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RNA interference:a potential novel therapeutic combating HIV-1 in the central nervous system

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Pomerantz R. J.

Archivum Immunologiae et Therapiae Experimentalis

2004

vol. 52

issue 6

401-409

RNA interference (RNAi) is a conserved process by which eukaryotic cells protect their genomes utilizing small, double-stranded RNAs to degrade target RNAs. This occurs in a sequence-specific manner and is different from the interferon effect of larger doublestranded RNAs. Post-transcriptional gene silencing by these nucleic acids can lead to degradation of either cellular or viral RNAs. It has been recently shown that doublestranded, small interfering RNAs (siRNAs) of 21 to 25 nucleotides can be transfected into relevant cells to target specific RNAs. In addition, utilizing hairpin motifs, siRNAs can be expressed intracellularly using molecular therapeutic vectors. This potent approach has been utilized to both inhibit pathogens, including viruses, as well as to dissect cellular molecular mechanisms via a potent knockout effect. At this time in the HIV-1-pandemic, one of the remaining, most enigmatic, and still vitally important areas of HIV-1 pathogenesis occurs in the central nervous system (CNS). HIV-1-induced encephalopathy remains difficult to treat in the developing world and in parts of the developed world, even in the era of highly active anti-retroviral therapy. As such, novel approaches which could lead to intracellular immunization, and life-long resistance against HIV-1 encephalopathy would be of important impact worldwide. Thus, we now seek to combine our background in molecular therapeutics and RNAi with our long-standing interest in HIV-1 neuropathogenesis to target the CNS using siRNAs.

Ludwik Hirszfeld Memorial Lecture:HIV-1 reservoirs: major molecular obstacles to viral eradication

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Pomerantz R. J.

issue 5

297-306

Over the last 18 years of study in one of our laboratories, we have observed the development of residual disease and latent reservoirs as major problems in the long-term therapy of HIV-1-infected individuals on highly active antiretroviral therapy (HAART).It was shown in the early 1990 's that HAART, as it is presently configured, is unlikely to lead to viral eradication due to several mechanisms of viral persistence. The two general mechanisms involved with persistence during HAART include low-level residual, cryptic replication and proviral latently-infected cells. As such, these are key areas of potential study for depletion and, hopefully in the future, eradication of residual disease in patients on suppressive HAART. To deplete these residual disease mechanisms will require multipronged approaches. These will include induction of HIV-1 latent proviruses, suppression of residual viral replication and destruction of long-lived cellular sanctuaries, such astissue-bound macrophages.

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RNA interference:a potential novel therapeutic combating HIV-1 in the central nervous system

Ludwik Hirszfeld Memorial Lecture:HIV-1 reservoirs: major molecular obstacles to viral eradication