UC San Diego

Chronic infection with HIV (human immunodeficiency virus) impairs immune cell function, and leads to immune cell exhaustion, and thus results in incapability of controlling virus replication. But the development and maintenance of immune cell exhaustion remain unclear to researchers still. Hereby this project uses single-cell RNA sequencing technique to unravel the gene expression landscape, and to study the effect of HIV infection on immune cell exhaustion. Peripheral blood mononuclear cells samples from six patients were used for sequencing, in which three were low viral load (15758 cell counts in total), and the other three were high viral load (12852 cell counts in total). Two healthy donor samples were used as control, with a total number of cells add up to 15121. Nine major immune cell clusters and eight T cell subtypes were identified based on their unique gene signatures. Among the T cell subclusters, exhausted memory CD8+ T cells and CD4+ T cells, and interferon high CD8+ T cells were only found in HIV-infected donor samples. An inhibitory receptor gene KLRG1 was found to be differentially expressed in HIV-infected donors, which was further identified to be a potential exhaustion marker. Experiments showed that there was an exhausted CD8+ T cell population expressing KLRG1, TIGIT, and T-bet (dim) EOMES (high) markers. Ex-vivo antibody blockade of KLRG1 restored the function of exhausted T cells, indicating that KLRG1 plays an important role in T cell exhaustion, which could be a potential immunotherapy target to treat chronic HIV infection. Also, analysis of integrated healthy and HIV-infected donor samples further revealed B cell and NK cell dysfunction induced by HIV infection. This project studied gene expression patterns of immune cell exhaustion as a result of HIV infection, providing potential immune cell exhaustion markers, which is useful in studying exhaustion mechanisms, and even developing new cure therapies.