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.Keywords: Pediatric, human immunodeficiency virus-1, simian immunodeficiency virus, animal models, neurological impairments, myelin, hippocampus, stereologyAs part of the United Nations Millennium Declaration, the global community took the initiative to halt and reverse the worldwide spread of HIV/AIDS by the year 2015.1 Through the collective effort of international governments, organizations, local communities and advancements in scientific discovery, the number of new HIV-1 infections continues to decline.2 Although there has been a decline in mother-to-child HIV-1 transmission over the past decade, an estimated 650 children under the age of 15 years become infected with HIV-1 each day,3–6 with approximately 50% of these children7 being perinatally infected through mother-to-child transmission (MTCT) via breast milk.8–10 The achievement in reducing perinatal infection rates has been accompanied by increased survival rates of HIV-1 infected children due, in part, to advances and access to antiretroviral therapy (ART),11 both in North America and worldwide.2,12–15 However, of the estimated 2.5 million children under the age of 14 living with HIV-1, only about 25% receive antiretroviral therapy.2 In 2012, over 200 000 children died from AIDS-related causes16 with resource-poor areas such as Sub-Saharan Africa accounting for the majority of children under the age of 14 years living with HIV-1 and new infections worldwide.4 Perinatal infection rates in North America are less than 2%, mainly due to interventions such as routine HIV-1 screening of pregnant women, use of antiretroviral drugs, avoidance of breastfeeding, and elective cesarean delivery.3,17–19 Currently, there are an estimated 10 000 perinatally infected HIV-1 children/adolescents in the United States, who are disproportionately distributed among Black/African-American and Hispanic/Latino populations.19Long-term survival poses a set of unique management challenges as perinatally HIV-1 infected children transition to adolescence and adulthood.13,20,21 Early adolescence marks a period whereby adolescents begin to take charge of their own health management and lifestyles (life-long habits). There is a general paucity of data concerning the health outcomes of perinatally HIV-1 infected children and adolescents.22 Existing data suggest poor adherence to antiretroviral medications21,23,24 and marked obesity rates leading to physical complications such as cardiovascular disorders.14,22,25–29 This is further complicated by a high prevalence of neurodevelopmental and cognitive deficits,30–36 as well as increased frequency of reported psychiatric disorders within the perinatally HIV-1 infected adolescent population.37