Immune perturbation is more profound in newborn than in infant macaques during acute SHIV infection

Background: Progress in preventing vertical HIV-1 transmission has stalled, with 160,000 infants infected annually. Newborns and infants exhibit higher viral loads and more rapid disease progression than adults and older children, with the lowest survival rates in those infected as newborns. While immunologic immaturity likely promotes pathogenesis and poor viral control, little is known about immune damage in infants. Neonatal immunity is distinct from that of adults in ways that are presumed to hinder newborns' ability to control viral infection. Methods: Here we examined virologic and immunologic outcomes in rhesus macaques exposed to [SHIV.sub.SF162P3] at one to two weeks or four months of age. To answer this question, we compared virologic outcomes, adaptive immune responses, frequencies and phenotypes of key leukocyte subsets, and transcriptome profiles during pathogenic SHIV infection in Newborn (one to two weeks old) and Infant (15 to 16 weeks old) rhesus macaques that were lacking the two major MHC-I alleles for post-acute viral control. Results: Although differences in plasma viremia and seeded reservoirs during acute infection were minimal, we observed age-dependent alterations in leukocyte subsets and gene expression. Compared with infants, newborns had stronger skewing of monocytes and CD8+ T cells toward differentiated subsets and little evidence of type I inter-feron responses by transcriptomic analysis. Infants had evidence of a robust antiviral program mediated by type I IFN responses. In contrast, newborns had a transcriptional signature dominated by the downregulation of genes involved in mitotic, cell cycle, and activation processes; the near-absence of a viral infection response; and upregulation of CXCL10, a biomarker of greater disease severity. Conclusions: Taken together, our findings suggest a role for defective innate defenses and elevated immune activation in age-dependent differences in pathogenesis. We conclude that SHIV, like HIV-1, wreaks greater havoc in newborns than in infants infected at older ages, reinforcing the validity of this model for understanding mechanisms of pathogenesis in vertically acquired HIV infection. Ultimately, therapeutic intervention as early as possible after birth is more likely to have a durable effect on disease progression by limiting damage to the immune system.