CD8+CD28-CD127loCD39+regulatory T-cell expansion: A new possible pathogenic mechanism for HIV infection?

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/?L. CD8(+)CD28(-)CD127(lo)CD39(+) 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.We sought to analyze the frequency of CD8(+)CD28(-)CD127(lo)CD39(+) Treg cells in the circulation of HIV-infected patients.The frequency of circulating CD8(+)CD28(-)CD127(lo)CD39(+) 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).HIV-infected patients had increased circulating levels of functional CD8(+)CD28(-)CD127(lo)CD39(+) 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.HIV infection induces remarkable expansion of CD8(+)CD28(-)CD127(lo)CD39(+) 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.