Use of Flaviviral genetic fragments as a potential prevention strategy for HIV-1 Silencing

Coinfection with certain members of the Flaviviridae, such as Dengue Virus (DV), West Nile Virus (WNV) Yellow Fever Virus (YFV) and most importantly, GBV-C have been documented to reduce HIV-1 viral load in vivo. Numerous studies strongly support the notion that persistent coinfection with non-pathogenic virus prolongs survival in HIV-1 infected individuals. Coinfected individuals show higher CD4+ cell counts, lower HIV-1 RNA viral loads and live three times longer than clinically matched HIV-1 monoinfected patients. We have previously shown that one of the major anti-HIV defenses conferred by GBV-C coinfection is the upregulation of intracellular miRNAs in CD4+ cells that share significant mutual homologies with GBV-C and HIV-1 (>80%) genomes.

Genome-wide bioinformatics analyses were carried out to search for miRNA binding sites in mutual homologies between HIV and several members of the Flaviviridae.

Several miRNAs shared significant mutual homology with HIV-1 genetic sequences and GBV-A, B, C, DV, WNV and YFV. These may be responsible for beneficial effects in HIV-1 infected individuals. Three highly mutual homologous miRNAs (i.e. miR-627-5, miR-369-5 and miR-548f), expressed in CD4+ cell lines, reduce HIV-1 replication by up to 90% whereas miRNAs with low mutual homologies (i.e. miR-34-1 and miR-508) impart only slight inhibition of HIV-1.

We hypothesize that a recombinant GBV-C-based vector can be constructed which expresses several beneficial genetic motifs of the Flaviviridae without causing any side effects while stimulating a wide array of beneficial miRNAs that can more efficiently prevent HIV-1 infection.