Clearance of HIV-1 or Siv Reservoirs by Promotion of Apoptosis and Inhibition of Autophagy: Targeting Intracellular Molecules in Cure-Directed Strategies

Authors

Min Chen
Min Li
Marietta M Budai
Andrew P Rice
Jason T Kimata
Mahesh Mohan
Jin Wang

Publication Date

11-1-2022

Journal

Journal of Leukocyte Biology

DOI

10.1002/JLB.4MR0222-606

PMID

35362118

PMCID

PMC9522917

PubMedCentral® Posted Date

11-1-2023

PubMedCentral® Full Text Version

Author MSS

Published Open-Access

yes

Keywords

Mice, Animals, HIV-1, Virus Latency, NF-kappa B, Macaca mulatta, Myeloid Cell Leukemia Sequence 1 Protein, Transcription Factor AP-1, HIV Infections, Autophagy, Apoptosis, CD4-Positive T-Lymphocytes, Virus Activation

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.

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