Identification of two unique naturally occurring Vpr sequence polymorphisms associated with clinical parameters in HIV‐1 chronic infection

Abstract

HIV-1 viral protein R (Vpr) plays important roles in HIV-1 replication. Despite the identification of a number of HLA class I-associated immune escape mutations; it is yet known whether immune-driven Vpr polymorphisms are associated with disease outcome. Hereby, we comprehensively analyzed Vpr sequence polymorphisms and their association with disease outcome and host HLA genotypes, by using plasma viral RNA isolated from 444 HLA-typed, treatment-naïve, chronically HIV-1 infected individuals. Vpr amino acid residues at positions 13, 37, 45, 55, 63, 77, 84, 85, 86, and 93 were significantly associated with patients' plasma viral load and/or CD4 count. Further analysis revealed Ala at position 55 was significantly associated with lower plasma viral load; and Thr at position 63 was significantly associated with lower plasma viral load and higher CD4 count. Also, the number of amino acid residues at the two positions, located in a functionally important α-helical domain, correlated inversely with plasma viral load and positively with CD4 count. Moreover, a phylogenetically corrected method revealed residues at positions 55 and 63 are associated with patients' HLA genotypes. Taken together, our results suggest that Vpr polymorphisms at functionally important and immune-reactive sites may contribute, at least in part, to viral replication and disease outcome in vivo. J. Med. Virol. 89:123-129, 2017. © 2016 Wiley Periodicals, Inc.

A Proteome-Wide Immunoinformatics Tool to Accelerate T-Cell Epitope Discovery and Vaccine Design in the Context of Emerging Infectious Diseases: An Ethnicity-Oriented Approach

“…Because these proteins are expressed earlier in the viral life cycle, their recognition may occur before Nef down-modulates HLA class I molecules on the surface of the infected cells and thus provide a window of opportunity to the immune system to clear the infected cell before the virus is released (81). Another CD8+ T-cell epitope predicted by Predivac-3.0 within a cluster region of Vpr is the HLA-A*02:01-restricted peptide AIIRILQQL (82,83), which is located in a functionally important region involved with perinuclear localization of the protein (84,85). This peptide has been shown to correlate inversely with plasma viral load and positively with CD4 count in a study involving a cohort of HIV-1 infected individuals expressing the HLA-A*02:01 allele (80).…”

The influence of viral protein R amino acid substitutions on clinical outcomes in people living with HIV: A systematic review

“…51,[64][65][66][67]74,76,78 Cross-sectional studies. 49,52,63,[70][71][72][73]75,77,79,[80][81][82]84 Case studies. [63][64][65][66][67] Studies that reported sample types other than blood.…”

“…In particular, the 63T has been associated with characteristics of slower disease progression. 75,76 When comparing the Vpr sequences between subtypes (Figure 1), subtype C was the only subtype that presented with the 63T substitution. Considering the fact that subtype C has been associated with slower disease progression and replication fitness, [85][86][87][88] it is plausible to speculate that 63T may have a functional role in this outcome.…”

“…The amino acid substitutions 2E, 18W, 29G, 31D, 33H, 41G, 44R, 55A, 63T, 65R, 70I, 70V, 76C, 77Q, 78H, 83V, 85P, 86G, 86R, 89G, 89T, 89S, 89A, 93A, 93S, 93R and 94G were associated with positive clinical outcomes (Table 1 and Figure 4A). In particular, these Vpr amino acid substitutions were more prevalent with long-term nonprogressors (LTNP), 64,67,[70][71][72][73][74] lower viral load 75 and higher CD4 + count 75,76 (Table 1). The amino acid substitutions 3R, 21I, 22L, 41S, 64P, 75R, 77Q and 79G were associated with negative clinical outcomes (Table 1) and were more prevalent with progressors and/or acute HIV-1 infection, 63,67,74 higher viral load 66 and lower CD4 + count 66 (Table 1).…”

The HIV-1 Vpr Protein: A Multifaceted Target for Therapeutic Intervention

“…Mutations at positions 3, 36, 37, 41, 55, 63, 68, 72, and 77 have been associated with variations in the disease progression or the degree of neurocognitive deficit in patients. The simultaneous presence of A55 and T63 in patient-derived Vpr sequences has been associated with lower plasma viral load and higher CD4 count compared with those that express either single or none of these residues [ 167 ]. The impact on the neurocognitive function of patients has been associated with the presence of G41N and A55 (detrimental effect) or I37 and S41 (beneficial effect) [ 168 ].…”