The Brain Retains: Nonhuman Primate Models for Pediatric HIV-1 in the CNS

Abstract

Purpose of Review Perinatal HIV-1 infection is associated with an increased risk for neurologic impairments. With limited access to clinical specimens, animal models could advance our understanding of pediatric central nervous system (CNS) disease and viral persistence. Here, we summarize current findings on HIV-1 CNS infection from nonhuman primate (NHP) models and discuss their implications for improving pediatric clinical outcomes. Recent Findings SIV/SHIV can be found in the CNS of infant macaques within 48 h of challenge. Recent studies show an impermeable BBB during SIV infection, suggesting neuroinvasion in post-partum infection is likely not wholly attributed to barrier dysfunction. Histopathological findings reveal dramatic reductions in hippocampal neuronal populations and myelination in infected infant macaques, providing a link for cognitive impairments seen in pediatric cases. Evidence from humans and NHPs support the CNS as a functional latent reservoir, harbored in myeloid cells that may require unique eradication strategies. Summary Studies in NHP models are uncovering early events, causes, and therapeutic targets of CNS disease as well as highlighting the importance of age-specific studies that capture the distinct features of pediatric HIV-1 infection.

Simian-Human Immunodeficiency Virus SHIV.C.CH505 Persistence in ART-Suppressed Infant Macaques Is Characterized by Elevated SHIV RNA in the Gut and a High Abundance of Intact SHIV DNA in Naive CD4 + T Cells

“…SHIV.C.CH505 persistence was also evaluated in myeloid cells isolated from the brain. Viral DNA was detected at low levels in brain CD11b + cells from two infant macaques, in line with previous reports of relatively low levels of infected cells in the brains of SIV/SHIV-infected infant macaques ( 57 ). Infrequent detection of viral DNA in the brain across animals may also be reflective of a limited capacity for neuroinvasion or restricted infection of myeloid cells by SHIV.C.CH505.…”

Understanding Viral and Immune Interplay During Vertical Transmission of HIV: Implications for Cure

“…However, presently over half of new infections occur postnatally through breast milk (9). As this route has become predominant in perinatal HIV infection, a nonhuman primate model has been established to better understand virologic and immunologic features of lentivirus infection following postpartum transmission, more precisely define anatomic sites of virus persistence, and test strategies to promote reservoir eradication or remission (46,47,(222)(223)(224). These and other ongoing studies may inform the design of future cure-directed clinical trials in children with HIV infection acquired through breast milk.…”

Therapeutic vaccination of SIV-infected, ART-treated infant rhesus macaques using Ad48/MVA in combination with TLR-7 stimulation

“…We hypothesize that the exponential increase in the size of the viral reservoir when ART is initiated at 4 weeks compared to 1 week after infection may have had the most significant impact on our results, although experimental evidence will be needed for confirmation. Additionally, distinct features of pediatric immunity during development or variance in composition of the viral reservoir between these age groups may be key [7,19,[39][40][41][42][43]. Our findings highlight the importance of a pediatric model to evaluate HIV-1 cure interventions in this unique setting of immune development.…”