Enhanced antagonism of BST-2 by a neurovirulent SIV envelope
Kenta Matsuda, … , Klaus Strebel, Vanessa M. Hirsch
Kenta Matsuda, … , Klaus Strebel, Vanessa M. Hirsch
Published May 9, 2016
Citation Information: J Clin Invest. 2016;126(6):2295-2307. https://doi.org/10.1172/JCI83725.
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Research Article AIDS/HIV

Enhanced antagonism of BST-2 by a neurovirulent SIV envelope

Abstract

Current antiretroviral therapy (ART) is not sufficient to completely suppress disease progression in the CNS, as indicated by the rising incidence of HIV-1–associated neurocognitive disorders (HAND) among infected individuals on ART. It is not clear why some HIV-1–infected patients develop HAND, despite effective repression of viral replication in the circulation. SIV-infected nonhuman primate models are widely used to dissect the mechanisms of viral pathogenesis in the CNS. Here, we identified 4 amino acid substitutions in the cytoplasmic tail of viral envelope glycoprotein gp41 of the neurovirulent virus SIVsm804E that enhance replication in macrophages and associate with enhanced antagonism of the host restriction factor BM stromal cell antigen 2 (BST-2). Rhesus macaques were inoculated with a variant of the parental virus SIVsmE543-3 that had been engineered to contain the 4 amino acid substitutions present in gp41 of SIVsm804E. Compared with WT virus–infected controls, animals infected with mutant virus exhibited higher viral load in cerebrospinal fluid. Together, these results are consistent with a potential role for BST-2 in the CNS microenvironment and suggest that BST-2 antagonists may serve as a possible target for countermeasures against HAND.

Authors

Kenta Matsuda, Chia-Yen Chen, Sonya Whitted, Elena Chertova, David J. Roser, Fan Wu, Ronald J. Plishka, Ilnour Ourmanov, Alicia Buckler-White, Jeffrey D. Lifson, Klaus Strebel, Vanessa M. Hirsch

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Figure 6

The SIVsm Env glycoprotein enhances HIV-1 particle release.

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The SIVsm Env glycoprotein enhances HIV-1 particle release. (A) Kinetic ...
(A) Kinetic analysis of viral particle release by the Vpu-deficient pNL4-3/Udel-1 in the presence of HIV-2 Env, SIV Env, or SIV Nef. 293T cells were transfected with pNL4-3/Udel-1 and rBST-2 DNA together with HIV-2 Env vectors pHA-ROD14-Env and pHA-ROD10-Env as controls, as well as vectors for the expression of HA-tagged Envs from SIVmac239 and SIVsmE543 or vectors for the expression of HA-tagged Nef from SIVmac239 and SIVsmE543. Samples were subjected to pulse-chase analysis, and viral proteins recovered by immunoprecipitation were separated by SDS–PAGE. The HIV-1 major Gag proteins p55gag and p24CA are identified on the right. (B) Protein expression for Env, Nef, and rBST-2 was verified by Western blot analysis using cellular α-tubulin as a loading control. Representative data from 2 independent experiments are shown. (C) Bands corresponding to the precursor and mature Gag proteins in A were quantified, and the efficiency of particle release at each time point was calculated and plotted as a function of time. Maximal virus release by ROD10 at the 5-hour time point was defined 100%, and the remaining data points were normalized accordingly. Data represent means ± SEM from 2 independent analyses. ***P ≤ 0.001 and ****P ≤ 0.0001, 2-way ANOVA (particle release kinetics in the presence of different SIV Env and Nef proteins compared with release by negative control ROD14Env).