macrophage (MDMs), but can express as a wild-type virus in permissive cells such as CEMx174 and 293T cells. Compared to HIV-1 89.6, HIV-1 89.6 vpr^- infected cells expressed more IFN, and also showed the degradation of Env protein by lysosomes and produced less Env containing virions. Furthermore, DCAF1 silencing or addition of IFN has showed a reduction in Env expression and virion production in wild-type HIV-1-infected MDMs.

In summary, this study provides an important insight of HIV-1 evading the innate immune pathways, via Vpr to overcome the restriction of HIV-1 infection in primary cells.

References:

1.         Blanco-Melo, D. et al. (2011). Intrinsic Cellular Defenses against Human Immunodeficiency Viruses. Immunity 37, 399–411.

2.         Laguette, N. et al. (2014). Premature activation of the SLX4 complex by Vpr promotes G2/M arrest and escape from innate immune sensing. Cell 156, 134–145.