CD8⁺CD28⁻CD127^loCD39⁺ regulatory T-cell expansion: A new possible pathogenic mechanism for HIV infection?

Background: HIV-associated immunodeficiency is related to loss of CD4⁺ T cells. This mechanism does not explain certain manifestations of HIV disease, such as immunodeficiency events in patients with greater than 500 CD4⁺ T cells/μL. CD8⁺CD28⁻CD127^loCD39⁺ T cells are regulatory T (Treg) lymphocytes that are highly concentrated within the tumor microenvironment and never analyzed in the circulation of HIV-infected patients. Objectives: We sought to analyze the frequency of CD8⁺CD28⁻CD127^loCD39⁺ Treg cells in the circulation of HIV-infected patients. Methods: The frequency of circulating CD8⁺CD28⁻CD127^loCD39⁺ Treg cells was analyzed and correlated with viral load and CD4⁺ T-cell counts/percentages in 93 HIV-1–infected patients subdivided as follows: naive (n = 63), elite controllers (n = 19), long-term nonprogressors (n = 7), and HIV-infected patients affected by tumor (n = 4). The same analyses were performed in HIV-negative patients with cancer (n = 53), hepatitis C virus–infected patients (n = 17), and healthy donors (n = 173). Results: HIV-infected patients had increased circulating levels of functional CD8⁺CD28⁻CD127^loCD39⁺ Treg cells. These cells showed antigen specificity against HIV proteins. Their frequency after antiretroviral therapy (ART) correlated with HIV viremia, CD4⁺ T-cell counts, and immune activation markers, suggesting their pathogenic involvement in AIDS- or non–AIDS-related complications. Their increase after initiation of ART heralded a lack of virologic or clinical response, and hence their monitoring is clinically relevant. Conclusion: HIV infection induces remarkable expansion of CD8⁺CD28⁻CD127^loCD39⁺ Treg cells, the frequency of which correlates with both clinical disease and signs of chronic immune cell activation. Monitoring their frequency in the circulation is a new marker of response to ART when effects on viremia and clinical response are not met.