Comprehensive analysis of HIV elite controllers’ and progressors’ transcriptional profiles from CD8+ T lymphocytes demonstrates heterogeneity of pathways and master regulators, which may be essential for disease nonprogression

Abstract

ABSTRACTCytotoxic and noncytotoxic CD8+ T lymphocyte responses are essential for the control of HIV infection. Understanding the mechanisms underlying HIV control in elite controllers (ECs), who do not progress to AIDS for many years without treatment, may facilitate the development of new effective therapeutic strategies.We performed a comprehensive analysis of the transcriptional profiles of CD8+ cells from ECs and treated and untreated progressors using an original pipeline. Cluster analysis enabled the identification of five distinct groups (EC groups 1-5) of ECs based on their transcription profiles. Profiles of EC groups 2-4 were associated with different numbers of differentially expressed genes, but the corresponding genes shared the same cellular processes. These three groups were associated with increased metabolism, survival, proliferation, and the absence of an “exhausted” phenotype of CD8+ lymphocytes, compared to untreated progressors. The transcriptional profiles of EC group 1 were opposite to those of EC groups 2-4 and similar to those of the treated progressors. This group may be associated with residual dysfunction of T lymphocytes. The EC group 5 was indistinguishable from normal. EC groups 1 and 5 can have mechanisms of nonprogression unrelated to CD8+ cells.The transcription changes in CD8+ lymphocytes from ECs may be attributable to the receptors that modulate the functional states of CD8+ cells. We identified 22 receptors, which are potential master regulators and may be responsible for the observed expression changes of CD8+ cells in ECs. These receptors can be considered potential targets of therapeutic intervention, which may decelerate disease progression.IMPORTANCEA small group of HIV-infected individuals, known as elite controllers (ECs), do not develop AIDS for many years, despite being untreated. Understanding the mechanisms governing HIV control in ECs may help develop new effective therapeutic strategies. Since CD8+ T lymphocytes seem to play a significant role in HIV control, we analyzed the large number of transcriptional profiles in total CD8+ cells from ECs, treated, and untreated progressors. We found distinct groups of ECs, which may have different mechanisms governing HIV nonprogression, and we identified related pathways and cellular processes that are dissimilar from those in progressors. We also identified master regulators, key proteins in the signaling network that can be responsible for observed transcriptional changes in CD8+ cells from ECs and may be essential for disease nonprogression. These proteins may represent potential targets for therapeutic interventions.