Clearance of HIV infection by selective elimination of host cells capable of producing HIV

Li, Min; Liu, Wei; Bauch, Tonya; Graviss, Edward A.; Arduino, Roberto C.; Kimata, Jason T.; Chen, Min; Wang, Jin

doi:10.1038/s41467-020-17753-w

Cited by 17 publications

(92 citation statements)

References 70 publications

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“…The late stages (post-integration) initiate with proviral transcription, assembly of viral components at cell-surface, viral egress, and maturation (Stevenson, 2003;Sutton et al, 2013;Deeks et al, 2015;Freed, 2015;Goodsell, 2015;Mailler et al, 2016). The HIV life cycle could end with cell death of infected cells or by HIV-1 Env-mediated cell death of uninfected bystander cells (Mohammadi et al, 2013;Cummins and Badley, 2014;Doitsh and Greene, 2016;Li et al, 2020) which occurs during early infection (Espert et al, 2008(Espert et al, , 2009. Hence, one of the most relevant HIV-1 modulators of cell death is the Env glycoprotein (Krüger et al, 1996;Blanco et al, 2001;Vlahakis et al, 2001;Blumenthal, 2006, 2008;Varbanov et al, 2006;Garg et al, 2009;Sivaraman et al, 2009;Gorry and Ancuta, 2011;Cicala et al, 2016;Joshi et al, 2016;Tsao et al, 2016;Evering, 2018;Daussy et al, 2020).…”

Section: The Role Of Autophagy In the Early Steps Of Hiv-1 Infectionmentioning

confidence: 99%

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The Interplay of HIV and Autophagy in Early Infection

et al. 2021

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HIV/AIDS is still a global threat despite the notable efforts made by the scientific and health communities to understand viral infection, to design new drugs or to improve existing ones, as well as to develop advanced therapies and vaccine designs for functional cure and viral eradication. The identification and analysis of HIV-1 positive individuals that naturally control viral replication in the absence of antiretroviral treatment has provided clues about cellular processes that could interact with viral proteins and RNA and define subsequent viral replication and clinical progression. This is the case of autophagy, a degradative process that not only maintains cell homeostasis by recycling misfolded/old cellular elements to obtain nutrients, but is also relevant in the innate and adaptive immunity against viruses, such as HIV-1. Several studies suggest that early steps of HIV-1 infection, such as virus binding to CD4 or membrane fusion, allow the virus to modulate autophagy pathways preparing cells to be permissive for viral infection. Confirming this interplay, strategies based on autophagy modulation are able to inhibit early steps of HIV-1 infection. Moreover, autophagy dysregulation in late steps of the HIV-1 replication cycle may promote autophagic cell-death of CD4+ T cells or control of HIV-1 latency, likely contributing to disease progression and HIV persistence in infected individuals. In this scenario, understanding the molecular mechanisms underlying HIV/autophagy interplay may contribute to the development of new strategies to control HIV-1 replication. Therefore, the aim of this review is to summarize the knowledge of the interplay between autophagy and the early events of HIV-1 infection, and how autophagy modulation could impair or benefit HIV-1 infection and persistence, impacting viral pathogenesis, immune control of viral replication, and clinical progression of HIV-1 infected patients.

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Section: The Role Of Autophagy In the Early Steps Of Hiv-1 Infectionmentioning

confidence: 99%

“…The inhibition of autophagy during active HIV-1 infection has been considered as a potential supplementary treatment to effective ART for controlling HIV-1 infection (Li et al, 2020).…”

Section: The Effect Of Autophagy Modulation In the Early Steps Of Hiv-1 Infectionmentioning

confidence: 99%

The Interplay of HIV and Autophagy in Early Infection

et al. 2021

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“…In a recent academic publication, the concept of SECH was proffered and discussed, providing constructive information regarding how HIV infection could be cured in the future. [ 17 ] The SECH concept involves the elimination of host cells harboring HIV-1 provirus through viral reactivation, induction of apoptosis, inhibition of autophagy, and blocking of new infections. Indeed, Li et al [ 17 ] advised that SECH treatments could contain (i) a latency reversal agent (LRA) acting as non-tumorigenic protein kinase c (PKC)-ε activator, [ 19 ] viz ., ingenol-3,20-dibenzoate (IDB, at 2.5 mg/kg b.w.…”

Section: Concept Of Sechmentioning

confidence: 99%

“…[ 17 ] The SECH concept involves the elimination of host cells harboring HIV-1 provirus through viral reactivation, induction of apoptosis, inhibition of autophagy, and blocking of new infections. Indeed, Li et al [ 17 ] advised that SECH treatments could contain (i) a latency reversal agent (LRA) acting as non-tumorigenic protein kinase c (PKC)-ε activator, [ 19 ] viz ., ingenol-3,20-dibenzoate (IDB, at 2.5 mg/kg b.w. ), (ii) an apoptosis inducer which inhibits B-cell lymphoma 2 (BCL-2) and B-cell lymphoma-extra-large (BCL-XL), [ 20 ] viz ., ABT-263 (50 mg/kg b.w.…”

Section: Concept Of Sechmentioning

confidence: 99%

“…The inhibition of such a process has been proven to be damaging for cells in general, [ 61 ] and cells infected with active provirus become highly sensitive, with a nearly zero survival rate, as demonstrated recently. [ 17 ] This is the reasoning behind why autophagy inhibitors should be included in HIV treatment protocols upon diligent investigation of reasonable dosage formulations and assessment of appropriate information regarding their safety.…”

Section: Mechanisms Of the Sech Strategymentioning

confidence: 99%

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Selective elimination of host cells harboring replication-competent human immunodeficiency virus reservoirs: a promising therapeutic strategy for HIV cure

Zaongo¹,

Ma²,

Song³

et al. 2021

Chinese Medical Journal

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Many seminal advances have been made in human immunodeficiency virus (HIV)/AIDS research over the past four decades. Treatment strategies, such as gene therapy and immunotherapy, are yielding promising results to effectively control HIV infection. Despite this, a cure for HIV/AIDS is not envisioned in the near future. A recently published academic study has raised awareness regarding a promising alternative therapeutic option for HIV/AIDS, referred to as “selective elimination of host cells capable of producing HIV” (SECH). Similar to the “shock and kill strategy,” the SECH approach requires the simultaneous administration of drugs targeting key mechanisms in specific cells to efficiently eliminate HIV replication-competent cellular reservoirs. Herein, we comprehensively review the specific mechanisms targeted by the SECH strategy. Briefly, the suggested cocktail of drugs should contain (i) latency reversal agents to promote the latency reversal process in replication-competent reservoir cells, (ii) pro-apoptotic and anti-autophagy drugs to induce death of infected cells through various pathways, and finally (iii) drugs that eliminate new cycles of infection by prevention of HIV attachment to host cells, and by HIV integrase inhibitor drugs. Finally, we discuss three major challenges that are likely to restrict the application of the SECH strategy in HIV/AIDS patients.

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

Chen

Budai

et al. 2022

Journal of Leukocyte Biology

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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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Clearance of HIV infection by selective elimination of host cells capable of producing HIV

Cited by 17 publications

References 70 publications

The Interplay of HIV and Autophagy in Early Infection

The Interplay of HIV and Autophagy in Early Infection

Selective elimination of host cells harboring replication-competent human immunodeficiency virus reservoirs: a promising therapeutic strategy for HIV cure

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

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