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


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.