HIV OVERVIEW

First Health Pharmaceuticals has started clinical development of the first ever generation of Translation Inhibitor antiretroviral compounds. Translation Inhibitors offer unique possibilities uncommon to traditional HIV antivirals, such as significantly reduced resistance development, improved delivery in the body, low toxicity and the possibility of successful co-application in wake-up strategies of dormant reservoir cells.

Like Cancer, the battle against HIV/AIDS is fought on several fronts. For decades already, the HIV virus has proven to be a formidable opponent, capable of rapidly developing resistance against all the retroviral drugs that have been thrown against it. The problem of resistance development has been largely circumvented by the latest generations of Highly Active Anti-Retroviral Therapies (HAART) which basically consist of the combined application of different classes of antiretroviral drugs with the aim of confusing the resistance development mechanisms of the virus.

The introduction of HAART combination drugs has greatly enhanced the life expectancy of HIV/AIDS patients, but thus far has not resulted in a definitive cure. The reason for this is not directly related to resistance development but rather to the annoying capacity of the virus to protect itself by remaining in a semi dormant stage in certain cells related to our own immune system where it is impossible to be detected and destroyed by the same immune system. This very clever survival mechanism of the HIV virus can not be resolved by more of the same antiretroviral drugs. It is a completely different battle and needs to be fought with different weapons.

Whilst antiretroviral drugs have proven to be active against the HIV virus, they all target some of HIV’s own viral proteins needed for its reproduction cycle. Some of these proteins are needed for the viral entrance into our cells while others are needed during the reproduction stage.

TRANSLATION INHIBITOR COMPOUNDS

Our DDX3 RNA Helicase inhibiting Translation Inhibitor class of compounds do not target viral proteins but temporarily inhibit an enzyme of our own RNA cell biology that is of vital importance for the virus during its reproduction cycle. As such the virus finds itself in an impossible situation in which mutating its own viral proteins is no longer helpful in escaping from the drug effect; thus no, or less drug-resistant strains are selected and expanded. Furthermore, the host cells as well as the non-infected cells are not particularly affected by the inhibition of their own enzyme as they can rely on different pathways for their functions. This is confirmed by the almost absent cytotoxic effects of our compounds both in vitro and in vivo. On this basis, a low systemic toxicity is expected even for long term treatments.

HIV LATENCY&SURVIVAL

As mentioned, HIV is a highly mutative retrovirus with a capability to develop rapid resistance towards any ART thrown against it. The high mutation rate of retroviruses itself is easily explained by the rapid replication rate and the high number of DNA copies retrotranscribed from viral RNA. The retrotranscriptase is prone to error and has no proofreading function, and taking into account that each infected cell in return produces thousands of new virions, it is easy to picture how even within a single infected HIV/AIDS patient, billions of novel virions will emerge which can potentially harbour small variations in their genetic code. ART medications will successfully inhibit most viruses during one of the  fundamental steps in their life cycle; however, sooner or later, virions will escape because their viral proteins are just ever so slightly different, carrying with them the genetic qualities that contributed to their survival. If one multiplies this process by the millions it will become clear that rapid resistance development towards traditional ART medication is an inevitable process.