EARLY ANTIBODY THERAPY CAN INDUCE SUSTAINED CELLULAR IMMUNITY TO SHIV INFECTIONS. Highly potent and broadly neutralizing anti-HIV-1 antibodies (bNAbs) have recently been used to prevent and treat lentivirus infections in humanized mice, macaques and humans. We previously reported that the administration of bNAbs during the acute SHIV infection of rhesus macaques led to long-term control of virus replication, in 6 of 13 animals challenged with SHIVAD8-EO by mucosal or intravenous routes, following a single 2-week course of 2 potent passively transferred bNAbs (3BNC117 and 10-1074). Plasma virus loads declined to undetectable levels in 6 of the elite controller macaques. The frequency of cells carrying replication-competent virus was less than 1 cell per 10e6 circulating CD4+ T cells in the 6 elite controller animals. Infusion of a T cell depleting anti-CD8 beta-mAb into the controller monkeys led to the specific decline in levels of CD8+ T cells and rapid reappearance of plasma viremia. No reduction of NK, NKT, or gamma/delta cells was observed following this treatment. In contrast, control macaques, treated for 2 or for 15 weeks with combination anti-retroviral therapy (cART), beginning on day 3 after infection, experienced a sustained rebound plasma viremia shortly following treatment interruption. In unpublished studies, we have discovered that a unique CXCR5+ CD8+ T cell subset accumulates in the lymph nodes (LNs) of elite controller monkeys. They are not detectable in LNs from non-controller animals and dare absent in the circulation of elite controller macaques. In other virus-infected animal systems, CXCR5+ CD8+ T cells have been shown to migrate into B-cell follicles, to express lower levels of inhibitory receptors and exhibit more potent cytotoxicity than the CXCR5 CD8+ T cell subset. We conclude that passive bNAb immunotherapy during the acute SHIV infection differs from cART by facilitating the emergence of potent CD8+ T cell immunity able to durably suppress virus replication. IMMUNOPROPHYLAXIS WITH A SINGLE DOSE OF DERIVATIZED ANTI-HIV NEUTRALIZING MONOCLONAL ANTIBODIES CONFERS UP TO 6 MONTHS OF PROTECTION AGAINST SHIV INFECTIONS. As a follow-up to a 2016 Nature report describing the protective efficacy of unmodified anti-HIV-1 bNAbs, the in vivo efficacy of antibodies (3BNC117 and 10-1074) carrying 2 mutations (M428L and N434S), referred to as LS, into their FC domains, was evaluated in macaques using a repeated low-dose (RLD) challenge regimen. A single intravenous infusion of 3BNC117-LS (20 mg/kg) protected macaques against weekly SHIVAD8-EO intrarectal challenges for 11 to 23 weeks (median = 17 weeks). Administration of 10-1074-LS blocked infection for 18 to 37 weeks (median = 27weeks). To model the less intrusive subcutaneous route of bNAb injection, which would be used in a human clinical setting, the protective effect of combination 3BNC117-LS plus 10-1074-LS immunoprophylaxis (using only 7.5 mg/kg of each mAb) was evaluated and found to delay virus acquisition 6 to 24 weeks (median = 20 weeks). The LS substitutions increased half-lives two to three-fold in macaques compared to unmodified parental antibodies. Because bNAb immunoprophylaxis must target HIV-1 swarms carrying a plethora of different envelope proteins, the latter administration of combination anti-viral neutralizing monoclonal antibodies would be the formulation of choice for human clinical use.
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