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Transcriptional profiling of CD4 T cells identifies distinct subgroups of HIV-1 elite controllers.

ABSTRACT: Human immunodeficiency virus type 1 (HIV-1) elite controllers maintain undetectable levels of viral replication in the absence of antiretroviral therapy (ART), but their underlying immunological and virological characteristics may vary. Here, we used a whole-genome transcriptional profiling approach to characterize gene expression signatures of CD4 T cells from an unselected cohort of elite controllers. The transcriptional profiles for the majority of elite controllers were similar to those of ART-treated patients but different from those of HIV-1-negative persons. Yet, a smaller proportion of elite controllers showed an alternative gene expression pattern that was indistinguishable from that of HIV-1-negative persons but different from that of highly active antiretroviral therapy (HAART)-treated individuals. Elite controllers with the latter gene expression signature had significantly higher CD4 T cell counts and lower levels of HIV-1-specific CD8(+) T cell responses but did not significantly differ from other elite controllers in terms of HLA class I alleles, HIV-1 viral loads determined by ultrasensitive single-copy PCR assays, or chemokine receptor polymorphisms. Thus, these data identify a specific subgroup of elite controllers whose immunological and gene expression characteristics approximate those of HIV-1-negative persons.

SUBMITTER: Vigneault F

PROVIDER: S-EPMC3067917 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:ObjectiveElite controllers, defined as persons maintaining undetectable levels of HIV-1 replication in the absence of antiretroviral therapy, represent living evidence that sustained, natural control of HIV-1 is possible, at least in relatively rare instances. Understanding the complex immunologic and virologic characteristics of these specific patients holds promise for inducing drug-free control of HIV-1 in broader populations of HIV-1 infected patients.DesignWe used an unbiased transcriptional profiling approach to characterize CD8+ T cells, the strongest correlate of HIV-1 immune control identified thus far, in a large cohort of elite controllers (n = 51); highly active antiretrovial therapy (HAART)-treated patients (n = 32) and HIV-1 negative (n = 10) served as reference cohorts.MethodsWe isolated mRNA from total CD8+ T cells isolated from peripheral blood mononuclear cell (PBMC) of each individual followed by microarray analysis of the transcriptional signatures.ResultsWe observed profound transcriptional differences [590 transcripts, false discovery rate (FDR)-adjusted P < 0.05] between elite controller and HAART-treated patients. Interestingly, metabolic and signalling pathways governed by mammalian target of rapamycin (mTOR) and eIF2, known for their key roles in regulating cellular growth, proliferation and metabolism, were among the top functions enriched in the differentially expressed genes, suggesting a therapeutically actionable target as a distinguishing feature of spontaneous HIV-1 immune control. A subsequent bootstrapping approach distinguished five different subgroups of elite controller, each characterized by distinct transcriptional signatures. However, despite this marked heterogeneity, differential regulation of mTOR and eIF2 signalling remained the dominant functional pathway in three of these elite controller subgroups.ConclusionThese studies suggest that mTOR and eIF2 signalling may play a remarkably universal role for regulating CD8 T-cell function from elite controllers.

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Transcriptional profiling of CD4 T cells identifies distinct subgroups of HIV-1 elite controllers.

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