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.
Highlights
Within days of infection, human immunodeficiency virus type 1 (HIV-1) rapidly disseminates to draining lymph nodes
Has transformed HIV-1 infection from a lethal and destructive disease into a controllable, but chronic condition, the establishment of HIV-1 latency is unaffected by early initiation of antiretroviral therapy (ART) [6], and there is no evidence that ART alone is able to eradicate latent HIV-1 [7,8]
Interruption despite possessing weak HIV-1-specific immune responses and low levels of pro-inflammatory markers [16,17,159,160]. These post-treatment controllers have relatively small HIV-1 reservoirs, it is theorised that a “block and lock” approach could achieve a similar transcriptionally repressive profile in people initially starting with much larger HIV-1 reservoirs, which result in normal CD4+ T cell counts, the absence of disease progression, and no release of replication competent virus after ART interruption (Figure 2)
Summary
Human immunodeficiency virus type 1 (HIV-1) rapidly disseminates to draining lymph nodes. As viral loads rebound to high pre-therapy levels following ART interruption, albeit with significant heterogeneity in the speed of viral rebound (days, weeks, or sometimes years [16,17]), lifelong ART is required for continued viral suppression These latent cellular reservoirs present the major obstacle in preventing the eradication of HIV-1. MTORC2 functions include actin cytoskeleton organization, control of Na+ transport, and the inhibition of apoptosis [22,23,24], while MTORC1 targets downstream RPS6KB1, EIF4EBP1, and others to promote cellular growth and proliferation via increased protein and lipid synthesis, while repressing catabolic programmes resulting in the inhibition of autophagy. It mediates the degradation of specific cargo such as mitochondria (mitophagy), endoplasmic reticulum (reticulophagy), or invading microorganisms (xenophagy) [35,36] In the latter, it extensively interacts with immunometabolism to control infection and inflammation [37]. We provide a brief summary of the potential role for autophagy as part of an HIV-1 cure strategy
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