HIV-1 accessory protein Vpr: relevance in the pathogenesis of HIV and potential for therapeutic intervention

Abstract

The HIV protein, Vpr, is a multifunctional accessory protein critical for efficient viral infection of target CD4+ T cells and macrophages. Vpr is incorporated into virions and functions to transport the preintegration complex into the nucleus where the process of viral integration into the host genome is completed. This action is particularly important in macrophages, which as a result of their terminal differentiation and non-proliferative status, would be otherwise more refractory to HIV infection. Vpr has several other critical functions including activation of HIV-1 LTR transcription, cell-cycle arrest due to DCAF-1 binding, and both direct and indirect contributions to T-cell dysfunction. The interactions of Vpr with molecular pathways in the context of macrophages, on the other hand, support accumulation of a persistent reservoir of HIV infection in cells of the myeloid lineage. The role of Vpr in the virus life cycle, as well as its effects on immune cells, appears to play an important role in the immune pathogenesis of AIDS and the development of HIV induced end-organ disease. In view of the pivotal functions of Vpr in virus infection, replication, and persistence of infection, this protein represents an attractive target for therapeutic intervention.

Figure 1

The role of Vpr in HIV-1 infection and host permissiveness. 1). HIV-1 enters human cells via interaction with cell-surface receptors CD4 and co-receptors CXCR4 (T-cell tropic viruses) or CCR5 (macrophage tropic viruses). The virus fuses with the cell surface membrane introducing genetic material and virion proteins, which include gag proteins that comprise the matrix and nucleocapsid, the latter containing significant quantities of Vpr. 2). Vpr promotes the binding of the PIC (including MA, integrase (IN) and proviral DNA) to importins and nucleoporins, thereby facilitating nuclear entry of HIV-1 provirus into the nucleus of non-dividing cells. 3). Vpr binds to the p300/transcription factor initiation complex. This binding activity may recruit additional elements to the promoter, such as glucocorticoid receptor (GR). Alternatively, Vpr may bind to GR bound to GRE elements in the promoter to recruit the p300/TF complex. This results in both increased HIV-1 production, and the regulation of cellular genes that may increase viral permissiveness. 4). Vpr induces G₂ cell-cycle arrest by promoting phosphorylation of Chk1, which increases viral production. Interestingly, the biochemical properties that contribute to this effect may be important in HIV-1 production in cells that do not divide. This property is dependent on the degradation of an unknown factor, which is recruited to Vpr via DCAF-1 interaction. The factor(s) involved in G₂ arrest and viral permissiveness may be overlapping or unique. 5). HIV-1 buds from the cell, promoting further infection and pathogenesis.

Figure 2

Summary of HIV-1 pathology involving Vpr. Vpr is likely important for both immune dysfunction as seen in AIDS and associated diseases including HIV-D and HIVAN.

Figure 3

Proposed timeline for HIV-1 Vpr mediated pathology and resistance to therapy. Early in infection, Vpr allows for productive viral infection of macrophages. These cells contribute to virus production and drug resistant reservoirs seen throughout the infection. During clinical latency, Vpr contributes to the depletion of CD4⁺ and CD8⁺ T-cells, as well as interferes with antigen presentation. Such properties may contribute to HIV-1 escape from immune surveillance, and effective humoral control of HIV infection. While it is yet unclear if neurocognitive dysfunction and HIV-D are related pathologies, Vpr mediated immune dysregulation and neurotoxicity may contribute to early neurological impairment in HIV-1 patients. Late in HIV-1 pathogenesis, increased expression of viral proteins including Vpr, contributes to the development of associated pathologies, such as HIV-D and HIVAN.