[en] A latent viral reservoir that resides in resting CD4+ T cells represents a major barrier for eradication of HIV infection. We test here the impact of HIV protease inhibitor (PI) based combination anti-retroviral therapy (cART) over nonnucleoside reverse transcriptase inhibitor (NNRTI)-based cART on HIV-1 reactivation and integration in resting CD4+ T cells. This is a prospective cohort study of patients with chronic HIV-1 infection treated with conventional cART with an undetectable viremia. We performed a seven-year study of 47 patients with chronic HIV-infection treated with cART regimens and with undetectable plasma HIV-1 RNA levels for at least 1 year. Of these 47 patients treated with cART, 24 were treated with a PI-based regimen and 23 with a NNRTI-based regimen as their most recent treatment for more than one year. We evaluated the HIV-1 reservoir using reactivation assay and integrated HIV-1 DNA, respectively, in resting CD4+ T cells. Resting CD4+ T cells isolated from PI-treated patients compared to NNRTI-treated patients showed a limited HIV-1 reactivation upon T-cell stimulation (p = 0.024) and a lower level of HIV-1 integration (p = 0.024). Our study indicates that PI-based cART could be more efficient than NNRTI-based cART for limiting HIV-1 reactivation in aviremic chronically infected patients.
Disciplines :
Genetics & genetic processes
Author, co-author :
Kumar, Amit
Abbas, Wasim
Bouchat, Sophie
GATOT, Jean-Stéphane ; Centre Hospitalier Universitaire de Liège - CHU > Service de génétique
Pasquereau, Sebastien
Kabeya, Kabamba
Clumeck, Nathan
De Wit, Stephane
Van Lint, Carine
Herbein, Georges
Language :
English
Title :
Limited HIV-1 Reactivation in Resting CD4+ T cells from Aviremic Patients under Protease Inhibitors.
Chun, T. W., Moir, S., Fauci, A. S. HIV reservoirs as obstacles and opportunities for an HIV cure. Nat. Immunol. 16, 584-589 (2015).
Perelson, A. S. et al. Decay characteristics of HIV-1-infected compartments during combination therapy. Nature 387, 188-191 (1997).
Palmer, S. et al. Low-level viremia persists for at least 7 years in patients on suppressive antiretroviral therapy. Proc. Natl. Acad. Sci. USA. 105, 3879-3884 (2008).
Ho, Y. C. et al. Replication-competent noninduced proviruses in the latent reservoir increase barrier to HIV-1 cure. Cell 155, 540-551 (2013).
Van Lint, C., Bouchat, S., Marcello, A. HIV-1 transcription and latency: an update. Retrovirology 10, 67 (2013).
Siliciano, R. F. Opening fronts in HIV vaccine development: targeting reservoirs to clear and cure. Nat. Med. 20, 480-481 (2014).
Le Douce, V. et al. Molecular mechanisms of HIV-1 persistence in the monocyte-macrophage lineage. Retrovirology 7, 32 (2010).
Kumar, A., Darcis, G., Van Lint, C., Herbein, G. Epigenetic control of HIV-1 post integration latency: implications for therapy. Clin. Epigenetics 7, 103 (2015).
INITIO Trial International Co-ordinating Committee et al. Virological and immunological outcomes at 3 years after starting antiretroviral therapy with regimens containing non-nucleoside reverse transcriptase inhibitor, protease inhibitor, or both in INITIO: open-label randomised trial. Lancet 368, 287-298 (2006).
Cummins, N. W., Sainski, A. M., Natesampillai, S., Bren, G. D., Badley, A. D. Choice of antiretroviral therapy differentially impacts survival of HIV-infected CD4 T cells. Mol. Cell. Ther. 2, 1 (2014).
Chéret, A. et al. Combined ART started during acute HIV infection protects central memory CD4+ T cells and can induce remission. J. Antimicrob. Chemother. 70, 2108-2120 (2015).
Dinoso, J. B. et al. Treatment intensification does not reduce residual HIV-1 viremia in patients on highly active antiretroviral therapy. Proc. Natl. Acad. Sci. USA. 106, 9403-9408 (2009).
Saéz-Cirión, A. et al. Post-treatment HIV-1 controllers with a long-term virological remission after the interruption of early initiated antiretroviral therapy ANRS VISCONTI study. Plos Pathog. 9, e1003211 (2013).
Buzón, M. J. et al. HIV-1 replication and immune dynamics are affected by raltegravir intensification of HAART-suppressed subjects. Nat. Med. 16, 460-465 (2010).
Costello, R. et al. Activation of primary human T-lymphocytes through CD2 plus CD28 adhesion molecules induces long-term nuclear expression of NF-kappa B. Cell Growth Differ. 4, 329-339 (1993).
Pierrès, A. et al. Triggering CD28 molecules synergize with CD 2 (T 11.1 and T 11.2)-mediated T cell activation. Eur. J. Immunol. 18, 685-690 (1988).
Molina, J. M. et al. On-demand preexposure prophylaxis in men at high risk for HIV-1 infection. N. Engl. J. Med. 373, 2237-2246 (2015).
Hatano, H. et al. Increase in 2-long terminal repeat circles and decrease in D-dimer after raltegravir intensification in patients with treated HIV infection: a randomized, placebo-controlled trial. J. Infect. Dis. 208, 1436-1442 (2013).
Rabi, S. A. et al. Multi-step inhibition explains HIV-1 protease inhibitor pharmacodynamics and resistance. J. Clin. Invest. 123, 3848-3860 (2013).
Darcis, G. et al. Reactivation capacity by latency-reversing agents correlates with the size of the HIV-1 reservoir. AIDS PMID: 27755105 (2016).
Noel, N. et al. Long-term spontaneous control of HIV-1 relates to low frequency of infected cells and inefficient viral reactivation. J. Virol. 90, 6148-6158 (2016).
Vranckx, L. S. et al. LEDGIN-mediated inhibition of integrase-LEDGF/p75 interaction reduces reactivation of residual latent HIV. EBioMedicine 8, 248-264 (2016).
Kourjian, G. et al. HIV protease inhibitor-induced cathepsin modulation alters antigen processing and cross-presentation. J. Immunol. 196, 3595-3607 (2016).
Kumar, A. et al. Fine tuning of AKT-pathway by Nef and its blockade by protease inhibitors results in limited recovery in latently HIV infected T-cell line. Sci Rep. 6, 24090 (2016).
Saleh, S. et al. HIV integration and the establishment of latency in CCL19-treated resting CD4+ T cells require activation of NF-kB. Retrovirology 13, 49 (2016).
Equils, O. et al. Human immunodeficiency virus type 1 protease inhibitors block Toll-like receptor 2 (TLR2)-and TLR4-induced NF-kappaB activation. Antimicrob. Agents Chemother. 48, 3905-3911 (2004).
Sainski, A. M. et al. Casp8p41 generated by HIV protease kill CD4 T cells through direct Bak activation. J Cell Biol 206, 867-876 (2014).
Assoumou, L. et al. A low HIV-DNA level in peripheral blood mononuclear cells at antiretroviral treatment interruption predicts a higher probability of maintaining viral control. AIDS 29, 2003-2007 (2015).
Goujard, C. et al. HIV-1 control after transient antiretroviral treatment initiated in primary infection: role of patient characteristics and effect of therapy. Antivir. Ther. 17, 1001-1009 (2012).
Bouchat, S. et al. Histone methyltransferase inhibitors induce HIV-1 recovery in resting CD4(+ ) T cells from HIV-1-infected HAART-treated patients. AIDS 26, 1473-1482 (2012).
Liszewski, M. K., Yu, J. J., O'Doherty, U. Detecting HIV-1 integration by repetitive-sampling Alu-gag PCR. Methods 47, 254-260 (2009).
