Elevated ATP via enhanced miRNA-30b, 30c, and 30e downregulates the expression of CD73 in CD8+ T cells of HIV-infected individuals

Author summaryCD8(+) T cells (killer T cells) play an important role against chronic viral infections, however, their functional properties get compromised during the course of HIV infection. CD73, is one of molecules that influences T cell functions, however, its role in the context of viral infections has not been well defined. Here, we analyzed the expression of CD73 on T cells in a cohort of 102 HIV-infected individuals including those on antiretroviral therapy (ART), ART-naive, and long-term non-progressors who were not on ART. We found that the frequency of T cells expressing this molecule was markedly lower among different T cell subsets obtained from the blood of HIV-infected individuals. Notably, CD73 was decreased at the intracellular protein and gene levels. Furthermore, we found that T cells expressing this molecule (CD73) had impaired functional properties. In contrast, we observed that T cells expressing CD73 had elevated levels of homing receptors, which suggests a migratory advantage for these cells. This was also supported by increased CD73(+) T cells in the cerebrospinal fluids of multiple sclerosis patients when they experienced disease replace. Moreover, we found that the elevated level of ATP in the plasma of HIV-infected individuals is responsible for the upregulation of miRNA30b, 30c and 30e, resulting in reduced expression of CD73. CD8(+) T cells play a crucial role against chronic viral infections, however, their effector functions are influenced by the expression of co-stimulatory/inhibitory receptors. For example, CD73 works with CD39 to convert highly inflammatory ATP to adenosine. However, its expression on T cells in the context of viral infections has not been well defined. Here, we analyzed the expression of CD73 on human T cells in a cohort of 102 HIV-infected individuals including those on antiretroviral therapy (ART), ART-naive, and long-term non-progressors who were not on ART. We found that the frequency of CD73(+) T cells was markedly lower among T cell subsets (e.g. naive, effector or memory) in the peripheral blood of all HIV-infected individuals. Notably, CD73 was decreased at the cell surface, intracellular and gene levels. Functionally, CD8(+)CD73(+) T cells exhibited decreased cytokine expression (TNF-alpha, IFN-gamma and IL-2) upon global or antigen-specific stimulation and impaired expression of cytolytic molecules at the gene and protein levels. In contrast, CD8(+)CD73(+) T cells expressed elevated levels of homing receptors such as CCR7, alpha 4 beta 7 integrin, which suggests a migratory advantage for these cells as observed in vitro. We also observed significant migration of CD73(+)CD8(+) T cells into the cerebrospinal fluids of multiple sclerosis (MS) patients at the time of disease relapse. Moreover, we found that elevated levels of ATP in the plasma of HIV-infected individuals upregulates the expression of miRNA30b-e in T cells in vitro. In turn, inhibition of miRNAs (30b, 30c and 30e) resulted in significant upregulation of CD73 mRNA in CD8(+) T cells. Therefore, we provide a novel mechanism for the downregulation of CD73 via ATP-induced upregulation of miRNA30b, 30c and 30e in HIV infection. Finally, these observations imply that ATP-mediated downregulation of CD73 mainly occurs via its receptor, P2X1/P2RX1. Our results may in part explain why HIV-infected individuals have reduced risk of developing MS considering the role of CD73 for efficient T cell entry into the central nervous system.