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BIRC5 maintains survival of HIV-1 infected CD4 T cells

ABSTRACT: Kuo H, Ahmad R, Lee GQ, Chen H, Ouyang Z, Szucs MJ, Kim D, Tsibris A, Chun T, Battivelli E, Verdin E, Rosenberg ES, Carr SA, Yu XG, Lichterfeld M. Immunity 2018. HIV-1 infection of CD4 T cells leads to cytopathic effects and cell demise, which is counterintuitive to the observation that certain HIV-1-infected cells possess a remarkable long-term stability and can persist for decades in infected individuals treated with suppressive antiretroviral therapy (ART). Using quantitative mass spectrometry-based proteomics, we show that HIV-1 infection can activate cellular survival programs that are governed by BIRC5, a molecular inhibitor of cell apoptosis that is frequently over-expressed in malignant cells. BIRC5 and its upstream regulator OX40 are upregulated in productively and latently infected CD4 T cells, and are functionally involved in maintaining their integrity and viability. Moreover, OX40-expressing CD4 T cells from ART-treated patients are strongly enriched for sequence-intact HIV-1, and pharmaceutical inhibition of BIRC5 results in a selective decrease of HIV-1-infected cells in vitro. Together, these findings suggest that BIRC5 supports long-term survival of HIV-1-infected cells and offer new perspectives for clinical strategies to reduce persisting viral reservoirs.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (ncbitaxon:9606)

SUBMITTER: Steven A. Carr

PROVIDER: MSV000082229 | MassIVE | Mon Apr 02 07:11:00 BST 2018

REPOSITORIES: MassIVE

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Project description:High levels of HIV-1 replication during the chronic phase of infection are usually associated with rapid disease progression (RP). However, a minority of HIV-infected individuals remain asymptomatic and show persistently high CD4+ T cell counts despite high viremia for many years (viremic non progressors, VNP). The latter profile is reminiscent of the non-pathogenic model of SIV infection in natural hosts such as the sooty mangabey. We used various genomic approaches to examine 66 RP and 6 VNP defined according to strict criteria. RP were characterized by depletion of protective HLA alleles, enrichment of HLA alleles associated with disease progression, and a characteristic transcriptome profile of CD4+ and CD8+ T cells similar to that observed in pathogenic SIV infection of rhesus macaque. In contrast, VNPs presented lower expression of interferon stimulated genes than RP, and shared with SIV-infected sooty mangabeys a common profile of regulation of a set of genes that includes CASP1, CD38, LAG3, TNFSF13B, SOCS1 and EEF1D. The estimated 8% of RP and 0.1% of VNP in human cohorts represent two subsets of HIV-infected individuals whose analysis may inform our understanding of HIV pathogenesis. Selection criteria rapid progressors (RP): HIV seroconversion window <1 year WITH documented negative and positive serology or biological proof of primary infection. AND One of A) or B) A) >2 CD4+ T cell counts below 350 cells/µl within 3 years of seroconversion AND no subsequent rise of CD4+ T cells above 350 cells/µl in the absence of ART. B) ART initiated within 3 years of seroconversion AND CD4+ T cell count within 1 month of ART-start <350 cells/µl. Selection criteria viremic non progressors (VNP): > 3 years of follow-up AND median HIV viremia from >3 measurements >100'000 viral RNA copies/ml AND HIV viremia consistently above 10’000 copies/ml AND CD4+ T cell count above 350 cells/µl AND no ART during follow-up. Selection criteria elite/viremic controllers (EC): see Casado et al. 2010. Host and viral genetic correlates of clinical definitions of HIV-1 disease progression. PLoS ONE 5:e11079. Total RNA from 41 samples obtained from CD4 T cells from HIV infected individuals to identify associations between gene expression and different distinct patterns of disease progression Total RNA from 38 samples obtained from CD8 T cells from HIV infected individuals to identify associations between gene expression and different distinct

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BIRC5 maintains survival of HIV-1 infected CD4 T cells

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