Chronic HIV infection results in exhaustion and loss of the immune system, a phenomenon characterized by dysfunctional HIV-specific killer T cells. The exhausted T cells display inhibitory proteins on their surface, and scientists hope to be able to restore immune function by interfering with the negative signals transmitted by such proteins. PD-1, Lag-3 and Tim-3, some examples of T-cell exhaustion markers that are associated with immune activation. In fact, expression of multiple inhibitory receptors has been demonstrated to correlate positively with both plasma viral load and disease progression in HIV infected individuals.
However, little is known about the development and maintenance, as well as heterogeneity of immune cell exhaustion. Another problem with chronic HIV infection is that a large number of people that are receiving antiviral therapy (ART) become resistant to treatment.
Researchers at UC San Diego have investigated the effects of HIV infection on immune cell exhaustion at the transcriptomic level by analyzing single-cell RNA sequencing of >43,000 peripheral blood mononuclear cells (PBMCs) from healthy subjects and HIV-infected donors. Researchers identified nine immune cell clusters and eight T cell subclusters according to their unique gene expression programs; three of these (exhausted CD4+ and CD8+ T cells and interferon-responsive CD8+ T cells) were detected only in samples from HIV-infected donors. PD-1 (program cell death-1) has also been associated with CD8 dysfunction in HIV infection. An inhibitory receptor (X) was identified in the exhausted T cell populations and further characterized in HIV infected individuals. When we blocked the identified receptor for immune exhaustion by an antibody using ex vivo PBMCs from HIV infected individuals, we observed a robust increase in HIV-specific CD8+ T cells immune responses by interferon and TNF-alpha production.
Blocking of the inhibitory receptor (X) allows CD8+ cytotoxic functions to normalize, allowing treatment of HIV/AIDS by immunotherapy and potentially other chronic viral infections.
We found that PD-1 and the inhibitory receptor (X) cell type was expressed only in HIV exhausted T cells.
To examine the landscape of immune cell exhaustion induced by HIV infection, PBMCs were isolated from healthy and HIV-infected donors which were subjected to single-cell RNA sequencing to identify cell clusters by expression cell type-specific gene signatures. These data provide a comprehensive analysis of gene signatures associated with immune cell exhaustion during HIV infection, which could be useful in understanding exhaustion mechanisms and developing new cure therapies.
This technology is patent pending and available for licensing and/or research sponsorship.
AIDS, CD8 exhaustion receptors in HIV/AIDS, immunotherapy, chronic viral infections