An ordeal that does not heal: understanding barriers to a cure for HIV-1 infection

Abstract

With more than 38 million people living with HIV-1 (PLWH) worldwide, developing a cure for HIV-1 remains a major global health priority. Lifelong persistence of HIV-1 is frequently attributed to a pool of stable, transcriptionally silent HIV-1 proviruses, which are unaffected by currently available antiretroviral therapy (ART) or host immune activity. In this opinion article, we propose a more dynamic interpretation of HIV-1 reservoir cell biology and argue that HIV-1 proviruses frequently display residual viral transcriptional activity, making them vulnerable to longitudinal immune-mediated selection processes. Such mechanisms may, over extended periods of ART, induce an attenuated viral reservoir profile characterized by intact proviruses preferentially integrated into heterochromatin locations. We suggest that intensifying and accelerating naturally occurring selection mechanisms might represent a promising strategy for finding a potential cure for HIV-1 infection.

Keywords: HIV; cure; eradication; immune selection; latency; reservoirs.

Key Figure, Figure 1:. Proposed model of HIV-1 reservoir CD4⁺ T cell selection via “autologous shock and kill”.

(A): Development of a hypothetical virological or Type I cure for HIV-1 infection through longitudinal, immune-mediated elimination of intact HIV-1 proviruses. (B): Development of a hypothetical HIV-1 Type II cure through progressive immune-mediated elimination of intact proviruses integrated in permissive chromatin locations, resulting in a highly-selected proviral reservoir landscape consisting primarily of intact proviruses in heterochromatin locations. Such a model for a cure has been suggested to occur in elite controllers [57]. (C): Development of an elite controller-like integration site profile after extended periods of ART; such a highly atypical reservoir configuration may promote post-treatment, drug-free control. Acceleration of immune selection through therapeutic vaccines or immune modulators might induce an elite controller-like viral reservoir profile after shorter ART durations.