Question

Explain how reverse transcriptase causes resistance to the viral protease inhibitor ritonavir

Answer 1

Ans.

• Protease inhibitors (PIs) inclusion in the antiviral regime has shown to be a very powerful and promising concept in the treatment of human immunodeficiency virus (HIV) infection.
• The viral protease is required for cleavage of the viral precursor Gag and GagPol polyproteins, which results in mature infectious viruses and their spread.
• PI resistance occurs frequently and it is generally a step-wise process.
• In the beginning, mutations in the substrate-binding pocket of the protease are selected, which results in reduced binding of the PI (i.e., resistance) and the natural Gag and GagPol substrate affecting viral replication.
• To compensate for loss of replication capacity (RC), additional mutations in the viral protease that improve processing efficiency of resistant protease are selected.
• Also, some compensatory changes have been identified in the Gag substrate of the viral protease which were thought to adapt the virus to the drug resistant viral protease, and were considered to be compensatory changes that do not directly affect PI resistance.
• However, several researh works carried out in cell lines as well as in lab animals have demonstrated that Gag cleavage site (CS) changes are able to reduce PI susceptibility and represent an alternative PI resistance mechanism.