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With 150,000 new infections in 2015, HIV continues to infect infants at an unacceptably high rate, partly due to a lack of an effective HIV vaccine. To better understand infant immune factors contributing to oral HIV transmission and disease in infants, we monitored several markers of peripheral immune cell activation in newborn infant Rhesus macaques. Infants in this study were orally challenged weekly until infected with SIVmac251. From 4–9 weeks post infection, macaques diverged into two distinct groups designated as High Viremic (HV) (7.2×107 – 3.9×108vRNA copies/mL plasma, n=4) and Low Viremic (LV) (3.8×105 – 6.2×106vRNA copies/mL plasma,, n=4) based on viral set points. Markers of immune activation on B cells, monocytes, T cells, and dendritic cells in blood were assessed by flow cytometry through 10 weeks post-infection. At 10 weeks post infection we observed significantly higher (p=0.015) inflammatory (CD14+, CD16+) monocytes in HV macaques, which has been observed in the literature in adult macaques. Unexpectedly, we also observed striking differences between these two groups of infants regarding the activation markers CD11c+ and CD80+ on B cells. LV infant macaques had significantly higher CD11c+ (p=0.036) and CD80+ (p=0.009) B cells by 5–6 weeks post infection compared to HVs (26 fold LV vs 13.2 fold HV at 10 weeks). These findings suggest that activation of B cells may contribute to reduced viral loads in these infants, or alternatively that high levels of SIV can suppress activation of B cells. Experiments are currently underway to explore B cell/antibody mediated viral control in LV infants as these findings have implications regarding development of SIV/HIV vaccines in infants.

Liver disease remains an important contributor to morbidity and mortality in HIV-infected patients. In addition to the effects of HIV replication, bacterial translocation from the gastrointestinal tract potentially contributes to liver dysfunction. Indeed, bacteria leaving the gut filter through the liver via portal vein circulation. Providing patients with combination anti-retroviral therapy (cART) does provide some reduction to the generalized immune inflammation, but also can induce liver toxicity. The SIV macaque model recapitulates HIV immune activation and bacterial translocation and was utilized here to evaluate livers of uninfected (n=3), SIV-infected (n=5), and SIV-infected/cART-treated rhesus macaques (n=6). Using immunofluorescence microscopy, CD68+ macrophages (associated with inflammation) were demonstrated to increase in livers of SIV+ macaques, but normalize in cART-treated SIV+ macaques. In addition, reverse-phase protein arrays (RPPA) identified a number of signaling proteins that were activated (phosphorylated) in SIV+ macaques, including proteins involved in the Wnt/beta-catenin pathway (e.g. Dvl-3, pGSK3αβ) as well as inflammatory STAT (e.g. pSTAT2) and NFkB signaling proteins. Assessment of SIV+/cART-treated macaques determined that the elevation in these same signaling pathways could be observed even after 7–8 months of cART. Collectively, this suggests that although cART treatment can reverse macrophage infiltration in the liver during SIV infection, it does not restore normal hepatocyte cellular signaling networks. We conclude that SIV infection results in liver immune activation and that residual liver inflammation persists following cART administration.