Tackling Drug Resistant HIV/AIDS Infections
Options to improve drug designs for resistant virus
On World AIDS Day, we remember the 34 million unfortunate people infected by HIV, pay tribute to those working to stem the pandemic, and anticipate new medical advances. Antiviral drugs for the treatment and pre-exposure prevention of infection are essential, since a fully effective vaccine has proved elusive despite much effort. Major challenges arise from the persistence of the virus in a latent form due to its integration into the host cell genome, and the prevalence of drug resistant viral strains due to the genetic diversity of HIV.
Current advances include improved techniques for predicting resistance from viral sequences and novel drug designs for combatting resistance and eliminating viral reservoirs. Information from the molecular structure of the viral proteins targets is invaluable for predicting resistance and designing high affinity inhibitors. The problem of resistance is magnified by the sheer number of possible variants. In the smallest drug target of HIV protease, mutations in nearly half of the amino acids are associated with resistance to one or more drugs. These mutations accumulate as the virus evolves higher levels of resistance and we have estimated at least twenty different mutations are needed to provide the highest resistance. In consequence, new inhibitors are being designed to retain high affinity for the resistant mutants as well as wild type enzyme by introducing strong interactions with conserved regions of the protein. Moreover, increasing the lipid solubility by adding fluorine is an attractive option for targeting inaccessible viral reservoirs in the central nervous system. These successes demonstrate the feasibility of developing a new repertoire of drugs for prevention and treatment of HIV infections. Tackling the problem of HIV genetic diversity and drug resistance is likely to require continued efforts to improve the design of antiviral drugs.
Read more in: Weber IT. Can we design drugs for HIV/AIDS that are less susceptible to resistance? Future Med. Chem. DOI: 10.4155/FMC.15.149 (In Press) (2015).