Oral manifestation of Herpes simplex virus (HSV-1) infection has frequently been observed in HIV infected patients. Initial treatments with anti viral agents (such as acyclovir for HSV and reverse transcriptase and viral protease inhibitors for HIV-1) have been found to be quite effective. Drug resistance and high sensitivity to multiple drugs, however, often developed in these patients with time. Anti viral strategies aimed at controlling the replication of wild type and mutants of both viruses by drugs which can control both viruses thus are clinically important. Transcription of pro viral HIV and HSV 1E genes (a0, a4, a22, a27, and a47 are essential for replication of these two respective viruses. The expressions are thoroughly host dependent, utilizing RNA polymerase II and cellular transcription factors. The promoter activities of proviral HIV and HSV a4 (ICP4) gene are regulated by host protein Sp1 in addition to other cellular factors. The applicant's laboratory has recently discovered that a plant lignan, 3-0-methyl nordihydroguaiaretic acid (3-0-methyl NDGA, Mal.4) can selectively inhibit HIV proviral transcription and HIV replication by blocking the binding of Sp1 to the Sp1 sites located in HIV promoter. The compound is also effective in inhibition of HIV-1 replication in Hu-PBL-SCID mice. Preliminary experiments have further shown that Mal.4 can inhibit HSV a4 transcription in vitro in a dose-dependent manner in HeLa cell extract.
Specific aims of this proposal are (1) to study the molecular mechanism and its effects underlying the binding of Mal.4 to Sp1 and Sp1 sites in the HIV LTR (2) to examine whether Mal.4 and / or related plant lignans can suppress wild type HSV-1 and recombinant HSV ICP4LACZ in African Green Monkey (VERO) cells,(3) to study the effect of plant lignan in controlling HSV 1 in infected Hu-PBL-SCID mice.
