Molecular Mechanisms of Human Immunodeficiency Virus Resistance to Antiretroviral

Antiretroviral therapy (ART) has transformed the treatment of human immunodeficiency virus (HIV) infection, improving life expectancy and quality of life for millions worldwide. However, the emergence of drug-resistant HIV strains poses a significant challenge to the effectiveness of ART. The molecular mechanisms underlying HIV resistance to antiretroviral drugs involve multiple genetic changes in the viral genome that reduce drug susceptibility, often through alterations in the viral enzymes targeted by the drugs. The primary targets of ART are the viral reverse transcriptase (RT), protease (PR), and integrase (IN) enzymes, which are essential for HIV replication. Resistance to nucleoside reverse transcriptase inhibitors (NRTIs) results from mutations in the viral RT enzyme that reduce drug incorporation into the viral DNA chain. Non-nucleoside reverse transcriptase inhibitors (NNRTIs) bind to a hydrophobic pocket near the RT active site, and resistance to these drugs arises from mutations that alter the binding pocket conformation. Protease inhibitors (PIs) bind to the viral PR enzyme, and resistance results from mutations that alter the enzyme's conformation, reducing drug binding affinity. Integrase strand transfer inhibitors (INSTIs) bind to the viral IN enzyme, and resistance arises from mutations that affect drug binding or alter the IN active site. The emergence of drug-resistant HIV strains can also result from poor adherence to ART, leading to the selection of pre-existing resistant viruses or the development of new resistance mutations. In addition, the genetic diversity of HIV and the high viral replication and mutation rate contribute to the rapid evolution and emergence of drug-resistant strains.

Keywords: Antiretroviral therapy, Drug resistance, Human immunodeficiency virus, Nucleoside reverse transcriptase inhibitors (NRTIs), Integrase, Nonnucleoside reverse transcriptase inhibitors (NNRTIs), Protease, Protease inhibitors, Viral genome.