Background
Latency reversal and immune-mediated clearance is a cure strategy based on eliminating HIV-infected CD4+ T cells during ART suppression. Here, we used AZD5582 to stimulate the non-canonical NF-κB pathway to reverse latency, as previously shown in adult rhesus macaques (RM). To target the reactivated reservoir via antibody-mediated cellular cytotoxicity, we used AAV9-delivered eCD4-Ig, a fusion protein comprising the CD4 ectodomain, an IgG1-Fc, and the TYR-sulfated regions of CCR5 that bind to HIV/SIV Env on the cell surface.
Methods
20 infant RM (10 male, 10 female) with no/low levels of AAV9 neutralizing antibodies were selected after screening. At 4 weeks old, the animals were orally infected with SIVmac251 and started on ART 21 days post-infection. Half received an IM injection of AAV9-eCD4-IgG1 on the day of ART initiation. AZD5582 was administered at 40 weeks post-infection. The dose was based on a pharmacokinetic model as prior work showed reduced latency reversal in infants vs adults. On-ART viremia and viral rebound dynamics following ART interruption were monitored.
Results
eCD4-IgG1 expression was >10 µg/mL in 10/10 RM, with sustained levels for at least 59 weeks. One animal developed transient anti-drug antibodies, which did not affect long-term eCD4-IgG1 expression. During AZD5582 treatment, 8/10 infant RM had on-ART viremia >60 copies/mL, peaking at 5600. Of 67 viral load measurements taken, 47 (65.7%) were above baseline, with significantly higher on-ART viremia in the intervention group versus controls (p=0.0147). 6 RM from each group underwent ART interruption. Despite continued eCD4-IgG1 expression, all treatment RM rebounded between 6-11 days off ART. 2/6 RM in the intervention group experienced a ~4.5 log decline in viremia post-rebound, which was not observed in controls. Partial correlation analyses indicated a negative correlation between peak AZD5582-induced on-ART viremia and the AUC of the viremia during ART interruption (r = -0.870, p = 0.055)
Conclusions
This study is an important proof-of-concept, as it is the first to combine an AAV9-delivered biologic with an LRA in infants. AAV9’s long-lasting transgene expression makes it a promising delivery platform for HIV-neutralizing molecules, including bNAbs. Peak levels of on-ART viremia during AZD5583 treatment surpassed those observed in prior studies of adult RM. Further research is needed to elucidate the mechanisms behind post-rebound viral control in the intervention group.