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Pharmacological METTL3 inhibition attenuates HIV-1 latency reversal in CD4+ T cells
Journal article   Open access   Peer reviewed

Pharmacological METTL3 inhibition attenuates HIV-1 latency reversal in CD4+ T cells

Tarun Mishra, Avary Edwards and Li Wu
Antimicrobial agents and chemotherapy, e0040026
05/29/2026
DOI: 10.1128/aac.00400-26
PMID: 42210692
url
https://doi.org/10.1128/aac.00400-26View
Published (Version of record) Open Access

Abstract

N6-methyladenosine (m6A) is a major epitranscriptomic modification that regulates RNA metabolism and affects the replication and latency reversal of human immunodeficiency virus type 1 (HIV-1) in cells. Methyltransferase-like 3 (METTL3) is the principal catalytic enzyme responsible for m6A deposition, and its pharmacological inhibition has emerged as a potential therapeutic strategy for cancer and viral infections. However, the relative potency of METTL3 inhibitors in reducing m6A levels and their effects on HIV-1 latency reversal remain undefined. Here, we compared three commercially available METTL3 inhibitors (STM2457, STM3006, and STC-15) to evaluate their ability to reduce RNA m6A levels, suppress HIV-1 latency reversal, and affect cell viability in latently infected J-Lat cells and primary CD4+ T cells. In J-Lat cells, STM3006 and STC-15 were more potent than STM2457 in reducing RNA m6A levels at 24 and 48 h post-treatment, as reflected by lower half-maximal inhibitory concentrations (IC50). However, STM3006 and STC-15 exhibited significant cytotoxicity at concentrations above 2 µM at 48 h post-treatment, whereas STM2457 displayed minimal toxicity across all tested doses. In primary CD4+ T cells from three healthy donors, all three inhibitors reduced RNA m6A levels except STC-15 treatment of one donor’s cells, while STM3006 induced significant cytotoxicity at 24 h post-treatment. Notably, reduced RNA m6A levels correlated with diminished HIV-1 latency reversal in both J-Lat cells and a primary central memory CD4+ T cell model. Together, these findings demonstrate differential potency and cytotoxicity among METTL3 inhibitors and support a critical role for m6A RNA modification in regulating HIV-1 latency reversal.
 Viral Infections Virology Antimicrobial Chemotherapy Antiviral Agents Antiviral Therapy Clinical Microbiology and Infectious Diseases Epigenetic Control of Viral Latency Epigenetic Mechanisms in Viral Reactivation Epigenetic Regulation Epigenetic Regulation and Antiviral Therapy Epigenetic Regulation of Latency Epigenetic Regulation of Viral Gene Expression Hiv Antiretroviral Therapy Human Immunodeficiency Virus (Hiv) Persistence and Latency Retroviruses Therapeutic Strategies Targeting Latency Viral Enzymes Viral Methyltransferases

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