Characterization of anti-gp41 antibodies eliciting viral neutralization and protecting against CD4 depletion in long-term non-progressors

Background: We previously showed that antibodies (Ab), which recognized a highly conserved motif of the gp41, called 3S, are protective against CD4+ T cell depletion. This was analyzed after immunization in a model of SHIV162P3-infected macaques, and naturally in asymptomatic long-term non-progressor (ALT) patients. More recently, we have detected the presence of anti-3S/W614A Ab, which recognized a point-modified form of 3S, in less than 5% of HIV-1 progressor patients. These Ab remain able to protect CD4+ T cells but have also acquired the capacity to elicit viral neutralization. Here, we quantified and characterized these anti-3S W614A Ab in non-treated patients from the French ANRS ALT cohort.
Methods: 64 HIV-1 untreated ALT patients who had enrolled with >600 CD4+ cells /mm3 (for at least 8 years), were followed-up each year during the first 3 years to evaluate anti-3S-W614A Ab. Ab level was measured by ELISA, and its presence was correlated with different biological parameters (CD4 count, CD4/CD8 ratio, viral DNA, viral load, ?). Viral neutralization was performed against a panel of tiers 1 and 2 viruses, using the standard TzM-bl assay.
Results: 25.7 % of patients had detectable anti-3S/W614A Ab at the enrollment period. The presence of these Ab is highly significantly correlated with an increased of the CD4/CD8 T cell ratio (p=0.006), and both decreased of the viral load (p< 0.0001) and viral DNA (p=0.0003). In the same subjects, measured again at 24-36 months following inclusion in the cohort, we observed that subjects with persistently specific Ab still had both significantly lower viral DNA and viral load, as compared to patients without anti-3S/W614A Ab. Importantly; we also report that the efficacy of viral neutralization mediated by anti-3S/W614A Ab, is time-dependent, increasing during the follow-up in term of breadth and potency.
Conclusions: The presence of anti-3S W614A Ab appears to confer crucial advantage in asymptomatic long-term non-progressor HIV-1 patients. These results bring new insights for both pathophysiological research and development of new vaccine strategy.

V. Vieillard1, A. Samri1, O. Lucar1,2, J. Crouzet2, D. Costagliola3, P. Debré1, French ALT Study Group
1CIMI-Paris, INSERM U 1135, Paris, France, 2InnaVirVax, Evry, France, 3Institut Pierre Louis d'Epidémiologie et de Santé Publique, Paris, France