Aug 2026· Microbiology spectrum· Vol 14· 0 citations· 67 references
Medicine
TL;DR
A simple and reproducible assay to identify compounds capable of reactivating latent virus, a key step in cure strategies, is developed and validated and identified Tandutinib, a tyrosine kinase and mTOR inhibitor, as a novel LRA candidate with appreciable latency-reversing activity in the ACH2 model.
Abstract
ABSTRACT Human immunodeficiency virus type 1 (HIV-1) persists in latent reservoirs, mainly within CD4+ T cells, which are refractory to antiretroviral therapy, and can lead to rapid viral rebound upon treatment interruption. The “shock and kill” strategy aims to eliminate latent reservoirs by inducing viral transcription through latency-reversing agents (LRAs), thereby exposing infected cells to immune-mediated clearance. We developed and validated a simple, low-cost, and highly reproducible in vitro screening protocol to evaluate the efficacy and safety of LRAs, using a two-color flow cytometry assay on ACH2 cells, a well-characterized model of HIV-1 latency. Using this method, we identified PEP005 and CUDC-907 as the most potent LRAs across multiple experimental settings. Their reactivation capacity was further confirmed through transcriptomic analysis, which revealed a significant upregulation of viral RNA copies following stimulation. In addition, we collaborated with Dompé for using the Exscalate platform, an innovative computer-aided drug discovery approach, together with the experimental validation, which led to the identification of Tandutinib, a tyrosine kinase and mTOR inhibitor, as a novel LRA candidate with appreciable latency-reversing activity in the ACH2 model. While the ACH2 cell line does not fully recapitulate the complexity of HIV latency in vivo, it offers a robust and scalable system for early-stage screening and prioritization of candidate LRAs. Importantly, the future application of these LRAs in ex vivo samples derived from people living with HIV, with a particular focus on pediatric samples, will be crucial to deepen our understanding of latency reactivation in clinically relevant settings and age-specific immune environments. IMPORTANCE This study addresses a major obstacle to curing human immunodeficiency virus type 1 (HIV-1) infection: the persistence of latent viral reservoirs that are not eliminated by current therapies. We developed a simple and reproducible assay to identify compounds capable of reactivating latent virus, a key step in cure strategies. Using this approach, we identified effective latency-reversing compounds and, through collaboration with Dompé using the EXSCALATE platform, we also identified Tandutinib as a promising new candidate for further investigation. This study addresses a major obstacle to curing human immunodeficiency virus type 1 (HIV-1) infection: the persistence of latent viral reservoirs that are not eliminated by current therapies. We developed a simple and reproducible assay to identify compounds capable of reactivating latent virus, a key step in cure strategies. Using this approach, we identified effective latency-reversing compounds and, through collaboration with Dompé using the EXSCALATE platform, we also identified Tandutinib as a promising new candidate for further investigation.
D10 is the first Tat activator available and the first LRA that targets an HIV protein, and induces strong HIV production by latent cell lines and latent cells from people living with HIV-1.
P. Tong, Laetitia Marty, Nawel Chekrit et al.· bioRxiv· 0 citations
Evidence is provided that targeting HIV-1 C-CT through ADCC and CAR NK/T cell therapies can overcome the limitations of bnAbs, and the first evidence to test these approaches to effectively target HIV-1 C-CT is offered.
Tanvi Mathur, D. Mazurov, Alon Herschhorn· Journal of Immunology· 0 citations
ABSTRACT Antiretroviral therapy (ART) has markedly improved the prognosis of people living with HIV (PLWH); however, latent viral reservoirs remain a major barrier to a cure. The “Shock and Kill” strategy aims to reactivate latent provirus with latency‐reversing agents (LRAs) and subsequently eliminate the infected cells, yet most LRAs characterized to date provide only the “shock” component. Through screening a small‐molecule library, we identified 2‐hydrido‐2,2'‐spirobi(1,3,2‐benzodioxaphosphole) (2‐HSB) as a novel candidate that both reactivates latent HIV provirus and selectively induces cytopathic effects in latently infected reservoir cell lines, thereby exhibiting a dual “Shock and Kill” activity within a single compound. Mechanistically, the HIV‐1 tat protein appears to contribute to this selectivity. At the single‐cell level, the two effects appeared largely independent, indicating that, under the conditions tested, reactivation was not a consequence of cell death and vice versa. Importantly, 2‐HSB induced viral transcription in ex vivo CD4+ T cells from ART‐suppressed PLWH. Together, these findings identify 2‐HSB as a dual‐action candidate that reactivates latent HIV‐1 and preferentially induces cytopathic effects in reservoir cell‐line models, while supporting further mechanistic and ex vivo validation in primary reservoir‐bearing cells.
Yuichiro Hara, Haruki Kitamura, K. Matsuda et al.· Journal of Medical Virology· 0 citations
Viral latency remains one of the major barriers to the prevention and treatment of Human Immunodeficiency Virus (HIV) infection. Despite effective antiretroviral therapy (ART), HIV persists in latent cellular reservoirs, necessitating lifelong treatment and preventing complete viral eradication. This review comprehensively explores the molecular mechanisms underlying HIV latency, therapeutic barriers, and emerging opportunities toward a functional or sterilizing cure. HIV latency is regulated through complex interactions involving integration site heterogeneity, transcriptional repression, chromatin remodeling, and epigenetic modifications that collectively maintain viral dormancy. Resting CD4+ T cells serve as the principal latent reservoir; however, persistence also occurs within lymphoid tissues, gut-associated lymphoid tissues, and the central nervous system, creating sanctuary sites resistant to immune surveillance and pharmacological intervention. Current cure strategies include the “shock and kill” approach using latency-reversing agents such as histone deacetylase inhibitors, bromodomain inhibitors, and protein kinase C agonists, as well as the “block and lock” strategy employing Tat inhibitors and epigenetic silencing agents to achieve durable viral suppression. Immunotherapeutic approaches, including immune checkpoint inhibitors, chimeric antigen receptor T-cell therapy, and broadly neutralizing antibodies, have demonstrated promising potential but remain limited by incomplete reservoir clearance, toxicity, and viral escape. Clinical translation is further complicated by difficulties in reservoir quantification, ethical concerns, and implementation challenges in resource-limited settings. Emerging technologies, particularly artificial intelligence-assisted drug discovery and personalized therapeutic modeling, provide new opportunities for optimizing HIV cure strategies. Future progress will require interdisciplinary collaboration, equitable healthcare access, and innovative interventions targeting both viral persistence and host immune dynamics.
Faiz Alfaiz, F. AlFaleh, Abdulrahman Al atiq et al.· Journal of Medico Informatic...· 0 citations
HIV persists as a pandemic to this day, and although current antiretroviral therapies (ART) are effective, their success relies on strict adherence to the treatment. Broadly neutralizing antibodies (bNAbs) have also been evaluated as a therapeutic approach, but their implementation is undermined by the need for repeated infusions. We previously showed that vectored delivery of individual bNAbs via a single adeno-associated viral (AAV) vector injection results in long-lived expression of antibodies. This approach was effective as prophylaxis but usually failed to suppress actively replicating HIV in humanized mice. Recent reports in humans show that infusion of bNAbs during ART, followed by treatment interruption (ATI), results in viral suppression for as long as serum antibody concentrations remain high. Moreover, recent studies with SIV in the NHP model suggest that Vectored Immunotherapy (VIT) coupled with ART can improve therapeutic outcomes.
To evaluate whether this would also apply to HIV, humanized BLT mice were infected with different clinical isolates, and then ART-containing food was administered. Following viral suppression, AAVs encoding different bNAbs were administered individually or in combinations and then subjected to ATI.
Administration of individual bNAbs during ART treatment followed by ATI resulted in significantly improved viral suppression, relative to mice treated with only AAV-bNAbs. However, antibody monotherapy was not sufficient to completely suppress all the HIV isolates tested. When double combinations of bNAbs were tested, the therapeutic success was further improved, achieving suppression of harder-to-neutralize isolates. Finally, when testing a combination of three antibodies replicating previous clinical trials, complete suppression was achieved for all tested isolates.
This finding suggests that vectored delivery of bNAbs via AAV is a potential therapeutic alternative to achieve a functional cure for HIV.
The National Institute for Allergy and Infectious Disease Career Transition Award K22AI102769, Research Grants R01AI174875, R01AI174276, the National Institutes for Drug Abuse (NIDA) Avenir New Innovator Award DP2DA040254, the NIDA Avant-Garde Award 1DP1DA060607, CDC subcontract 200-2016-91773-T.O.2, the Executive Committee on Research (ECOR) of the Mass General Hospital (MGH) Fund for Medical Discovery, MGH Transformative Scholars Program, the Charles H. Hood Foundation, and the Gilead Sciences Research Scholars Program in HIV.
Vaccines and Immunotherapy (VAC)
N. Galvez, Adam D Nitido, Seon-Hee Yoo et al.· Journal of Immunology· 0 citations
HIV-SCRIBE is developed, a CRISPR-based molecular recorder in which a self-targeting guide RNA locus is placed under a Tat-responsive minimal HIV-1 5'LTR promoter, coupling Cas9-mediated cleavage and error-prone repair to Tat-driven transcriptional activation to generate a durable molecular record of HIV-1 reactivation and, more broadly, of cell-type-specific CRISPR editing dynamics.
Nahia Urturi Ortiz, M. Nonnemacher, Brian Wigdahl· 0 citations
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