A computational analysis of transcriptional profiles from CD8(+) T lymphocytes reveals potential mechanisms of HIV/AIDS control and progression

Cytotoxic and noncytotoxic CD8(+) T lymphocyte responses are essential for the control of HIV infection. Understanding the mechanisms underlying HIV control in elite controllers (ECs), which maintain undetectable viral load in the absence of antiretroviral therapy, may facilitate the development of new effective therapeutic strategies. We developed an original pipeline for an analysis of the transcriptional profiles of CD8(+) cells from ECs, treated and untreated progressors. Hierarchical cluster analysis of CD8(+) cells’ transcription profiles allowed us to identify five distinct groups (EC groups 1–5) of ECs. The transcriptional profiles of EC group 1 were opposite to those of groups 2–4 and similar to those of the treated progressors, which can be associated with residual activation and dysfunction of CD8(+) T-lymphocytes. The profiles of groups 2–4 were associated with different numbers of differentially expressed genes compared to healthy controls, 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, compared to both untreated progressors and healthy controls. The CD8(+) lymphocytes from these groups of ECs may contribute to the control under HIV replication and slower disease progression. The EC group 5 was indistinguishable from normal. Application of master regulator analysis allowed us to identify 22 receptors, including interferon-gamma, interleukin-2, and androgen receptors, which may be responsible for the observed expression changes and the functional states of CD8(+) cells from ECs. These receptors can be considered potential targets of therapeutic intervention, which may decelerate disease progression.