Genetic determinants of HIV-1 elite control

Elite controllers, rare individuals who maintain undetectable HIV-1 viremia without antiretroviral therapy, represent a human model of a functional cure. Understanding the host genetic factors that enable this spontaneous viral control is a key goal of HIV-1 research. This review synthesizes recent findings that are challenging and expanding the classic, human leucocyte antigen (HLA)-centric view of elite control.

While the dominant association of specific HLA class I alleles (e.g., HLA-B*57, HLA-B*27) with low set-point viral load remains the cornerstone of the field, recent research has highlighted three emerging themes. First, the discovery of a large-effect, Africa-specific genetic association near the CHD1L locus has underscored the critical importance of studying genetically diverse populations. Second, novel approaches have highlighted a multilayered cellular response to HIV-1, suggesting more complex mechanisms of control beyond genetics alone. Third, a central paradox has emerged: the host genetic factors that strongly impact viral load do not show any association with the size or decay rate of the latent viral reservoir in treated individuals, complicating the path from "control" to "cure."

The genetic architecture of HIV-1 elite control is more complex than previously appreciated. The field has moved beyond HLA to uncover new, ancestry-specific pathways, explore multiple biological variables, and confront the critical disconnect between controlling viremia and eliminating the latent reservoir.