One of the main challenges in HIV research remains understanding the mechanisms of viral latency and of viral rebound after antiretroviral treatment interruption. It remains essential not only to characterize viral reservoirs, both at the cellular and molecular level, but also to understand the mechanisms involved in their reactivation in order to be able to consider eradication therapeutic strategies.
Over the years, we have contributed to the characterization of viral reservoirs in HIV-1 and HIV-2 infected patients, both in CD4+ T-cell subsets from blood and tissue (Ribeiro Dos Santos et al. 2011, Fabre-Mersseman et al. 2011, Samri et al. 2019) and in DCs or splenic macrophages (Mc Ilroy et al. 1995 and 1996), but also in resident tissue macrophages of the male urethra (Ganor, et al 2019). Additionally, through the development of ultra-sensitive, high-throughput DNA quantification technology called DUSQ (DNA Ultra-Sensitive Quantification), we have recently demonstrated that unintegrated linear HIV-1 DNAs can persist for more than 3 months in the recently infected cells, showing that the pre-integrative latency has an important role in the dynamics of establishment of the viral reservoir. Finally, we have demonstrated that treatment with IL-7 can, in the medium term, reduce viral reservoirs in patients (Logerot et al. 2018).
Our aims now are:
- To characterize the dynamics and parameters of pre-integrative latency in vitro and in vivo and more precisely to specify the molecular environment responsible for the stability of non-integrated linear DNAs.
- To define therapeutic combinations (Shock and Kill) likely to stimulate the reactivation of reservoirs and their elimination by the immune system.
Nicolas A, Migraine J, Dutrieux J, Salmona M, Tauzin A, Hachiya A, Estaquier J, Molina J-M, Clavel F, Hance A J and Mammano F. (2022) Genotypic and phenotypic diversity of the replication-competent HIV reservoir in treated patients. Microbiology Spectrum, In Press.
Ganor Y, Real F, Sennepin A, Dutertre CA, Prevedel L, Xu L, Tudor D, Charmeteau B, Couedel-Courteille A, Marion S, Zenak AR, Jourdain JP, Zhou Z, Schmitt A, Capron C, Eugenin EA, Cheynier R, Revol M, Cristofari S, Hosmalin A, Bomsel M. HIV-1 reservoirs in urethral macrophages of patients under suppressive antiretroviral therapy. Nat Microbiol. 2019 Apr;4(4):633-644.
Samri A, Charpentier C, Diallo MS, Bertine M, Even S, Morin V, Oudin A, Parizot C, Collin G, Hosmalin A, Cheynier R, Thiébaut R, Matheron S, Collin F, Zoorob R, Brun-Vézinet F, Autran B; ANRS CO5 IMMUNOVIR-2 Study Group. Limited HIV-2 reservoirs in central-memory CD4 T-cells associated to CXCR6 co-receptor expression in attenuated HIV-2 infection. PLoS Pathog. 2019 May 16;15(5): e1007758.
de Verneuil A, Migraine J, Mammano F, Molina J-M, Gallien S, Mouquet H, Hance A J, Clavel F and Dutrieux J. (2018) Genetically intact but fonctionally impaired HIV-1 Env glycoproteins in the T-Cell reservoir. J. Virol. 92 (4).
Logerot S, Rancez M, Charmeteau-de Muylder B, Figueiredo-Morgado S, Rozlan S, Tambussi G, Beq S, Couëdel-Courteille A and Cheynier R. (2018) HIV reservoir dynamics in HAART-treated poor immunological responder patients under IL-7 therapy. AIDS. Mar 27;32(6):715-720.
Ribeiro Dos Santos P., Rancez M., Prétet J.L., Michel-Salzat A., Messent V., Bogdanova A., Couëdel-Courteille A., Souil E., Cheynier R. and Butor C. (2011). Rapid Dissemination of SIV Follows Multisite Entry after Rectal Inoculation. PLoS One. May 9;6(5).
Fabre-Mersseman V., Dutrieux J., Louise A., Rozlan S., Lamine A., Parker R., Rancez M., Nunes-Cabaço H., Sousa AE., Lambotte O. and Cheynier R. (2011). CD4+ recent thymic emigrants are infected by HIV in vivo, implication for pathogenesis. AIDS. Jun 1;25(9):1153-1162.
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Mc Ilroy, D., Autran, B, Cheynier, R., Wain-Hobson, S., Clauvel, J.P., Oksenhendler, E., Debré, P. and A. Hosmalin. Infection frequency of Dendritic cells and CD4+ T lymphocytes in spleens of HIV-positive patients. J. Virol., 1995; 69:4737-4745.