(+)-Catechin:lysine 1:2 promotes HIV-1 quiescence through a biphasic and dose-dependent mechanism: Implications for block-and-lock cure strategies.

HIV-1 persists in cellular reservoirs of latent virus that resist antiretroviral therapy (ART) and immune clearance, necessitating novel therapeutic strategies. While "shock-and-kill" approaches aim to reactivate latent virus under immune pressure, this strategy has demonstrated limited clinical efficacy. In contrast, "block-and-lock" strategies that reinforce and maintain HIV-1 quiescence represent a complementary approach to prevent reservoir expansion and enable long-term ART-free remission. We previously demonstrated that EGCG, the major phenolic compound of green tea, reverses HIV-1 latency by inhibiting UHRF1 expression, a key regulator involved in the epigenetic silencing of HIV-1. However, EGCG exhibits poor bioavailability and dose-dependent cytotoxicity, which severely limit its clinical use. Here, we evaluated (+)-catechin:lysine 1:2, a more stable and bioavailable polyphenol complex with unexplored anti-HIV properties. In J-Lat cell subclones, high concentrations (50-300 μg/mL) of (+)-catechin:lysine 1:2 induced HIV-1 reactivation to levels comparable to those induced by EGCG, but without dose-dependent cellular toxicity. Mechanistically, HIV-1 reactivation operated through UHRF1-independent pathways, distinguishing (+)-catechin:lysine 1:2 from EGCG. Additionally, sequential vitamin C pre-treatment at a 1:2 molar ratio significantly potentiated catechin-mediated reactivation, whereas concurrent co-treatment antagonized the effect, demonstrating that precise dosing time schedules critically determined efficacy. Strikingly, short-term exposure (24 h) of therapeutically achievable low doses of (+)-catechin:lysine 1:2 (10 μg/mL) paradoxically promoted HIV-1 quiescence, suppressing spontaneous viral reactivation. Importantly, this quiescence-promoting effect was confirmed in cells isolated from ART-treated people with HIV (PWH). These findings position of (+)-catechin:lysine 1:2 as a safely administrable and bioavailable molecule with promising potential for "block-and-lock" anti-HIV-1 cure strategies.