Flavonoid-based inhibition of cyclin-dependent kinase 9 without concomitant inhibition of histone deacetylases durably reinforces HIV latency

HPLC-Based Purification and Isolation of Potent Anti-HIV and Latency Reversing Daphnane Diterpenes from the Medicinal Plant Gnidia sericocephala (Thymelaeaceae)

“…Following 24 h incubation, the cell viability was assessed by trypan blue staining, and the absolute viral RNA in each culture supernatant was determined by qRT-PCR [ 22 ]. Consistent with our previous observations, we observed considerable donor-to-donor variability [ 22 ]. Despite this, both yuanhuacine A ( 1 ) and yuanhuacine (as an isomeric mixture) ( 2 ) were generally well tolerated by CD4+ T cells as measured by direct cell counting with trypan blue (average 96.4 ± 32.2 and 79.6 ± 41.5% viability, respectively, compared to 65.9 ± 12.4% viability in the presence of prostratin; Figure 6 A).…”

“…Primary cell viability and latency reversal in the presence of test agents were performed as described previously [ 22 ]. Briefly, 2 × 10 6 cells were treated with 0.1% DMSO, test agent, or anti-CD3/CD28 dynabeads (Invitrogen, Carlsbad, CA, USA) in a 1:1 ratio for 24 h. Following incubation, live cells were counted visually by trypan blue staining.…”

“…Briefly, 2 × 10 6 CD4+ T-cells per donor were cultured in the presence of 0.1% DMSO, anti-CD3/CD28 dynabeads (a positive control CD4+ T cell activator), 10 µM prostratin, or 1.5 µM of yuanhuacine A (1) or yuanhuacine (as an isomeric mixture) (2). Following 24 h incubation, the cell viability was assessed by trypan blue staining, and the viral RNA in each culture supernatant was determined by qRT-PCR [22]. Consistent with our previous observations, we observed considerable donor-to-donor variability [22].…”

Potential Role of Polyphenolic Flavonoids as Senotherapeutic Agents in Degenerative Diseases and Geroprotection

“…Such effects include maintaining SASP, inducing apoptosis in SCs, and activating different protective cellular mechanisms. Although the precise mechanisms of action have not been elucidated, their antioxidant and anti-inflammatory activities have been suggested to play a vital role since they are the main factors implicated in ageing and various ageing-related diseases [ 12 , 50 , 51 ]. Ample evidence from experimental animal studies has shown the anti-senescence effects of flavonoids to be senomorphic, with only a few exerting senolytic effects [ 4 , 5 , 52 – 54 ].…”

“…Apart from their beneficial metabolic effects, flavonoids could be considered suitable adjuvants in treating human immunodeficiency virus type (HIV) infection-induced immune senescence [ 127 ]. Some naturally occurring flavonoids and several senotherapeutics, especially the tyrosine kinase inhibitors and Bcl-2 inhibitors, which are commonly used to treat cancer, hold therapeutic promise of suppressing viral replication of latently infected HIV cells [ 50 , 51 , 128 ], as well as immunomodulatory effects of reducing proinflammatory mediators [ 52 ], leading to abrogation of neuroinflammation and persistent immune activation associated with HIV infection. By inhibiting CDK9 and Tat transactivation, chrysin, apigenin, and luteolin reinforce HIV latency and induce transcriptional quiescence [ 51 ], suggesting a role in silencing HIV reservoirs in humans.…”