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Transcriptional analysis of HIV-specific CD4+ T cells after suppression of viremia by ART.

ABSTRACT: The virus-specific CD4+ T cell dysfunction associated with failure to control chronic infections is poorly understood in humans. An issue of critical clinical relevance is the lack of restoration of effective anti-HIV immunity after suppressive ART: viral rebound is the rule after cessation of therapy. Whether persistent HIV-specific CD4+ T cell dysfunction on ART contribute to this failed response is an important, yet unresolved, question. To decipher the consequences of ongoing viral antigen exposure, versus the results of durable cell-fate decision programs that would persist in former CP individuals after successful viral suppression on ART, we compared trancriptional profiles of chronic progressor before and after the initiation of ART, with the transcriptional profiles of elite controllers, HIV-infected individuals that spontaneously control viral load. Suppression of viremia by ART resulted in a distinct transcriptional landscape, with reduction in TFH gene expression but no correction of the TH1, TH17 and TH22 gene levels compared to the elite controller profile.

ORGANISM(S): Homo sapiens

PROVIDER: GSE128296 | GEO | 2019/07/15

REPOSITORIES: GEO

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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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Transcriptional analysis of HIV-specific CD4+ T cells after suppression of viremia by ART.

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