Early elevated IFN is a key mediator of HIV pathogenesis

BackgroundA complete understanding of the different steps of HIV replication and an effective drug combination have led to modern antiretroviral regimens that block HIV replication for decades, but these therapies are not curative and must be taken for life. "Elite controllers" (ECs) is a term for the 0.5% of HIV-infected persons requiring no antiretroviral therapy, whose status may point the way toward a functional HIV cure. Defining the mechanisms of this control may be key to understanding how to replicate this functional cure in others.MethodsIn ECs and untreated non-EC patients, we compared IFN alpha serum concentration, distribution of immune cell subsets, and frequency of cell markers associated with immune dysfunction. We also investigated the effect of an elevated dose of IFN alpha on distinct subsets within dendritic cells, natural killer cells, and CD4+ and CD8 + T cells.ResultsSerum IFN alpha was undetectable in ECs, but all immune cell subsets from untreated non-EC patients were structurally and functionally impaired. We also show that the altered phenotype and function of these cell subsets in non-EC patients can be recapitulated when cells are stimulated in vitro with high-dose IFN alpha.ConclusionsElevated IFN alpha is a key mediator of HIV pathogenesis. Currently, HIV infection is not curable, but infected individuals can manage their condition by taking daily doses of antiretroviral therapy. Some individuals, known as elite controllers (ECs), control their infection without antiretroviral treatment, and studying how their immune system responds to HIV exposure could lead to a potential cure for others. Here, we compare immune cell responses between ECs and untreated non-ECs. We find that IFN alpha, a small protein with an important role in controlling white blood cell activity, is produced in excess in immune cells from non-ECs compared with ECs during early infection. This insight provides an important clue for the future development of a targeted cure for HIV. Le Buanec et al. compared distribution and frequency of cell markers associated with immune dysfunction between HIV elite controllers (EC) and untreated non-EC. They demonstrate that untreated HIV-infected individuals exhibit structurally and functionally impaired immune subsets, as a consequence of excessive levels of serum IFN alpha.