Induction of Autophagy to Achieve a Human Immunodeficiency Virus Type 1 Cure

Abstract

Effective antiretroviral therapy has led to significant human immunodeficiency virus type 1 (HIV-1) suppression and improvement in immune function. However, the persistence of integrated proviral DNA in latently infected reservoir cells, which drive viral rebound post-interruption of antiretroviral therapy, remains the major roadblock to a cure. Therefore, the targeted elimination or permanent silencing of this latently infected reservoir is a major focus of HIV-1 research. The most studied approach in the development of a cure is the activation of HIV-1 expression to expose latently infected cells for immune clearance while inducing HIV-1 cytotoxicity—the “kick and kill” approach. However, the complex and highly heterogeneous nature of the latent reservoir, combined with the failure of clinical trials to reduce the reservoir size casts doubt on the feasibility of this approach. This concern that total elimination of HIV-1 from the body may not be possible has led to increased emphasis on a “functional cure” where the virus remains but is unable to reactivate which presents the challenge of permanently silencing transcription of HIV-1 for prolonged drug-free remission—a “block and lock” approach. In this review, we discuss the interaction of HIV-1 and autophagy, and the exploitation of autophagy to kill selectively HIV-1 latently infected cells as part of a cure strategy. The cure strategy proposed has the advantage of significantly decreasing the size of the HIV-1 reservoir that can contribute to a functional cure and when optimised has the potential to eradicate completely HIV-1.

Modulation of the autophagic pathway inhibits HIV-1 infection in human lymphoid tissue cultured ex vivo

“…Very recently, the inhibition of autophagy during active HIV-1 infection is being considered as a potential supplementary treatment to effective ART for controlling HIV-1 infection 36 . Likewise, the induction of autophagy as a complement to a “block and lock” approach, designed to induce a state of deep viral latency, has been also lately proposed as a new strategy to achieve a functional HIV-1 cure (Review 37 ).…”

Friends and Foes: The Ambivalent Role of Autophagy in HIV-1 Infection

“…However, components of the autophagic machinery that are exploited by HIV-1, i.e., host-dependency factors, could identify so far unexplored targets for therapy [ 152 ]. It has been proposed that modulation of autophagy may also aid cure strategies [ 64 , 142 , 158 ]. Indeed, host-directed autophagy-inhibiting drugs were shown to increase autosis (autophagic cell death) [ 154 ].…”

“…In vitro studies showed that despite inhibition of autophagy by several viral proteins, pharmacological activation of autophagy can overcome these antagonists leading to the autophagic-degradation of HIV-1 capsid proteins and a decrease in virion release through an ATG5- and autophagy-dependent mechanism [ 142 , 143 ]. For example, HIV-1 is restricted by rapamycin-induced autophagy in ex vivo cultures [ 144 ].…”

“…For example, HIV-1 is restricted by rapamycin-induced autophagy in ex vivo cultures [ 144 ]. Other mTOR inhibitors like vorinostat, panobinostat, givinostat and romidepsin and the non-histone chromatin modulating Bromodomain and extra terminal (BET) inhibitor JQ1, dactolisib (NVP-BEZ235), and SF2523 were reported to decrease both intracellular and extracellular HIV-1 capsid protein in an autophagy-dependent manner [ 142 , 145 , 146 ]. Induction of autophagy by an artificial Tat-Beclin-1 derived peptide restricts HIV-1 replication in an autophagy-dependent manner [ 143 ].…”

“…As autophagy does not impact transcriptionally latent HIV-1, all strategies explored so far only target actively replicating or incoming HIV-1. However, it has been suggested that autophagy modulation may complement strategies to target the reservoir, thereby enhancing their efficiency [ 142 ]. A lipid-coated hybrid poly(lactic-co-glycolic acid) (PLGA) nanoparticle loaded with the Tat-Beclin-1 peptide was reported to preferentially induce cell death of latently infected CD4+ T cells via autophagic-cell death induction (autosis) [ 143 , 154 , 155 ].…”