Changes in Mutation Patterns of Reverse Transcriptase and Protease Genes in Treated HIV Infected Patients in Marseille Area from 1997 to 1999. A Unique Molecular Mechanism of Resistance to Multiple Dideoxynucleosides provided by MDR Mutations and Insertions/Deletions in the RT Gene.
C. TAMALET*, N. YAHI, P. COLSON, I. POIZOT-MARTIN, A. M. QUINSON, H. GALLAIS, F. VOLOT, and J. FANTINI.
CHRU de la Timone; CISIH Marseille; DIM Timone; Faculte des Sciences St. Jerome, Marseille, France
Objectives: (1) To assess the evolution of resistance associated mutations (RAM) in 782 HIV-1 infected patients with virologic failure from 1997 to 1999 in parallel with antiretroviral use over time. (2) To propose a unique mechanism accounting for multidrug resistance.
Methods: Direct sequencing of RT and protease genes derived from plasma viruses (ABI 377). Antiretroviral use was documented from the local database on HIV.
Results: Frequency of RAM was as follows: RT gene: T215Y/F (53% vs 63%); M184V (29% vs 57%); K70R (25% vs 19%); T69D (19% vs 17%); L74V (3% vs 9%); MDR mutations and insertions/deletions in the 5' part of the RT gene emerged in mid 98 (3.2%). Protease gene : M46I/L (7% vs 27%); L90M (5% vs 30%); V82A/F/T (9% vs 29%); G48V (4% vs 5%); D30N (1% vs 6%). The proportion of patients with multidrug resistant viruses (harboring major mutations to 2 or 3 classes of inhibitors increased from 3% in 1997 to 30% in 1999 for viruses resistant to PIs and NRTIs, and from 1% in 1997 to 23% in 1999 for triple resistant viruses (NRTIs+NNRTIs+PIs). Based on previous crystallographic studies, we propose that Q151M mutation as well as insertions/deletions in the B3-B4 loop might likely confer multidrug resistance through conformational changes of the dNTP-binding pocket. Data showing the evolution of B3-B4 insertions over time and transient patterns of mutations leading to Q151M will be presented. These data underscore the need for continued epidemiological survey of drug resistance at a community level and for finding new antiretroviral strategies.
Key Words: insertions, multi-drug resistance, mutations