Immune evasion activities of accessory proteins Vpu, Nef and Vif are conserved in acute and chronic HIV-1 infection.
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ABSTRACT:
SUBMITTER: Mlcochova P
PROVIDER: S-EPMC4503796 | biostudies-literature | 2015 Aug
REPOSITORIES: biostudies-literature
Publications
Immune evasion activities of accessory proteins Vpu, Nef and Vif are conserved in acute and chronic HIV-1 infection.
Mlcochova Petra P Apolonia Luis L Kluge Silvia F SF Sridharan Aishwarya A Kirchhoff Frank F Malim Michael H MH Sauter Daniel D Gupta Ravindra K RK
Virology 20150330
Heterosexual HIV-1 transmission has been identified as a genetic bottleneck and a single transmitted/founder (T/F) variant with reduced sensitivity to type I interferon initiates productive infection in most cases. We hypothesized that particularly active accessory protein(s) may confer T/F viruses with a selective advantage in establishing HIV infection. Thus, we tested vpu, vif and nef alleles from six T/F and six chronic (CC) viruses in assays for 9 immune evasion activities involving the cou ...[more]
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Project description:HIV-1 accessory proteins Nef and Vpu enhance viral pathogenesis through partially overlapping immune evasion activities. Attenuated Nef or Vpu functions have been reported in individuals who display slower disease progression, but few studies have assessed the relative impact of these proteins in non-B HIV-1 subtypes or examined paired proteins from the same individuals. Here, we examined the sequence and function of matched Nef and Vpu clones isolated from 29 long-term survivors (LTS) from Rwanda living with HIV-1 subtype A and compared our results to those of 104 Nef and 62 Vpu clones isolated from individuals living with chronic untreated HIV-1 subtype A from the same geographic area. Nef and vpu coding regions were amplified from plasma HIV RNA and cloned. The function of one intact, phylogenetically-validated Nef and Vpu clone per individual was then quantified by flow cytometry following transient expression in an immortalized CD4+ T-cell line. We measured the ability of each Nef clone to downregulate CD4 and HLA class I, and of each Vpu clone to downregulate CD4 and Tetherin, from the cell surface. Results were normalized to reference clones (Nef-SF2 and Vpu-NL4.3). We observed that Nef-mediated CD4 and HLA downregulation functions were lower in LTS compared to the control cohort (Mann-Whitney p=0.03 and p<0.0001, respectively). Moreover, we found a positive correlation between Nef-mediated CD4 downregulation function and plasma viral load in LTS and controls (Spearman ρ= 0.59, p=0.03 and ρ=0.30, p=0.005, respectively). In contrast, Vpu-mediated functions were similar between groups and did not correlate with clinical markers. Further analyses identified polymorphisms at Nef codon 184 and Vpu codons 60-62 that were associated with function, which were confirmed through mutagenesis. Overall, our results support attenuated function of Nef, but not Vpu, as a contributor to slower disease progression in this cohort of long-term survivors with HIV-1 subtype A.
| S-EPMC9383652 | biostudies-literature
Project description:The HIV-1 accessory protein Nef is well known for its manipulation of host cell endosomal trafficking. By linking transmembrane proteins to endosomal coats, Nef removes them from the surface of infected cells. Modulation of MHC proteins leads to viral evasion of cellular adaptive immunity, whereas modulation of receptors for the HIV envelope glycoprotein, including CD4, enhances viral infectivity. The other HIV-1 accessory proteins, Vif, Vpr and Vpu, share a mechanism of action distinct from Nef in that each interacts with a multi-subunit ubiquitin ligase complex to target cellular proteins for proteosomal degradation. However, newly uncovered functions and mechanistic aspects of Vpu likely involve endosomal trafficking: these include counteraction of the innate antiviral activity of the cellular transmembrane protein BST-2 (tetherin), as well as the removal of the lipid-antigen presenting protein CD1d and the natural killer cell ligand NTB-A from the cell surface. This review focuses on how Nef and Vpu interfere with normal intracellular membrane trafficking to facilitate the spread and virulence of HIV-1.
| S-EPMC3173656 | biostudies-literature