Pegylated Interferon-alpha-Induced Natural Killer Cell Activation Is Associated With Human Immunodeficiency Virus-1 DNA Decline in Antiretroviral Therapy-Treated HIV-1/Hepatitis C Virus-Coinfected Patients

Background. Interferon alpha (IFN-alpha) can potently reduce human immunodeficiency virus type 1 (HIV-1) replication in tissue culture and animal models, but may also modulate residual viral reservoirs that persist despite suppressive antiretroviral combination therapy. However, mechanisms leading to viral reservoir reduction during IFN-alpha treatment are unclea. Methods. We analyzed HIV-1 gag DNA levels in CD4 T cells by digital droplet polymerase chain reaction and CD8 T-cell and natural killer (NK) cell phenotypes by flow cytometry in a cohort of antiretroviral therapy-treated HIV-1/hepatitis C-virus-coinfected patients (n = 67) undergoing treatment for hepatitis C infection with pegylated IFN-alpha and ribavirin for an average of 11 months. Results. We observed that IFN-alpha treatment induced a significant decrease in CD4 T-cell counts (P <.0001), in CD4 T-cellassociated HIV-1 DNA copies (P = .002) and in HIV-1 DNA copies per microliter of blood (P < .0001) in our study patients. Notably, HIV-1 DNA levels were unrelated to HIV-1-specific CD8 T-cell responses. In contrast, proportions of total NK cells, CD56brightCD16-NK cells, and CD56brightCD16+ NK cells were significantly correlated with reduced levels of CD4 T-cell-associated HIV-1 DNA during IFN-alpha treatment, especially when coexpressing the activation markers NKG2D and NKp30. Conclusions. These data suggest that the reduction of viral reservoir cells during treatment with IFN-a is primarily attributable to antiviral activities of NK cells.