Abstract
The Vpr protein of human immunodeficiency virus type 1 (HIV-1) contributes to viral replication in non-dividing cells, specifically those of the myeloid lineage. However, the effects of Vpr in enhancing HIV-1 infection in dendritic cells have not been extensively investigated. Here, we evaluated the role of Vpr during infection of highly permissive peripheral blood mononuclear cells (PBMCs) and CD4+ T-cells and compared it to that of monocyte-derived dendritic cells (MDDCs), which are less susceptible to HIV-1 infection. Infections of dividing PBMCs and non-dividing MDDCs were carried out with single-cycle and replication-competent HIV-1 encoding intact Vpr or Vpr-defective mutants. In contrast to previous findings, we observed that single-cycle HIV-1 infection of both PBMCs and MDDCs was significantly enhanced in the presence of Vpr when the viral stocks were carefully characterized and titrated. HIV-1 DNA quantification revealed that Vpr only enhanced the reverse transcription and nuclear import processes in single-cycle HIV-1 infected MDDCs, but not in CD4+ T-cells. However, a significant enhancement in HIV-1 gag mRNA expression was observed in both CD4+ T-cells and MDDCs in the presence of Vpr. Furthermore, Vpr complementation into HIV-1 virions did not affect single-cycle viral infection of MDDCs, suggesting that newly synthesized Vpr plays a significant role to facilitate single-cycle HIV-1 infection. Over the course of a spreading infection, Vpr significantly enhanced replication-competent HIV-1 infection in MDDCs, while it modestly promoted viral infection in activated PBMCs. Quantification of viral DNA in replication-competent HIV-1 infected PBMCs and MDDCs revealed similar levels of reverse transcription products, but increased nuclear import in the presence of Vpr independent of the cell types. Taken together, our results suggest that Vpr has differential effects on single-cycle and spreading HIV-1 infections, which are dependent on the permissiveness of the target cell.
Highlights
Among the four accessory proteins of human immunodeficiency virus type 1 (HIV-1), the viral protein R (Vpr) has been widely investigated due to its efficient incorporation in the virion particle, its ability to alter the cell cycle, and its cytopathic nature
To better understand the effects of Vpr on HIV-1 infection under highly permissive and less permissive cell type conditions, we examined the role of Vpr in activated peripheral blood mononucleocytes (PBMCs), CD4+ T-cells, and monocyte-derived dendritic cells (MDDCs) in the context of single-cycle and replication-competent HIV-1 infections
Our results indicate that Vpr significantly enhances singlecycle HIV-1 infection in peripheral blood mononuclear cells (PBMCs), CD4+ T-cells and MDDCs
Summary
Among the four accessory proteins of HIV-1, the viral protein R (Vpr) has been widely investigated due to its efficient incorporation in the virion particle, its ability to alter the cell cycle, and its cytopathic nature (reviewed in [1,2,3]). 96-amino acid protein that is expressed in the infected cell from the provirus as a late viral gene product from a singly spliced mRNA [4], and is efficiently incorporated into the viral particle through its interaction with the C-terminal p6 region of the Gag precursor [5]. Due to its ability to interact with numerous cellular proteins [6,7], several functions have been ascribed to Vpr. Due to its ability to interact with numerous cellular proteins [6,7], several functions have been ascribed to Vpr These include the induction of cell cycle arrest in the G2 phase [8], long-terminal-repeat (LTR)-transactivation [9,10,11,12], induction of apoptosis [13], enhancement of the fidelity of reverse transcription [14], and impairment of host immune function for HIV-1 evasion [15,16]. The role of DCAF1 in HIV-1 infection remains to be examined
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