Abstract
Acquired immunodeficiency syndrome is a pandemic disease due to increased variability in causative agent in global distribution; it is attributed to various complications in developing the vaccine, namely, error-prone reverse transcriptase, rapid replication, and high recombination rate. Vpu downmodulates CD4 in infected cells, and it targets the newly synthesized CD4 molecules from the endoplasmic reticulum. The aim of this study was to identify the level of genetic changes in the Vpu gene from HIV-1-infected North Indian individuals and determine the functional relevance with respect to the CD4 downregulation potential of this protein. Genomic DNA was isolated from peripheral blood mononuclear cells, and the Vpu gene was polymerase chain reaction amplified with specific primers followed by cloning, sequencing, and sequence analyses using bioinformatic tools for predicting HIV-1 subtypes, recombination events, conservation of domains, and phosphorylation sites. Among all Vpu variants, three of the variants having serine substitution (serine-52 and serine-56 conversion to isoleucine; S52I and S56I) had lost their functional β-TrcP binding motif. However, the specific determinants for CD4 (V20, W22, S23) and BST-2 (A11, A15, I17, and A19) binding remained highly conserved. The data obtained with Vpu mutants recommend that the serine residue substitutions in cytoplasmic domain distress the CD4 downregulation activity of Vpu. These events are likely to have implications for viral pathogenesis and vaccine formulations.
Highlights
Acquired immunodeficiency syndrome (AIDS) is a pandemic disease and is complex to study due to its high genetic diversity of causative agent, that is, human immunodeficiency virus (HIV)
Genomic DNA was isolated from peripheral blood mononuclear cells, and the Vpu gene was polymerase chain reaction amplified with specific primers followed by cloning, sequencing, and sequence analyses using bioinformatic tools for predicting HIV-1 subtypes, recombination events, conservation of domains, and phosphorylation sites
We noticed for the first time the genetic evidence for positive selection of Vpu variants showing substitution of a serine residue in four of our variants (Vpu D72, Vpu 44, Vpu D97, and Vpu 84)
Summary
Acquired immunodeficiency syndrome (AIDS) is a pandemic disease and is complex to study due to its high genetic diversity of causative agent, that is, human immunodeficiency virus (HIV) It is one of the features with attendant consequences in global distribution, success of therapy disease progression, vaccine design, and transmissibility. HIV type-1 is accountable for the AIDS epidemic and consisting of four groups: M (main), O (outlier), N (non-M, non-O), and P.3,4 Among these four groups, the M group is successfully established in humans.[5] The M-group is responsible for a majority of infections worldwide that evolved into a pandemic and diversified into distinct genetic subtypes or clades (A, B, C, D, F, G, H, J, and K),[6] as well as many circulating recombinant forms (CRFs) and unique recombinant forms.
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