New Resistance Mechanism To Anti-HIV Drugs Discovered

A recently published study in the Journal of Molecular Biology directed by Dr. Luis Menéndez-Arias from the Centro de Biología Molecular “Severo Ochoa”, (CSIC-UAM) identifies the existence of compensating mechanisms for reverse transcriptase deficiency and suggests new resistance mechanisms to drugs in the preclinical development phase.

Reverse transcriptase is the enzyme that replicates the genetic material of the HIV virus by converting RNA into DNA (the inverse procedure to transcription) and it represents the main target for current antiretroviral drugs. This enzyme can be destabilised in different ways by making it susceptible to degradation by protease which effectively renders the virus inactive.

Antiretroviral drugs currently represent the only hope of a better future for millions of HIV positive patients; and among these, reverse transcriptase inhibitors (RTIs) are the most important group in the fight against HIV. The role of reverse transcriptase in retrovirus replication was stated in 1970 when Temin and Baltimore discovered its role in the Rous sarcoma virus which is a type of avian retrovirus.

However, regardless of the time passed and the development of powerful new inhibitors for its function in the HIV virus, important details of the generation process of reverse transcriptase inside the virus remain unknown. For example, it is known that the viral protease intervenes in the biosynthesis of reverse transcriptase, producing cuts in large viral proteins that are precursors of reverse transcriptase and other proteins of the HIV virus. The activity of protease must be well regulated, since excessive cutting would hinder the virus viability; but how that process is regulated or the precise moment at which protease becomes active is not yet clear. Understanding these mechanisms would help the design of antiretroviral drugs with new action methods against the virus.

The investigation of Dr. Luis Menéndez-Arias (Centro de Biología Molecular “Severo Ochoa”, CSIC-UAM) in collaboration with researchers from the Centro Nacional de Microbiología (Instituto Carlos III, Majadahonda), Alabama University (EE.UU.) and Debrecen university (Hungary) proves that some mutations in reverse transcriptase make it much more sensitive to degradation by protease, which implies a reduction of the infecting capability of the virus.

However, using this attenuated viruses, the research team arrived at very interesting conclusions - they noticed that when the attenuated virus was cultivated over time, the infecting capability grew. They discovered that the appearance of mutations in the protease were reducing its proteolytic activity, hence increasing the stability of the reverse transcriptase in the virus with the consequent increase in infectious capability.

These results suggest a resistance mechanism to some reverse transcriptase inhibitors that are currently at the preclinical development phase, and that work by destabilising the structure of this important enzyme.