Activation of latent HIV-1 expression by the potent anti-tumor promoter 12-deoxyphorbol 13-phenylacetate.
Agents that induce HIV-1 out of latency would be useful adjuvants for currently available anti-retroviral therapy. We report that nanomolar concentrations of 12-deoxyphorbol 13-phenylacetate (DPP), an anti-tumor-promoting phorbol ester originally isolated from a West African plant, induce the expression of HIV-1 in latently infected T cells and render them sensitive to killing by an immunotoxin targeted to the viral envelope glycoprotein. DPP also regulates an extensive series of genes under the control of protein kinase C, including several involved in T cell activation and cytoskeleton reorganization, and represses expression of the HIV-1 receptor CD4 and coreceptor CXCR4. DPP is 20-40-fold more potent than the related phorbol ester prostratin, probably due to its more lipophilic side chain structure. The combination of high potency and anti-tumor promoting activity make DPP an attractive candidate for the adjunctive therapy of persistent HIV-1 infection.
Bocklandt
Sven
S
National Cancer Institute, NIH, 9000 Rockville Pike, Bethesda, MD 20892, USA.
Blumberg
Peter M
PM
Hamer
Dean H
DH
D019380:Anti-HIV Agents / Q000737:chemistry / Q000494:pharmacology*; D015704:CD4 Antigens / Q000378:metabolism; D002273:Carcinogens / Q000037:antagonists & inhibitors; D002460:Cell Line; D015536:Down-Regulation / Q000187:drug effects; D020869:Gene Expression Profiling; D015658:HIV Infections / Q000188:drug therapy; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D006801:Humans; D046911:Macromolecular Substances; D008958:Models, Molecular; D020411:Oligonucleotide Array Sequence Analysis; D010703:Phorbol Esters / Q000737:chemistry / Q000494:pharmacology*; D011493:Protein Kinase C / Q000737:chemistry / Q000502:physiology; D019718:Receptors, CXCR4 / Q000378:metabolism; D014775:Virus Activation / Q000187:drug effects; D014779:Virus Replication / Q000187:drug effects
D019380:Anti-HIV Agents; D015704:CD4 Antigens; D002273:Carcinogens; D046911:Macromolecular Substances; D010703:Phorbol Esters; D019718:Receptors, CXCR4; C029704:12-deoxyphorbolphenylacetate; C070999:prostratin; D011493:Protein Kinase C