Current develoments and future prospects for HIV gene therapy using interfering RNA-based strategies

Molecular strategies to inhibit HIV-1 replication

“…The major co-receptors required for entry of HIV-1 are the chemokine receptor molecules CCR-5 (R5 HIV-1 isolates) and CXCR-4 (X4 HIV-1 isolates), which are used by monocytes/macrophage-tropic and T-cell tropic HIV-1 viruses, respectively [6]. When the SU protein binds to the co-receptor the result is another structural alteration exposing the N-terminal part of TM.…”

“…This knowledge has led to the development of strategies that directly target the mRNA encoding CCR5 or CXC4, either by ribozymes [6,18], anti-sense RNA [6,18,19] or RNAi [20]. The latter strategy, the siRNA approach, has led to successful blocking of HIV-1 entry, protection of cells from infection and delay of virus replication [21-24].…”

“…This process is mediated by the viral reverse transcriptase (RT) enzyme in a complex consisting of RT, the viral genome, and a cellular tRNA 3 lys . The latter acts as primer and initiates negative strand DNA synthesis by binding to the primer binding site (PBS) region, located immediately 3' to the U5 region [6,4]. RT possesses three essential activities important for replication of the virus: RNA-dependent DNA polymerase (i.e.…”

“…cleaves the genomic RNA in RNA/DNA hybrids during DNA synthesis), DNA-dependent DNA polymerase activity (i.e. for synthesis of the second strand of the proviral DNA) [6,4]. …”

“…The RNA competes with HIV-1 RNA when RT makes the first jump during the first strand transfer [6]. Another decoy was designed to be co-packaged together with genomic RNA into new virions where it competes subsequently with genomic RNA for RT binding [6]. Also, a designed tRNA 3 Lys mutant containing an 11 nucleotide 3'-end complementary to the HIV-1 TAR region, shows an inhibiting effect.…”