HIV controllers: hope for a functional cure

Abstract

Elite controllers (ECs) and post-treatment controllers (PTCs) represent important models for achieving a functional cure for HIV. This review synthesizes findings from immunological, genetic, and virological studies to compare the mechanisms underlying HIV suppression in ECs and PTCs. Although ECs maintain viral control without antiretroviral therapy (ART), PTCs achieve suppression following ART discontinuation. Both groups rely on adaptive and innate immunity, host genetic factors, and characteristics of the HIV reservoir; however, they exhibit distinct immune responses and genetic profiles. These differences provide insights into strategies for sustained ART-free remission. Understanding the shared and unique mechanisms in ECs and PTCs can inform the development of novel therapeutic approaches, including immune-based therapies and genome editing, to achieve a functional cure for HIV-1.

Keywords: HIV controllers; HIV reservoirs; functional cure; genetic polymorphisms; immune response.

Figure 1

Potential mechanisms of innate immunity and adaptive immunity possibly contributing to the spontaneous control of viremia in HIV controllers. HIV controllers have a more robust and effective immune response, with functional DCs and NKs, highly cytotoxic and activated CD8⁺ T cells, and CD4⁺ T cells that can better maintain immune function. (1) DCs from HIV controllers are less permissive to HIV-1 infection but more efficient at capturing HIV-1 particles, and they have distinct phenotypes and functions, such as the presence of a highly functional CD64^hi PD-L1^hi mDC state, enhanced antigen presentation, and improved sensing of cytosolic HIV-1 replication products, which can trigger stronger T-cell responses. (2) CD4⁺ T cells, which are the main target of HIV, are severely depleted in AIDS patients. In HIV controllers, CD4⁺ T cells maintain their numbers and functions, are less sensitive to HIV-1 infection, and have high - affinity TCRs. (3) In HIV controllers, CD8⁺ T cells show stronger HIV antigen - induced cell proliferation, cytotoxic activity, and can effectively inhibit HIV-1 replication in autologous CD4⁺ T cells. (4) In HIV controllers, NK cell activity is enhanced. These NK cells secrete higher levels of IFN-γ and TNF-α, express more NKp46/NKG2D-activated receptors, and possess a stronger ADCC capacity.