Acquisition of multi-PI (protease inhibitor) resistance in HIV-1 in vivo and in vitro.
Protease inhibitors are effective antiviral agents which can lead to a severe decrease in HIV RNA copies in plasma of naive patients, however even successful suppression of the virus with antiretroviral agents including protease inhibitor(s) (PI(s)) generates PI-resistant HIV-1 after long term treatment. Occasionally HIV-1 acquires cross-resistance to other PIs with which the patients have not been treated. Cross-resistance to multiple PIs (multi-PI resistance) leads to a restricted salvage strategy; therefore multi-PI resistance is one of the serious obstacles to efficient antiretroviral chemotherapy. The most common PI-resistance mechanism in HIV-1 is the emergence and accumulation of multiple amino acid substitutions within the viral protease. As well, additional substitutions in protease cleavage sites or substitutions in the Gag protein at non-cleavage sites are involved in recovery of the reduced replication fitness of HIV-1 caused by these mutations in the viral protease. To address or predict the resistance mechanisms of PIs, resistant HIV-1 variants have been intensively studied in vitro. However, the profiles of the amino acid substitutions obtained in PI resistant variants are more diverse and complex than that found in vitro. More elaborate in vitro systems for further analysis of acquisition of PI resistance mechanisms are needed.
Yusa
Keisuke
K
Department of Medical Virology, Graduate School of Medical Sciences, Kumamoto University, 2-1-1 Honjo, Kumamoto 860-0586 Japan. yusak@kaiju.medic.kumamoto-u.ac.jp
Harada
Shinji
S
D000818:Animals; D019380:Anti-HIV Agents / Q000494:pharmacology / Q000627:therapeutic use; D024921:Drug Resistance, Multiple, Viral / Q000187:drug effects*; D015658:HIV Infections / Q000188:drug therapy* / Q000201:enzymology; D016333:HIV Protease / Q000235:genetics; D017320:HIV Protease Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology / Q000235:genetics; D006801:Humans; D009154:Mutation
D019380:Anti-HIV Agents; D017320:HIV Protease Inhibitors; D016333:HIV Protease