Conversion of the HIV RNA genome into DNA by viral reverse transcriptase (RT) is a key step in the early stages of the HIV life cycle, making the enzyme an ideal target for antiretroviral therapy. In the animation above, RT inhibitors are colored in orange. Two classes of reverse transcriptase inhibitors are commercially available: nucleos(t)ide reverse transcriptase inhibitors (NRTI's) and non-nucleoside reverse transcriptase inhibitors (NNRTI's). The NRTI's were the first antiretrovirals to be made available for the treatment of HIV. Based on their similarity to the natural nucleotide building blocks of DNA and RNA, NRTI's are incorporated into the growing DNA strand and terminate further strand elongation. On the other hand, NNRTI's are a chemically diverse class of drugs that bind to the same pocket near the active site of RT and as such inhibit the enzyme.
Tibotec's multi-disciplinary research has yielded two novel NNRTI's: etravirine which is being commercialized around the world, and TMC278 which is currently in late-stage clinical development. They demonstrate high intrinsic activity against both wild-type HIV-1, and HIV-1 strains harboring resistance-inducing mutations.
Curing the body of HIV
During HIV infection a reservoir of latent HIV genomes is quickly deposited in various cells. After cessation of HAART therapy these proviral genomes can reactivate and lead to new viruses and a rebound infection. The longest lived reservoirs are the memory T cells - those cells that carry the immunological memory of the person - which have a half-life of 3-4 years. It has been estimated that if a person could maintain complete HIV suppression for approximately 60 years these cells would completely die off and the patient would be cured. Tibotec scientists are looking for ways to accelerate this process. The basic strategy is to find drugs or mixtures of drugs that will reactivate these latent HIV genomes while the patient is maintained on HAART. This would cause the reservoir to disappear more rapidly and allow patients to be effectively cured and allow them to cease live-long HAART therapy.
