Reduction of pyramidal and immature hippocampal neurons in pediatric simian immunodeficiency virus infection

Pediatric HIV infection remains a global health crisis with a worldwide infection rate of 2.5 million (WHO, Geneva Switzerland, 2009). Children are much more susceptible to HIV-1 neurological impairments than adults, which is exacerbated by co-infections. A major obstacle in pediatric HIV research is sample access. The proposed studies take advantage of ongoing pediatric SIV pathogenesis and vaccine studies to test the hypothesis that pediatric SIV infection diminishes neuronal populations and neurogenesis in the hippocampus. Newborn rhesus macaques (Macaca mulatta) that received intravenous inoculation of highly virulent SIVmac251 (n=3) or vehicle (control n=4) were used in this study. After a 6–18 week survival time, the animals were sacrificed and the brains prepared for quantitative histopathological analysis. Systematic sections through the hippocampus were either Nissl stained or immunostained for doublecortin (DCX+), a putative marker of neurogenesis. Using design-based stereology, we report a 42% reduction in the pyramidal neuron population of the CA1, CA2, and CA3 fields of the hippocampus (p < 0.05) in SIV-infected infants. The DCX+ neuronal population was also significantly reduced within the dentate gyrus of the hippocampus. The loss of hippocampal neurons and neurogenic capacity may contribute to the rapid neurocognitive decline associated with pediatric HIV infection. These data suggest that pediatric SIV infection, which leads to significant neuronal loss in the hippocampus within 3 months, closely models a subset of pediatric HIV infections with rapid progression

Of Mice and Monkeys: Can Animal Models Be Utilized to Study Neurological Consequences of Pediatric HIV-1 Infection?

Pediatric human immunodeficiency virus (HIV-1) infection remains a global health crisis. Children are much more susceptible to HIV-1 neurological impairments than adults, which can be exacerbated by coinfections. Neurological characteristics of pediatric HIV-1 infection suggest dysfunction in the frontal cortex as well as the hippocampus; limited MRI data indicate global cerebral atrophy, and pathological data suggest accelerated neuronal apoptosis in the cortex. An obstacle to pediatric HIV-1 research is a human representative model system. Host-species specificity of HIV-1 limits the ability to model neurological consequences of pediatric HIV-1 infection in animals. Several models have been proposed including neonatal intracranial injections of HIV-1 viral proteins in rats and perinatal simian immunodeficiency virus (SIV) infection of infant macaques. Nonhuman primate models recapitulate the complexity of pediatric HIV-1, neuropathogenesis while rodent models are able to elucidate the role specific viral proteins exert on neurodevelopment. Nonhuman primate models show similar behavioral and neuropathological characteristics to pediatric HIV-1 infection and offer a stage to investigate early viral mechanisms, latency reservoirs, and therapeutic interventions. Here we review the relative strengths and limitations of pediatric HIV-1 model systems

Hippocampal Neuronal Loss in Infant Macaques Orally Infected with Virulent Simian Immunodeficiency Virus (SIV)

The neurological impact of Human Immunodeficiency Virus (HIV) on children includes loss of brain growth, motor abnormalities and cognitive dysfunction. Despite early antiretroviral treatment (ART) intervention to suppress viral load, neurological consequences of perinatal HIV-1 infection persist. Utilizing the pediatric simian immunodeficiency virus (SIV) infection model, we tested the hypothesis that early-life SIV infection depletes neuronal population in the hippocampus. A total of 22 ART-naïve infant rhesus macaques (Macaca mulatta) from previous studies were retrospectively analyzed. Infant macaques were either intravenously (IV) inoculated with highly virulent SIVmac251 at ~1 week of age and monitored for 6–10 weeks, or orally challenged with SIVmac251 from week 9 of age onwards with a monitoring period of 10–23 weeks post-infection (19–34 weeks of age), and SIV-uninfected controls were euthanized at 16–17 weeks of age. We have previously reported that the IV SIVmac251-infected neonatal macaques (Group 1) displayed a 42% neuronal reduction throughout the hippocampal cornu ammonis (CA) fields. The orally-infected infant macaques displayed a 75% neuronal reduction in the CA1 region compared to controls and 54% fewer neurons than IV SIV infants. The CA2 region showed a similar pattern, with a 67% reduction between orally-infected SIV subjects and controls and a 40% difference between IV-and orally-infected SIV groups. In the CA3 region, there were no significant differences between these groups, however both SIV-infected groups had significantly fewer pyramidal neurons than control subjects. There was no correlation between plasma viral load and neuronal populations in any of the CA fields. The loss of hippocampal neurons may contribute to the rapid neurocognitive decline associated with pediatric HIV infection. While each subfield showed vulnerability to SIV infection, the CA1 and CA2 subregions demonstrated a potentially enhanced vulnerability to pediatric SIV infection. These data underscore the need for early diagnosis and treatment, including therapeutics targeting the central nervous system (CNS)

Of Mice and Monkeys: Can Animal Models Be Utilized to Study Neurological Consequences of Pediatric HIV-1 Infection?

Pediatric human immunodeficiency virus (HIV-1) infection remains a global health crisis. Children are much more susceptible to HIV-1 neurological impairments than adults, which can be exacerbated by coinfections. Neurological characteristics of pediatric HIV-1 infection suggest dysfunction in the frontal cortex as well as the hippocampus; limited MRI data indicate global cerebral atrophy, and pathological data suggest accelerated neuronal apoptosis in the cortex. An obstacle to pediatric HIV-1 research is a human representative model system. Host-species specificity of HIV-1 limits the ability to model neurological consequences of pediatric HIV-1 infection in animals. Several models have been proposed including neonatal intracranial injections of HIV-1 viral proteins in rats and perinatal simian immunodeficiency virus (SIV) infection of infant macaques. Nonhuman primate models recapitulate the complexity of pediatric HIV-1, neuropathogenesis while rodent models are able to elucidate the role specific viral proteins exert on neurodevelopment. Nonhuman primate models show similar behavioral and neuropathological characteristics to pediatric HIV-1 infection and offer a stage to investigate early viral mechanisms, latency reservoirs, and therapeutic interventions. Here we review the relative strengths and limitations of pediatric HIV-1 model systems. [Image: see text