Abstract
Functional studies of HIV-1 proteins are normally conducted using lab adapted strains of HIV-1. The extent of those functions in clinical strains is sometimes unknown. In this study, we amplified and sequenced HIV-1 Vpu from 10 Iranian patients infected with HIV-1. Phylogenetic analysis indicated that the Vpu alleles were closely related to the CRF35_AD from Iran and subtype A Vpu. We addressed some of the well-established functions of the HIV-1 Vpu, as well as some of its recently reported functions. Ability of the clinical strains of subtype A Vpu alleles for downregulation of CD4 was similar to that of the lab adapted NL4.3 Vpu. Majority of the subtype A Vpu alleles performed stronger than NL4.3 Vpu for downregulation of SNAT1. The Vpu alleles differentially induced downregulation of HLA-C, ranging from no effect to 88% downregulation of surface HLA-C. Downregulation of tetherin and enhancement of virus release was similar for the subtype A Vpu alleles and NL4.3. Subtype A Vpu alleles were more potent when compared with NL4.3 for inhibition of NF-κB activation. Our study shows that subtype A Vpu alleles exert the classical functions of HIV-1 Vpu.
Highlights
Viral protein U (Vpu) is a small accessory protein unique to HIV-1 and closely related lentiviruses[1]
It was hypothesized that antagonism of SNAT1 by HIV-1 Vpu interferes with amino acid metabolism which is required for primary CD4+ T cell mitogenesis[12]
Phylogenetic analysis of the sequences indicated that all the Vpu alleles clustered with the previously described isolates of CRF35_AD (Fig. 1A)
Summary
Viral protein U (Vpu) is a small accessory protein unique to HIV-1 and closely related lentiviruses[1]. There are cell lines in which Vpu is dispensable for virus release. This discrepancy in cell line dependency of Vpu prompted the research for finding a potential restriction factor responsible for restricting HIV-1 virion release This restriction factor was identified as a membrane protein, tetherin, called CD317 or BST24. Tetherin is an interferon-induced restriction factor that inhibits release of many enveloped viruses by tethering the newly formed virions to the cell membrane. Downregulation of tetherin by Vpu inhibits secondary anti-HIV responses, such as interferon production and antibody-dependent cellular cytotoxicity that are mediated by tetherin[6, 7]. A recent study demonstrated that de novo expression of Vpu resulted in downregulation of the neutral amino acid transporter SNAT1 on plasma membrane of activated primary human CD4+ T cells. Functional analysis of the Vpu alleles showed that they form a coherent group with similar activities despite sequence differences
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