S.24. HIV-1 resistant genes in India: catalytic RNA and DNA molecules for therapy

HIV-1 pathogenesis involves complex interaction of host factors and viral genes besides several other factors. HIV1 exploits the chemokine receptors to gain entry into a susceptible cell. Although there are several chemokine receptors, CCR5 and CXCR4 have attracted a great deal of attention. CCaR5 - chemokine receptor is a seven transmembrane G -coupled protein receptor present on the surface of langerhan and macrophages. Infection is usually initiated by the marcophage tropic (R5) HIV-1 that uses CCR5 and CD4 glycoprotein on the host surface. A successful trimolecular interaction involving HIV-1 gp160 - CD4 and CCR5 results in cell membrane fusion and entry of the virus. That CCR5 is involved in transmission was established earlier by observing HIV-1 protective effects in normal individuals who were homozygous for D32 mutation of CCR5. These individuals do not express a functional CCR5 molecule and are resistant to infection by R5 tropic virus. We reported few years back the presence of this remarkable mutation (heterozygous for D32 CCR5) in a normal healthy individual from North-India. This protective mutation is extremely rare in India but quite prevalent in North-America and Europe. During the course of the disease, an evolution of coreceptor usage occurs and dual tropic viruses (R5/X4), followed by X4 tropic viruses (present on T-helper lymphocytes) are generated towards the end of the disease spectrum. Since individuals homozygous for D32 are perfectly normal, this host gene has become a very attractive target for interfering with virus entry. We exploited various nucleic acid based approaches (ribozymes, DNA-enzymes and siRNAs) to interfere with the entry of HIV-1. Since escape mutants are very common in case of HIV-1, this target site was combined with other sites important for virus replication. Potential therapeutic applications along with problems will be discussed.