CD8CD28CD127CD39 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. CD8CD28CD127CD39 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 CD8CD28CD127CD39 Treg cells in the circulation of HIV-infected patients.

Methods: The frequency of circulating CD8CD28CD127CD39 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 CD8CD28CD127CD39 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 CD8CD28CD127CD39 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.