Background-The BTB domain of BCL6 protein was identified as a therapeutic target for Bcell lymphoma. This study compared the pharmacokinetics (PK) of the BCL6 BTB inhibitor (FX1) between mice and macaques, as well as evaluating its lymphoid suppressive effect in uninfected macaques with lymphoid hyperplasia.Materials & Methods-Eight uninfected adult Indian rhesus macaques (Macaca mulatta) were used in the study, four animals carrying lymphoid tissue hyperplasia. Plasma FX1 levels were measured by HPLC-MS/MS. Lymph node biopsies were used for H&E and immunohistochemistry staining, as well as mononuclear cell isolation for flow cytometry analysis.Results-Inhibition of the BCL6 BTB domain with FX1 led to a reduction in the frequency of GC, Tfh CD4 + , and Tfh precursor cells, as well as resolving lymphoid hyperplasia, in rhesus macaques.Conclusions-BCL6 inhibition may represent a novel strategy to reduce hyperplastic lymphoid B cell follicles and decrease Tfh cells.

Early antiretroviral therapy (ART) in HIV-infected infants generally fails to achieve a sustained state of ART-free virologic remission, even after years of treatment. Our studies show that viral reservoir seeding is different in neonatal macaques intravenously exposed to SIV at birth, in contrast to adults. Furthermore, one month of ART including an integrase inhibitor, initiated at day 3, but not day 4 or 5 post infection, efficiently and rapidly suppresses viremia to undetectable levels. Intervention initiated at day 3 post infection and continued for 9 months achieves a sustained virologic remission in 4 of 5 infants. Collectively, an early intervention strategy within a key timeframe and regimen may result in viral remission or successful post-exposure prophylaxis for neonatal SIV infection, which may be clinically relevant for optimizing treatment strategies for HIV-infected or exposed infants.

Background: Our previous study suggested newborns have competent immune systems with the potential to respond to foreign antigens and vaccines. In this study, we examined infant immune responses to tetanus toxoid (TT) vaccination in the presence of maternal antibody to TT. Methods: We examined changes in plasma levels of tetanus toxoid-specific IgG1 (anti-TT IgG1) in a total of eight infant rhesus macaques from birth through 6 months of age using a commercial Monkey Anti-TT IgG1 ELISA kit. Results: A significant correlation between anti-TT IgG1 levels in vaccinated dams and their paired newborn infants was detected in control (non-vaccinated) infants as previously reported. Maternal anti-TT IgG1 levels declined rapidly within 1 month of birth in non-vaccinated infants (n=4). In four infants vaccinated with TT at birth, we found two had rapid and robust antibody responses to vaccination. Interestingly, the other two first showed declining TT antibody levels for 2 weeks followed by increasing levels without additional vaccine boosts, indicating all four had good antibody responses to primary TT vaccination at birth, despite the presence of high levels of maternal antibodies to TT in all four infants. Conclusions: Our data indicate that newborn macaques have competent immune systems that are capable of generating their own primary antibody responses to vaccination, at least to tetanus antigens. Maternal antibodies thus do not significantly impair antibody response to the vaccination, even when received on the day of birth in infant rhesus macaques.

Early antiretroviral therapy (ART) in HIV-infected infants generally fails to achieve a sustained state of ART-free virologic remission, leading to rapid viral rebound, even after years of analytical treatment interruption. Our studies showed that in contrast to adults, skewing of viral integration was observed in neonatal macaques intravenously exposed to SIV at birth. Further, one month of ART regimen combined an integrase inhibitor, initiated at day 3 but not day 4 and 5 post infection, efficiently and rapidly suppressed viremia to undetectable levels. Finally, interventions initiated at day 3 post infection for 9 months achieved a sustained virologic remission in ~80% infants. Collectively, an early intervention strategy with a key time checkpoint and regimen may resulted in viral remission for neonatal SIV infection, which may be clinically relevant for optimizing treatment strategies for HIV-infected infants.