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Early antiretroviral therapy favors post-treatment SIV control, which is associated with enhanced CD8+ T-cell antiviral activity against rebounding virus ' the pVISCONTI study

Title
Early antiretroviral therapy favors post-treatment SIV control, which is associated with enhanced CD8+ T-cell antiviral activity against rebounding virus ' the pVISCONTI study
Presenter
Caroline Passaes
Authors
C. Passaes * (1), D. Desjardins (2), V. Avettand-Fenoel (3), A. Chapel (1), V. Monceaux (1), A. Melard (4), N. Dimant (2), F. Perdomo-Celis (1), A. David (1), A. Barrail-Tran (5), O. Lambotte (6), J. Guedj (7), N. Dereuddre-Bosquet (2), M. Muller-Trutwin (1), C. Rouzioux (8), R. Le Grand (2), A. Saez-Cirion (1), pVISCONTI Study Group
Institutions
(1) Institut Pasteur, Unité HIV, Inflammation et Persistance, Paris, France, (2) UMR 1184, Immunology of Viral, Auto-Immune, Hematological and Bacterial Diseases (IMVA-HB), IBFJ, CEA ' Université Paris-Saclay - INSERM, IDMIT Department, Fontenay-aux-Roses / Le Kremlin-Bicêtre, France, (3) Université de Paris , INSERM U 1016, CNRS 8104, APHP Hôpital Necker - Enfants Malades, Paris, France, (4) Université de Paris, INSERM U 1016, CNRS 8104, Paris, France, (5) Université Paris Saclay, Faculté de Pharmacie , AP-HP, Hôpital Bicêtre, UMR 1184, Immunologie des Maladies Virales, Auto-Immunes, Hématologiques et Bactériennes, Le Kremlin-Bicêtre, France, (6) APHP Université Paris-Saclay, Hôpital Bicêtre, Inserm, CEA, Center for Immunology of Viral, Auto-Immune, Hematological and Bacterial Diseases (IDMIT/IMVA-HB), UMR 1184, Clinical Immunology Department, Le Kremlin Bicêtre, France, (7) Université de Paris, IAME, INSERM, Paris, France, (8) Université de Paris, CNRS 8104, APHP Hôpital Necker - Enfants Malades, Paris, France

BACKGROUND: The VISCONTI study proposed that post-treatment control (PTC) might be favored by early antiretroviral treatment (cART) initiation. However, a formal demonstration has not been established and the underlying mechanisms leading to PTC remain elusive. We used a non-human primate model to assess, in standardized conditions, the impact of early versus late cART initiation on immune responses and the outcome after analytical treatment interruption (ATI).
METHODS: SIVmac251-infected cynomolgus macaques (CyMs) remained untreated (n=17) or initiated cART at primary (day 28 post-infection [p.i.], n=12) or at chronic (6 months p.i., n=12) infection. cART was maintained for 24 months. The animals were then monitored for 12 months after ATI. Plasma viral loads (pVL), CD4+ T-cells, and CD8+ T-cell responses (phenotype and viral inhibition assay) were analyzed throughout the study.
RESULTS: pVL levels were similar at cART initiation for both groups of CyMs receiving cART (D28 and M6). After ATI, all CyMs experienced viral rebound (>1000 copies/mL), except one animal in the D28 group. Viral rebound occurred earlier in the M6 group (17.5 days) when compared with D28 group (28 days) (p=0.0009). Early treatment significantly impaired definitive loss of viral control (p=0.012). Moreover, 82% of CyMs in the D28 group were defined as PTC (<400 copies/mL) at the end of the study, which was higher than in the M6 group (25%) or among non-treated (12%) CyMs (p=0.0003). The anti-SIV activity of CD8+ T-cells, as measured in the viral inhibition assay, was weak in all animals at primary SIV-infection, but strongly increased after ATI, in particular in D28 CyMs (6.6x fold [3.5-9.8] post-ATI vs primary infection). The CD8-antiviral activity that emerged following viral rebound was stronger in PTCs (p= 0.016) early after ATI and at the end of the study in blood and lymphoid tissues (spleen, peripheral and mesenteric lymph nodes). A negative correlation was found between the anti-SIV activity of CD8+ T-cells and cumulated pVLs post-ATI (r=-0.41, p=0.05).
CONCLUSIONS: Early cART initiation favored PTC in SIVmac251-infected CyMs. This was associated with the promotion of a robust secondary SIV-specific CD8+ T-cell response, which might contribute to efficiently counteract viral rebound after ATI in PTCs.