Resistance to human immunodeficiency virus infection: a rare but neglected state

The natural history of human immunodeficiency virus (HIV) infection is well understood. In most individuals sexually exposed to HIV, the risk of becoming infected depends on the viral load and on sexual practices and gender. However, a low percentage of individuals who practice frequent unprotected sexual intercourse with HIV‐infected partners remain uninfected. Although the systematic study of these individuals has made it possible to identify HIV resistance factors including protective genetic patterns, such epidemiological situations remain paradoxical and not fully understood. In vitro experiments have demonstrated that peripheral blood mononuclear cells (PBMCs) from HIV‐free, unexposed blood donors are not equally susceptible to HIV infection; in addition, PBMCs from highly exposed seronegative individuals are generally resistant to infection by primary HIV clinical isolates. We review the literature on permissiveness of PBMCs from healthy blood donors and uninfected hyperexposed individuals to sustained infection and replication of HIV‐1 in vitro. In addition, we focus on recent evidence indicating that the gut microbiota may either contribute to natural resistance to or delay replication of HIV infected individuals. We review the literature on permissiveness to infection and sustained replication of HIV‐1 in vitro by peripheral blood mononuclear cells from either healthy blood donors or uninfected individuals hyperexposed to HIV‐1. We discuss what is known, or may have been neglected, regarding differences in susceptibility to HIV infection, including genetic, epigenetic, and environmental factors, such as the intestinal microbiota.