Gnidimacrin, a Potent Anti-HIV Diterpene, Can Eliminate Latent HIV-1 Ex Vivo by Activation of Protein Kinase C β.
HIV-1-latency-reversing agents, such as histone deacetylase inhibitors (HDACIs), were ineffective in reducing latent HIV-1 reservoirs ex vivo using CD4 cells from patients as a model. This deficiency poses a challenge to current pharmacological approaches for HIV-1 eradication. The results of this study indicated that gnidimacrin (GM) was able to markedly reduce the latent HIV-1 DNA level and the frequency of latently infected cells in an ex vivo model using patients peripheral blood mononuclear cells. GM induced approximately 10-fold more HIV-1 production than the HDACI SAHA or romidepsin, which may be responsible for the effectiveness of GM in reducing latent HIV-1 levels. GM achieved these effects at low picomolar concentrations by selective activation of protein kinase C βI and βII. Notably, GM was able to reduce the frequency of HIV-1 latently infected cells at concentrations without global T cell activation or stimulating inflammatory cytokine production. GM merits further development as a clinical trial candidate for latent HIV-1 eradication.
Weihong
W
Lai
Li
L
Huang
Lei
L
Zhu
Guido
G
Ferrari
Cliburn
C
Chan
Faculty of Pharmaceutical Sciences, Toho University , Miyama 2-2-1, Funabashi, Chiba 274-8510, Japan.
Wei
W
Li
Natural Products Research Laboratories, UNC Eshelman School of Pharmacy, University of North Carolina , Chapel Hill, North Carolina 27599, United States.|Chinese Medicine Research and Development Center, China Medical University and Hospital , Taichung, Taiwan.
Kuo-Hsiung
KH
Lee
Chin-Ho
CH
Chen
D019380:Anti-HIV Agents / Q000494:pharmacology*; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000201:enzymology / Q000821:virology; D004224:Diterpenes / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects*; D015658:HIV Infections / Q000188:drug therapy* / Q000201:enzymology / Q000821:virology; D015497:HIV-1 / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000201:enzymology / Q000821:virology; D064546:Protein Kinase C beta / Q000378:metabolism*; D017735:Virus Latency / Q000187:drug effects*
D019380:Anti-HIV Agents; D004224:Diterpenes; C013006:gnidimacrin; D064546:Protein Kinase C beta