Abstract
Despite the success of combination antiretroviral therapy (cART), HIV persists in low- and middle-income countries (LMIC) due to emerging drug resistance and insufficient drug accessibility. Furthermore, cART does not target latently-infected CD4+ T cells, which represent a major barrier to HIV eradication. The “shock and kill” therapeutic approach aims to reactivate provirus expression in latently-infected cells in the presence of cART and target virus-expressing cells for elimination. An attractive therapeutic prototype in LMICs would therefore be capable of simultaneously inhibiting viral replication and inducing latency reversal. Here we report that Gnidia sericocephala, which is used by traditional health practitioners in South Africa for HIV/AIDS management to supplement cART, contains at least four daphnane-type compounds (yuanhuacine A (1), yuanhuacine as part of a mixture (2), yuanhuajine (3), and gniditrin (4)) that inhibit viral replication and/or reverse HIV latency. For example, 1 and 2 inhibit HIV replication in peripheral blood mononuclear cells (PBMC) by >80% at 0.08 µg/mL, while 1 further inhibits a subtype C virus in PBMC with a half-maximal effective concentration (EC50) of 0.03 µM without cytotoxicity. Both 1 and 2 also reverse HIV latency in vitro consistent with protein kinase C activation but at 16.7-fold lower concentrations than the control prostratin. Both 1 and 2 also reverse latency in primary CD4+ T cells from cART-suppressed donors with HIV similar to prostratin but at 6.7-fold lower concentrations. These results highlight G. sericocephala and components 1 and 2 as anti-HIV agents for improving cART efficacy and supporting HIV cure efforts in resource-limited regions.
Funder
Department of Science and Technology
Canadian Institutes for Health Research
Wellcome Trust
Subject
Virology,Infectious Diseases
Reference36 articles.
1. Global AIDS update: Seizing the Moment: Tackling Entrenched Inequalities to End Epidemics. Geneva 2020
https://healtheducationresources.unesco.org/library/documents/global-aids-update-2020-seizing-moment-tackling-entrenched-inequalities-end#:~:text=to%20end%20epidemics-Global%20AIDS%20update%202020%3A%20seizing%20the%20moment%3A%20tackling,entrenched%20inequalities%20to%20end%20epidemics&text=380%20p.&text=UNAIDS%20report%20on%20the%20global,HIV%20progress%20way%20off%20course
2. Bioassay-Guided Investigation of the Tanzanian Plant Pyrenacantha kaurabassana for Potential Anti-HIV-Active Compounds
3. Prevalence of pretreatment HIV drug resistance in West African and Southeast Asian countries
4. Moderate-to-High Levels of Pretreatment HIV Drug Resistance in KwaZulu-Natal Province, South Africa
5. HIV drug resistance profile in South Africa: Findings and implications from the 2017 national HIV household survey