The human immunodeficiency virus type 2 vpr gene is essential for productive infection of human macrophages.

Abstract

The human immunodeficiency virus (HIV) genetic determinant(s) responsible for tropism in human T cells or macrophages are not well defined. We studied the role of the HIV type 2 (HIV-2) nef and vpr genes in viral tropism. HIV-2 mutants, lacking either vpr or nef genes, or both vpr and nef, were obtained by site-specific mutagenesis of a biologically active HIV-2 proviral clone (HIV-2sbl/isy), which is infectious in both human T cells and macrophages. Viral progeny carrying mutations of nef, vpr, or of both nef and vpr genes replicated more efficiently than the parental virus in primary human peripheral blood cells and in the human Hut 78 T-cell line. In contrast, the HIV-2 nef- mutant infected human macrophages as efficiently as the parental virus, whereas viruses lacking the vpr gene either alone or in conjunction with the lack of the nef gene did not replicate in macrophages. Thus, some lack of nef in HIV-2 enhances viral replication in T cells and does not interfere with viral replication in primary macrophages, whereas vpr is essential for replication of HIV-2 in human macrophages. Because the parental HIV-2sbl/isy cloned virus also infects rhesus macaques, the use in animal studies of these HIV-2 mutants with differences in cell tropism and rates of replication will be highly useful in understanding the mechanism of viral infectivity and possibly pathogenicity in vivo.

Definition of the range and distribution of human immunodeficiency virus macrophage tropism using PCR-based infectivity measurements

“…Fusion of the viral and cellular membranes is a candidate step, although a recent study using fluorescence dequenching suggests that tropism is determined by a post-fusion event (Potash et al, 1992). Other studies have found regions outside env that influence replication in m4, suggesting that entry may not be the sole determinant of tropism (Hattori et al, 1990;Westervelt et al, 1992). The precise resolution of which viral functions are modified by the type of host cell will depend on more accurate measurements of infectivity and productivity in HIV infection.…”

Synthetic Vpr Protein Activates Activator Protein-1, c-Jun N-terminal Kinase, and NF-κB and Stimulates HIV-1 Transcription in Promonocytic Cells and Primary Macrophages

“…Although this protein does not confer a significant viral growth advantage in primary T cells (28), its function is strictly required for viral replication in nondividing cells, such as monocytes/macrophages (3,29). However, positive effects of Vpr on HIV replication have been observed in a number of cell types as a result of its ability to delay infected cells at the G 2 /M phase of the cell cycle, in which the HIV long terminal repeat (LTR) is transcriptionally more active (4).…”

Using death to one's advantage: HIV modulation of apoptosis

“…Recent reports suggest that Vpr disrupts the regulation of Cdc2 kinase, which leads to G2 arrest. 104,105,109 Vpr interacts with highly conserved components of the cell cycle regulation pathways. Interestingly, others have reported that Vpr specifically binds to the highly conserved DNA repair enzyme uracil DNA glycoslyase (UNG), that is involved in removing uracil from DNA.…”

“…99,100 In proliferating T cells and stimulated peripheral blood mononuclear cells (PBMCs), Vpr appears to be dispensable for the in vitro replication of HIV. [101][102][103][104][105][106][107] However, under certain conditions, Vpr contributes substantially to HIV-1 replication in these cells. 99 Vpr has been shown to induce cell cycle arrest of cells in the G2 phase of the cell cycle.…”