Unravelling the mechanisms of durable control of HIV-1

Key Points HIV controllers are a small group of HIV-1-infected patients who maintain undetectable or minimal levels of HIV-1 replication in the absence of antiretroviral therapy. Many elite controllers harbour replication-competent viruses, and several studies have consistently failed to identify specific viral sequence abnormalities in these patients, which suggests that the controller phenotype is primarily achieved by host factors. Genome-wide association studies have shown that genetic variations associated with HIV-1 immune control are exclusively located in the human HLA class I locus. Such genetic variations are most frequently detectable in the HLA-B binding pocket, but can also be found in selected areas encoding non-pocket elements of HLA-B or HLA-C. Highly-potent HIV-1-specific CD8 + T cells seem to be the backbone of antiviral immune defence in many — but not all — elite controllers. These cells are highly effective at restricting HIV-1 replication in in vitro inhibition assays and they have functional and phenotypic characteristics that distinguish them from HIV-1-specific T cells from individuals with progressive HIV-1 infection. Innate immune defence mechanisms are likely to modulate immune activity in HIV-1 controllers. In particular, dendritic cells, γδ T cells and the cell-intrinsic restriction of viral replication seem to support antiviral immune activities in HIV-1 controllers. Elite controllers provide living evidence that the human immune system is able to effectively control HIV-1 replication. A better understanding of the mechanisms involved in HIV-1 immune control in these patients might enable the design of clinical strategies to improve the immune response to HIV-1 in broader patient populations. This article describes recent progress in delineating the factors that contribute to spontaneous HIV-1 immune control, with the ultimate aim of translating these studies into clinical strategies to induce a 'functional cure' of HIV-1 infection. Untreated HIV-1 infection typically progresses to AIDS within 10 years, but less than 1% of infected individuals remain healthy and have normal CD4 + T cell counts and undetectable viral loads; some individuals have remained this way for 35 years and counting. Through a combination of large population studies of cohorts of these 'HIV-1 controllers' and detailed studies of individual patients, a heterogeneous picture has emerged regarding the basis for this remarkable resistance to AIDS progression