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Background: Maraviroc (MVC) is an allosteric CCR5 inhibitor used against HIV-1 infection. While MVC-resistant viruses have been identified in patients, it still remains incompletely known how they adjust their CD4 and CCR5 binding properties to resist MVC inhibition while preserving their replicative capacity. It is thought that they maintain high efficiency of receptor binding. To date however, information about the binding affinities to receptors for inhibitor-resistant HIV-1 remains limited. Results: Here, we show by means of viral envelope (gp120) binding experiments and virus-cell fusion kinetics that a MVC-resistant virus (MVC-Res) that had emerged as a dominant viral quasispecies in a patient displays reduced affinities for CD4 and CCR5 either free or bound to MVC, as compared to its MVC-sensitive counterpart isolated before MVC therapy. An alanine insertion within the GPG motif (G310_P311insA) of the MVC-resistant gp120 V3 loop is responsible for the decreased CCR5 binding affinity, while impaired binding to CD4 is due to sequence changes outside V3. Molecular dynamics simulations of gp120 binding to CCR5 further emphasize that the Ala insertion alters the structure of the V3 tip and weakens interaction with CCR5 ECL2. Paradoxically, infection experiments on cells expressing high levels of CCR5 also showed that Ala allows MVC-Res to use CCR5 efficiently, thereby improving viral fusion and replication efficiencies. Actually, although we found that the V3 loop of MVC-Res is required for high levels of MVC resistance, other regions outside V3 are sufficient to confer a moderate level of resistance. These sequence changes outside V3, however, come with a replication cost, which is compensated for by the Ala insertion in V3. Conclusion: These results indicate that changes in the V3 loop of MVC-resistant viruses can augment the efficiency of CCR5-dependent steps of viral entry other than gp120 binding, thereby compensating for their decreased affinity for entry receptors and improving their fusion and replication efficiencies. This study thus sheds light on unsuspected mechanisms whereby MVC-resistant HIV-1 could emerge and grow in treated patients. [ABSTRACT FROM AUTHOR]

An abstract of the article "Allosteric Regulation by Non Peptidic, Low Molecular Weight Compounds of CCR5 Coupling to G-Poteins and Iteraction Wth GP 120- Consequences on Inhibition of R5 HIV-1 Infection," by Patricia Rueda, Javier Garcia-Perez, Isabelle Staropoli, Esther Kellenberger, Jose Alcami, Fernando Arenzana-Seisdedos and Bernard Lagane is presented.

Background: Emissions from refineries include a wide range of substances, such as chrome, lead, nickel, zinc, arsenic, cadmium, benzene, dioxins and furans, all of which are recognized by the International Agency for Research on Cancer (IARC) as carcinogens.Various studies have shown an association between non-Hodgkin lymphoma (NHL) and residence in the vicinity of industrial areas; however, evidence of specific association between refineries and residence in the vicinity has been suggested but not yet established.The aim of this study is to investigate potential links between environmental exposure to emissions from refineries and non-Hodgkin lymphoma mortality in Spain.The spatial distribution of NHL in Spain has an unusual pattern with regions some showing higher risk than others., Methods: We designed an analysis of matched geographical areas to examine non-Hodgkin lymphoma mortality in the vicinity of the 10 refineries sited in Spain over the period 1997-2006. Population exposure to refineries was estimated on the basis of distance from town of residence to the facility in a 10 km buffer.We defined 10 km radius areas to perform the matching, accounting for population density, level of industrialization and socio-demographic factors of the area using principal components analysis.For the matched towns we evaluated the risk of NHL mortality associated with residence in the vicinity of the refineries and with different regions using mixed Poisson models. Then we study the residuals to assess a possible risk trend with distance., Results: Relative risks (RRs) associated with exposure showed similar values for women and for men, 1.09 (0.97-1.24) and 1.12 (0.99-1.27). RRs for two regions were statistically significant: Canary Islands showed an excess of risk of 1.35 (1.05-1.72) for women and 1.50 (1.18-1.92) for men, whilst Galicia showed an excess of risk of 1.35 (1.04-1.75) for men, but not significant excess for women., Conclusions: The results suggest a possible increased risk of NHL mortality among populations residing in the vicinity of refineries; however, a potential distance trend has not been shown. Regional effects in the Canary Islands and Galicia are significantly greater than the regional average.