講演要旨

Introduction: We have reported that rhesus macaques (RM) with elite control of pathogenic SIV infection show exquisite restriction of replication-competent virus to CD4+ follicular helper T cells (TFH) resident within B cell follicles of secondary lymphoid tissues, suggesting that the highly effective anti-viral CD8+ T cell responses in these RM are able to almost completely clear and/or suppress productive SIV infection in extra-follicular T cell zones but not within B cell follicles. Here we evaluated whether disruption of this B cell follicular sanctuary can facilitate the clearance of persistent virus replication in elite controllers (EC).

Method: A total of 7 SIV-infected EC RM (plasma viral load: less than 1,000 copies/ml) received multiple doses of a B cell depleting anti-CD20 antibody (Ab) subcutaneously for 1^st dose, then intravenously for 2^nd and 3^rd doses.  Next we asked whether disruption of B cell follicles in SIV-infected RM on antiretroviral therapy (ART) would facilitate the clearance of reactivating virus in TFH and enhance virological control after ART cessation. A total of 21 RM determined to be mamu B*08⁺ (n=9) or B*08^–/B*17^–/A*01^– (n=11) were intravenously inoculated with SIVmac239 and placed on ART 12 days later. Once all RM achieved stable virus suppression, they were randomized into 2 groups and received multiple doses of anti-CD20Ab or control Ab starting ~2 weeks before and up to 6 weeks after ART cessation.

Results: Anti-CD20Ab treatment decreased plasma viral load by 1-2 log. This result indicates that disruption of B follicles by B cell depletion improves overall CD8+ T cell-mediated viral control in EC. In ART treated RM, anti-CD20Ab treated RM showed enhanced control of virus replication immediately after ART cessation and a trend towards lower viral load set points.

Conclusion: Overall these data suggest that the B cell follicular sanctuary must be overcome to fully evaluate the ability of virus-specific CD8+ T cells to reduce viral reservoirs or control viral rebound to achieve durable viral remission.