HIV-1 IN alternative molecular recognition of DNA induced by raltegravir resistance mutations
ABSTRACT Virologic failure during treatment with raltegravir, the first effective drug targeting HIV integrase, is associated with two exclusive pathways involving either Q148H/R/K, G140S/A or N155H mutations. We carried out a detailed analysis of the molecular and structural effects of these mutations. We observed no topological change in the integrase core domain, with conservation of a newly identified Omega-shaped hairpin containing the Q148 residue, in particular. In contrast, the mutations greatly altered the specificity of DNA recognition by integrase. The native residues displayed a clear preference for adenine, whereas the mutant residues strongly favored pyrimidines. Raltegravir may bind to N155 and/or Q148 residues as an adenine bioisoster. This may account for the selected mutations impairing raltegravir binding while allowing alternative DNA recognition by integrase. This study opens up new opportunities for the design of integrase inhibitors active against raltegravir-resistant viruses.
Conference Paper: Analysis of equal-gain diversity receiver in correlated fading channels[Show abstract] [Hide abstract]
ABSTRACT: Performance evaluation of equal-gain combining (EGC) diversity receivers are known to be a much more difficult task in comparison with other diversity combining techniques such as the selection diversity or the maximal-ratio combining method. The difficulty of the above mathematical problem is compounded when the diversity branches are correlated. This paper presents a novel mathematical framework for analyzing a dual-branch EGC receiver performance over nonidentical Rayleigh and Nakagami-m fading channels when the diversity branches are correlated. It is also shown that the average bit error rate (ABER) formula for coherent BPSK and BFSK schemes reduces to the familiar expressions in the literature for the limiting case of independent diversity paths by setting the correlation coefficient to zero. Selected numerical plots that illustrate the effect of branch correction on the ABER performance are also provided.Vehicular Technology Conference, 2002. VTC Spring 2002. IEEE 55th; 02/2002
- [Show abstract] [Hide abstract]
ABSTRACT: Integrase (IN), the HIV-1 enzyme responsible for the integration of the viral genome into the chromosomes of infected cells, is the target of the recently approved antiviral raltegravir (RAL). Despite this drug's activity against viruses resistant to other antiretrovirals, failures of raltegravir therapy were observed, in association with the emergence of resistance due to mutations in the integrase coding region. Two pathways involving primary mutations on residues N155 and Q148 have been characterized. It was suggested that mutations at residue Y143 might constitute a third primary pathway for resistance. The aims of this study were to investigate the susceptibility of HIV-1 Y143R/C mutants to raltegravir and to determine the effects of these mutations on the IN-mediated reactions. Our observations demonstrate that Y143R/C mutants are strongly impaired for both of these activities in vitro. However, Y143R/C activity can be kinetically restored, thereby reproducing the effect of the secondary G140S mutation that rescues the defect associated with the Q148R/H mutants. A molecular modeling study confirmed that Y143R/C mutations play a role similar to that determined for Q148R/H mutations. In the viral replicative context, this defect leads to a partial block of integration responsible for a weak replicative capacity. Nevertheless, the Y143 mutant presented a high level of resistance to raltegravir. Furthermore, the 50% effective concentration (EC(50)) determined for Y143R/C mutants was significantly higher than that obtained with G140S/Q148R mutants. Altogether our results not only show that the mutation at position Y143 is one of the mechanisms conferring resistance to RAL but also explain the delayed emergence of this mutation.Antimicrobial Agents and Chemotherapy 11/2009; 54(1):491-501. DOI:10.1128/AAC.01075-09 · 4.45 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Integration of the HIV-1 viral DNA generated by reverse transcription of the RNA genome into the host cell chromosomes is a key step of viral replication, catalyzed by the viral integrase. In October 2007, the first integrase inhibitor, raltegravir, was approved for clinical use under the name of Isentress superset. The results of the various clinical trials that have evaluated raltegravir have been very encouraging with regard to the immunological and virological efficacy and tolerance. However, as observed for other anti-retrovirals, specific resistance mutations have been identified in patients failing to respond to treatment with raltegravir. Although knowledge of the integrase structural biology remains fragmentary, the structures and modeling data available might provide relevant clues on the origin of the emergence of these resistance mutations. In this review, we describe the mechanism of action of this drug and the main data relating to its use in vivo, together with recent structural data important to our understanding of the origin of viral resistance.European journal of medical research 11/2009; 14 Suppl 3(Suppl 3):5-16. DOI:10.1186/2047-783X-14-S3-5 · 1.40 Impact Factor