Antisense RNA cleavers that target the HIV-1 Rev response element.

摘要

The APOBEC3 family of genes have varying inhibitory activities against HIV, HBV and retro-elements. Studying expression and transcriptional regulation of these host antiviral factors may lead to development of therapeutics which can utilize the innate factors to defend against viral infection. Here, we demonstrated that A3G, the most potent inhibitor of HIV and HBV among the APOBEC3 genes, is regulated by interferons (IFN) in a cell-type dependent manner. IFN-alpha significantly upregulated A3G in liver cells and macrophages, but not in CD4 T cells. IFN-gamma also upregulated A3G in liver cells. Our significant finding was that, in liver cells, A3G induction by IFN-alpha was mediated through a novel STAT1-independent pathway. It was uniquely regulated since the drug Rottlerin specifically inhibits A3G induction and not PKR induction by IFN-alpha.;In order to study the potential role(s) of APOBEC3 expression in vivo, we have profiled the mRNA expression of these genes in an extensive cDNA panel of normal human tissues, and in a cohort of HIV-1 uninfected and infected individuals from Southern China. A3G, A3F, and A3B expression was significantly higher in HIV infected individuals than in uninfected individuals. While there was no correlation between A3G or A3F expression with clinical markers, A3B mRNA expression positively correlated with HIV-1 viral load when controlling for the CCR2 V64I mutation. A higher A3B deletion allelic frequency was found in uninfected individuals (0.52) compared to infected individuals (0.35). This is the first study showing expression of an antiviral gene correlating with HIV-1 viral load. This work will lay the groundwork for future studies to determine if A3B expression can be used as a marker of disease progression, and if A3B deleted alleles are protective against infection.