Novel phorbol esters exert dichotomous effects on inhibition of HIV-1 infection and activation of latent HIV-1 expression.
Two new phorbol esters, NPB-11 (12-O-methoxymethylphorbol-13-decanoate) and NPB-15 (12-O-benzyloxymethylphorbol-13-decanoate) were synthesized. The compounds exhibited potent anti-HIV-1 activity and low cytotoxicity in MT-4 cells by MTT assay even at a high concentration [50% cytotoxic concentrations (CC50) were 8.32 and 4.39 microg/ml, respectively]. Two inhibitors strongly suppressed HIV-1 (IIIB strain) replication in MT-4 cells with a 50% effective concentration (EC50) of 1.3 and 0.27 ng/ml, respectively. NPB-11 efficiently blocked replication of both X4 and R5 HIV-1 in PHA-activated peripheral blood mononuclear cells and MT-4 cells as revealed by p24 assay. The antiviral activity appeared to be mediated, at least partially, by the down-regulation of the expression of CD4 and the HIV-1 co-receptors, CXCR4 and CCR5. The compounds were also capable of selectively up-regulating HIV-1 expression in a variety of latently infected cell lines and inducing cell death in HIV-1 infected cells. The effect of NPBs on the induction of HIV-1 was specifically blocked by nontoxic doses of a protein kinase C blocker, staurosporine. NPB-11 blocked the spread of HIV-1 released from latently infected ACH-2 cells to MT-4 cells in a co-culture system. When combined with AZT, NPB-11 synergistically inhibited HIV-1 replication in MTT assay using MT-4 cells. These data suggest that these agents might be useful in reducing persistent viral reservoirs in patients and as adjuvant therapy in patients treated with HAART.
Zhong
Yu
Y
Department of Molecular Virology, Bio-Response, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan.
Matsuya
Yuji
Y
Nemoto
Hideo
H
Mori
Masao
M
Saito
Haruo
H
Yamamoto
Naoki
N
D019380:Anti-HIV Agents / Q000494:pharmacology*; D002460:Cell Line; D015536:Down-Regulation; D005434:Flow Cytometry; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D010703:Phorbol Esters / Q000494:pharmacology*; D014775:Virus Activation / Q000187:drug effects*; D014779:Virus Replication / Q000187:drug effects
C508043:12-O-benzyloxymethylphorbol-13-decanoate; D019380:Anti-HIV Agents; D010703:Phorbol Esters; C508044:12-O-methoxymethylphorbol-13-decanoate