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Review
. 2022 Nov;112(5):1245-1259.
doi: 10.1002/JLB.4MR0222-606. Epub 2022 Mar 31.

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

Min Chen  1 , Min Li  2 , Marietta M Budai  2 , Andrew P Rice  3 , Jason T Kimata  3 , Mahesh Mohan  4 , Jin Wang  2   5
Affiliations
Review

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

Min Chen et al. J Leukoc Biol. 2022 Nov.

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.

Keywords: HIV-1, apoptosis, autophagy, HIV cure, SECH.

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Conflict of interest statement

DISCLOSURE

The authors declare no competing interest.

Figures

FIGURE 1
FIGURE 1
Challenges in finding a cure for HIV infections. A small portion (<3%) of integrated HIV-1 is capable of producing infectious virus, whereas most integrated proviruses are defective. The majority of integrated HIV in ART-suppressed individuals are nonproductive and do not need to be cleared to achieve a cure. Therefore, eradicating the component of the HIV-1 reservoir capable of producing the virus is essential for achieving an HIV cure
FIGURE 2
FIGURE 2
Protection of long-term survival of immune memory cells by autophagy and antiapoptosis molecules. Autophagy is important for quality control of proteins and organelles to protect cell survival. Mitochondrial quality control can remove damaged or surplus mitochondria to improve the mitochondrial fitness to meet cellular metabolic requirements. Bax- and Bak-mediated mitochondrial outer membrane permeabilization leads to the release of cytochrome c (Cyto c) and the formation of apoptosome containing Cyto c, Apaf-1, and Caspase-9. Activation of Caspase-9 in the apoptosome initiates apoptosis signaling. Clearing damaged mitochondria by autophagy can prevent the release of mitochondrial molecules into the cytosol to trigger apoptosis. Increased expression of antiapoptotic molecules, such as Bcl-2, in immune memory cells can inhibit Bax- and Bak-mediated mitochondrial outer membrane permeabilization to prevent apoptosis
FIGURE 3
FIGURE 3
Induction of cell death by HIV-1 gene products after latency reversal. LRAs such as IDB reactivate latent HIV-1 and induce expression of viral gene products. Several HIV-1 proteins, including Tat, Nef, Protease, and Vpr, can trigger mitochondrion-dependent apoptosis
FIGURE 4
FIGURE 4
Dual roles of the LRA, IDB, in the induction of cell survival and cell death in host cells latently infected with HIV-1. As a protein kinase c-ε activator, IDB can induce the expression of transcription factors, NF-κB, and AP-1. These transcription factors can bind to the promoter regions of the HIV-1 LTR, as well as those of cellular antiapoptotic and autophagy genes. Consequently, latency reversal induces the expression of HIV-1 genes to promote host cell death. However, the expression of antiapoptotic molecules and the up-regulation of autophagy promote cell survival that counteracts cell death caused by HIV-1 gene products
FIGURE 5
FIGURE 5
Treatment of HIV-1 infection in Hu-HSC mice by SECH. (A) The SECH regimen includes: (1) latency reversion; (2) induction of cell death; (3) inhibition of autophagy; and (4) blocking of new infections with inhibitors for HIV-1 attachment and integration. (B) Three months after reconstitution with human CD34+ stem cells, 1 set of HIV-1-infected Hu-HSC mice were infected with HIV-1 (AD8 strain, 1000 pfu/mouse) intraperitoneally. Ten days after HIV-1 infections, the mice were used for treatments by ART or SECH. - (C) Clearance of HIV-1 in humanized mice was demonstrated by the following 3 approaches: (1) lack of HIV-1 rebound after 2 months of SECH withdrawal; (2) lack of infectious HIV-1 by in vitro TZA assay; and (3) lack of infectious HIV-1 by in vivo hmVOA
FIGURE 6
FIGURE 6
SECH efficacy. The percentage of reduction of HIV-1 reservoir by each cycle of SECH treatment is defined as SECH efficacy. Based on our previous studies, we estimate SECH efficacy to be between 30% and 50% in Hu-HSC mice. A SECH efficacy of 30–50% would correspond to 22–40 cycles of SECH treatments, which is expected to reduce the HIV-1-infected cells from 1,000,000 to under 0.5 indicated by a dotted line, resulting in a 50% rate of HIV clearance
FIGURE 7
FIGURE 7
Evaluation of the safety for SECH. The safety of SECH was evaluated by measuring body weight and observing mobility of the mice daily. Histochemistry and flow cytometry analyses were performed to determine tissue integrity and immune cell composition at the end of experiments. Total cell counts, cell viability, and immune cell composition were examined in PBMCs from HIV-1 patients following treatments by SECH or ART
FIGURE 8
FIGURE 8
SECH treatment of SIV-infected macaques PBMCs ex vivo. PBMCs from SIV-infected rhesus macaques were treated with SECH containing IDB (25 nM), ABT-263 (20 nM), SAR405 (100 nM), and JQ1 (250 nM), in the presence of azidothymidine (0.5 μM) and raltegravir (200 nM) as ART for 2 days as 1 cycle, with a total of 5 cycles. Cells were then stimulated with IDB and used for RNA extraction. RT-PCR for SIV gag was performed as described. The dashed line indicates detection limit
FIGURE 9
FIGURE 9
Analyses of SIV-infected macaque PBMCs treated by SECH. (A) PBMCs from SIV-infected RMs treated by SECH (containing ART) or ART alone were used for flow cytometry analyses of T cells and T cell subsets, including CD45RA+CCR7+ naïve T cells (N), CD45RA−CCR7+ central memory T cells (CMT), CD45RA−CCR7− effector memory T cells (EMT), and CD45RA+CCR7− effector T cells (E). NS, statistically not significant. (B) In PBMCs treated as in (A), CD3−CD19− cells were gated to analyze CD123+CD163−MHC-II+ dendritic cells (DC), CD123−CD163−MHC-II+ M1 and CD123−CD163+MHC-II+ M2 macrophages. NS, statistically not significant. (C) Total cell counts of macaque PBMCs after treatments by SECH or ART. NS, statistically not significant
FIGURE 10
FIGURE 10
Specificity for SECH regimens in the killing of HIV-1-infected cells but not uninfected bystander cells. (A) Latency reversal with IDB induces the expression of HIV components that trigger apoptosis. However, IDB simultaneously up-regulates prosurvival autophagy and antiapoptotic molecules that counteract viral product-induced cell death, resulting in incomplete killing of HIV-1-infected cells. (B) Inhibiting prosurvival autophagy and antiapoptotic molecules allows viral products to induce high levels of cell death after latency reversal by IDB. (C) IDB induces prosurvival signaling in uninfected bystanders. (D) Up-regulation of prosurvival autophagy and antiapoptotic molecules by IDB confers the resistance in uninfected bystanders to cell death induced by the suppression of these prosurvival mechanisms
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