Clearance of HIV-1 or SIV reservoirs by promotion of apoptosis and inhibition of autophagy: Targeting intracellular molecules in cure-directed strategies

Abstract

The reservoirs of the HIV display cellular properties resembling long‐lived immune memory cells that could be exploited for viral clearance. Our interest in developing a cure for HIV stems from the studies of immunologic memory against infections. We and others have found that long‐lived immune memory cells employ prosurvival autophagy and antiapoptotic mechanisms to protect their longevity. Here, we describe the rationale for the development of an approach to clear HIV‐1 by selective elimination of host cells harboring replication‐competent HIV (SECH). While reactivation of HIV‐1 in the host cells with latency reversing agents (LRAs) induces viral gene expression leading to cell death, LRAs also simultaneously up‐regulate prosurvival antiapoptotic molecules and autophagy. Mechanistically, transcription factors that promote HIV‐1 LTR‐directed gene expression, such as NF‐κB, AP‐1, and Hif‐1α, can also enhance the expression of cellular genes essential for cell survival and metabolic regulation, including Bcl‐xL, Mcl‐1, and autophagy genes. In the SECH approach, we inhibit the prosurvival antiapoptotic molecules and autophagy induced by LRAs, thereby allowing maximum killing of host cells by the induced HIV‐1 proteins. SECH treatments cleared HIV‐1 infections in humanized mice in vivo and in HIV‐1 patient PBMCs ex vivo. SECH also cleared infections by the SIV in rhesus macaque PBMCs ex vivo. Research efforts are underway to improve the efficacy and safety of SECH and to facilitate the development of SECH as a therapeutic approach for treating people with HIV.

HibeRNAtion: HIV-1 RNA Metabolism and Viral Latency

“…For the “kill” of the shock-and-kill strategy, the elimination of HIV-1 reservoirs could also be accomplished by triggering intrinsic cell death (ICD) mechanisms that promote selective apoptosis of HIV-1 infected cells by the pharmacological targeting of apoptosis pathways ( Chen et al., 2022 ). Recent reports have highlighted the role of intron-containing vRNA accumulation in stimulating the antiviral host cell response, which can potentially trigger apoptosis pathways in HIV-1 infected cells selectively ( Li et al., 2016 ; Garcia-Vidal et al., 2017 ; Fong et al., 2017 ; Rao et al., 2021 ).…”

Targeting HIV persistence in the tissue

“…Lastly, alternative approaches such as genome wide CRISPR-Cas9 screening may identify new targets [105], as shown for aryl hydrocarbon receptor involved in CD4 + T cell viral replication and tissue residency [106]. Other promising approaches to reach the tissue reservoir combine LRA with another therapy, such as a PKC modulator combined with autologous NK cells [107], trispecific antibodies (N6/aCD3-aCD28) [108], IL-15 superagonist N-803 [109], or the targeting of antiapoptotic and autophagy molecules [110].…”

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

“…Modulation of autophagy may also enhance ‘shock and kill’ approaches, where latently infected reservoirs are first reactivated and then eliminated. It was shown that in combination with agents that promote latency reversal, selective killing of reactivated T cells can be achieved by autophagy inhibition via chloroquine or SAR405 [ 157 , 158 ].…”