Gene Defects Clustered at the C-Terminus of the vpr Gene of HIV-1 in Long-Term Nonprogressing Mother and Child Pair:In VivoEvolution of vpr Quasispecies in Blood and Plasma

Abstract

Earlier studies on HIV-1 strains from HIV-1-infected long-term nonprogressors (LTNP) have reported that nef deletions and/or attenuations may be crucial in the survival of these patients. Other reports have suggested that the nef gene may not be the only gene involved, but attenuations in other accessory genes (vif, vpr, vpu), which play an important role in the viral life cycle, may be similarly important in chronic HIV-1 infection in LTNPs. Here we show the molecular and phylogenetic analyses of the vpr gene in HIV-1 strains derived from both blood and plasma of an HIV-1 infected long-surviving mother-child pair which has survived for > 13 years with HIV infection: both have maintained stable CD4+ T-cell counts. Analyses of blood-and plasma-derived HIV-1 vpr clones indicated the presence of defects (insertions and deletions) and length polymorphisms. Interestingly, all the vpr defects in PBMCs and plasma were clustered at the C-terminus of the Vpr protein, between amino acid residues 83 and 89, which has been implicated in the G2 cell cycle arrest as a step to early HIV-1 infection. In contrast, the vpr sequence analysis of HIV-1 strains derived from 30 different patients, who either died of AIDS-related illnesses or have AIDS, showed neither C-terminal defects nor length polymorphism in the vpr gene. Also, secondary structure predictions suggest that the naturally occurring mutations at the C-terminal region (aa 83-89) have the potential to affect the secondary structure of the Vpr protein. Also, in some cases, the out-of-frame mutations and the length polymorphisms affect the tat gene reading frame. Together, these mutations may have potential significance in conferring chronic HIV-1 infection in this long-surviving nonprogressing mother-child pair.

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

“…In agreement with this observation, gene defects clustered at the C terminus of the vpr gene of HIV-1 have been reported in long-term nonprogressors (41,83,84). In these long-term nonprogressors all the vpr defects in human peripheral blood mononuclear cells and plasma were clustered at the C-terminal moiety of the Vpr protein, between amino acid residues 83 and 89 (84). Vpr association with both Tat and cyclin T1 results in superactivation of LTR by Tat and is not observed with the R73S mutant of Vpr (49).…”

“…By contrast, the C-terminal moiety of synthetic Vpr was more active in acutely HIV-infected primary M⌽, resulting in a sustained enhancement of HIV-1 replication. In agreement with this observation, gene defects clustered at the C terminus of the vpr gene of HIV-1 have been reported in long-term nonprogressors (41,83,84). In these long-term nonprogressors all the vpr defects in human peripheral blood mononuclear cells and plasma were clustered at the C-terminal moiety of the Vpr protein, between amino acid residues 83 and 89 (84).…”

Evidence for a cytopathogenicity determinant in HIV-1 Vpr

“…In all cases, non-progressors containing deletions and hard-torevert polymorphisms in viral genes maintained low to undetectable levels of plasma viral RNA. Defects have been identified in vpr alleles obtained from a non-progressing mother and child pair (29). The influence of such defects on an activity of Vpr that could have contributed to the non-progressor phenotype was not evaluated although many of the mutations affected the tat reading frame and were likely to severely compromise viral replication capacity.…”

Cyclin-dependent kinase-1: linking apoptosis to cell cycle and mitotic catastrophe

“…59 Rather, current observations are in line with the hypothesis that Vpr induces apoptosis through a mitochondrial pathway not related to Cdk1. 59,60 It will be interesting to follow the cell cycle characteristics of peripheral T cells from HIV-1-infected long-term non-progressors lacking the apoptogenic domain of Vpr, either due to a point mutation (R77Q) 61,62 or due to stop mutations. 57 …”