Additional mutations detected in sequential HIV-1 isolates from ZDV-treated patients

Area of Science:

• Virology
• Molecular Biology
• Pharmacology

Background:

• Zidovudine (ZDV) is a nucleoside reverse transcriptase inhibitor used in HIV therapy.
• Emergence of drug resistance is a major challenge in managing HIV infection.
• Understanding resistance mechanisms is crucial for optimizing antiviral treatment strategies.

Purpose of the Study:

• To investigate the emergence of ZDV resistance in sequential HIV isolates from patients undergoing ZDV therapy.
• To identify mutations in the reverse transcriptase gene associated with ZDV resistance.
• To evaluate the predictive value of early isolates for future resistance development.

Main Methods:

• Sequential peripheral blood mononuclear cell (PBMC) coculture from four patients on ZDV therapy.
• HIV susceptibility assays performed in the presence and absence of ZDV.
• Partial reverse transcriptase gene sequencing of proviral DNA from amplified products.

Main Results:

• PBMC-based assays confirmed the emergence of ZDV resistance in sequential isolates.
• Numerous mutations, beyond previously known critical codons (41, 67, 70, 215, 219), were identified in both sensitive and resistant isolates.
• No clear mutational pattern predictive of ZDV resistance was established; highly variable regions near critical codons were noted.
• The Thr215Tyr mutation was absent in a highly resistant isolate, while Lys70Arg was found in both sensitive and resistant strains.

Conclusions:

• Sequential HIV isolates from ZDV-treated patients exhibit increasing resistance.
• The genetic basis of ZDV resistance is complex, involving numerous mutations beyond established key sites.
• Early-stage isolates, whether pre-therapy or early on-therapy, did not provide unambiguous predictive data for future ZDV resistance.
• Further research into highly variable regions may elucidate complex resistance mechanisms.