Background
Globally, >1.4 million children are living with HIV. Life-long ART adherence predisposes children to drug-associated complications, necessitating development of adjunctive therapies that can achieve drug-free viral suppression. Our group recently demonstrated development of VRC01-like broadly neutralizing antibody (bNAb) precursor responses in pediatric rhesus macaques (RMs) upon immunization with a germline-targeting native-like HIV SOSIP trimer. In this study, our objective is to determine the impact of germline-targeting SOSIP trimer immunization of SHIV-infected infant RMs on viral rebound post-ART interruption (ATI).
Methods
Infant RMs (n=11) were orally challenged with SHIV SF162P3 and started on ART at 1 week post-infection (wk pi). Of these, 5 RMs were immunized with 4 doses of BG505 GT1.1 SOSIP+3M052-SE, followed by 3 doses of autologous SF162P3 SOSIP+3M052-SE, and 6 RMs did not receive any immunizations (controls). ART was interrupted at 30 wk pi for controls and 47 wk pi for immunized animals. Plasma viral load (PVL), HIV-trimer-specific IgG, and autologous virus-neutralizing antibodies were measured longitudinally. Finally, using a virus that is neutralized by germline-reverted forms of VRC01, the development of CD4bs-specific bNAb precursors in plasma was evaluated.
Results
While there was no difference in the time to viral rebound in control [median(range) wks: 2(1-3) wks] vs. immunized RMs [Median(range) wks: 2(1.5-3) wks], 1 RM did not experience viral rebound and 1 achieved plasma viral control 5 wks post-rebound in the immunized group. Compared to controls, the immunized group had a 22.9 fold lower post-rebound peak PVL (p=0.004) and 43.9 fold lower post-ATI PVL-AUC0-15 wk (p=0.004). Immunized animals had higher magnitude and more durable BG505 GT1.1 SOSIP-specific and SF162 trimer-specific plasma IgG compared to control RMs. The GT1-specific (r=-0.62; p=0.04) and SF162-specific (r=-0.88; p<0.001) IgG levels at ATI inversely correlated to post-ATI PVL-AUC0-15 wk. Importantly, none of the controls and 2/5 immunized animals developed VRC01-class bNAb precursor response, and the RM with the highest level of autologous virus-neutralizing antibody at 2 weeks post-ATI did not experience viral rebound.
Conclusions
Germline-targeting native-like HIV env trimer immunization of SHIV-infected infant RMs, induced potent HIV-specific antibody levels and CD4bs-specific bNAb precursor response resulting in dampened viral replication for 15 weeks post-ATI.
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