Stage Master

HIV-1 replication cycle starts with the virus entry into the host human cell. It is known for 20 years that the glycoprotein gp120 at the virus surface directly recognises both a receptor, CD4, and a coreceptor, mainly CCR5. The binding triggers conformational changes in the viral Env trimer gp120 belongs to, thereby promoting the fusion of the viral and cellular membrane.
HIV is constantly evolving. This explains change of infection virulence, resistence to antiviral drugs, including maraviroc which targets CCR5, viral transmission, and cell tropism. Recently, it has been proposed that there is an interplay between the virus physiopathology and the conformation state of CCR5. Our laboratory works in collaboration with B Lagane, A Brelot and F Arenzana-Seisdenos to demonstrate the biological and therapeutical relevence of this relationship and to elucidate its molecular basis.[1-3]
The project overall consists in the exploration of the conformational plasticity of CCR5 in different contexts (dimer/monomer, free/bound to maraviroc, wild type/mutant), the simulation of the dynamics of gp120 variants with different phenotypic profiles, and finally the modeling of gp120 binding to CCR5. The two first points have been already well addressed in the laboratory using accelerated molecular dynamics. Some more experiments are needed to confirm the observed trends. The internship student will work on one of the three parts depending on the project progress.
The candidate must show a strong interest in molecular dynamics and protein structure analysis. A well-structured and well-organised way of working is required to conduct the project. Basic programming skills in Linux environment are desirable.

[1] CCR5 adopts three homodimeric conformations that control cell surface delivery (2018) Jin J, Momboisse F, Boncompain G, Koensgen F, Zhou Z, Cordeiro N, Arenzana-Seisdedos F, Perez F, Lagane B, Kellenberger E, Brelot A. Sci Signal. 11: 529
[2] A single-residue change in the HIV-1 V3 loop associated with maraviroc resistance impairs CCR5 binding affinity while increasing replicative capacity (2015) Garcia-Perez J, Staropoli I, Azoulay S, Heinrich JT, Cascajero A, Colin P, Lortat-Jacob H, Arenzana-Seisdedos F, Alcami J, Kellenberger E, Lagane B. Retrovirology. 12: 50.
[3] Modeling the allosteric modulation of CCR5 function by Maraviroc (2013) Lagane B, Garcia-Perez J, Kellenberger E. Drug Discov Today Technol. 10: e297-305.