The Importance of Pediatric Nonhuman Primate Models in Translational HIV Research

ABSTRACT

Despite extraordinary global progress in the prevention and treatment of HIV, pediatric HIV remains a significant and under‐addressed component of the global epidemic. In her keynote presentation at the Pediatric Nonhuman Primate (NHP) Workshop in October 2024, Dr. Ann Chahroudi delivered a comprehensive and compelling argument for the essential role of pediatric NHP models in translational HIV research. Her talk (summarized below) provided a detailed overview of how infant monkeys have contributed uniquely to our understanding of HIV pathogenesis, immune development, and therapeutic strategies in early life—and why continued investment in these models is critical for advancing pediatric HIV prevention, treatment, and cure.

1. Review and Current Status

The stark epidemiological reality is that, as of 2023, an estimated 1.4 million children (aged 0–14 years) are living with HIV globally, yet only about half are receiving lifesaving antiretroviral therapy (ART) [1]. An additional 120 000 new perinatal HIV infections occurred in 2023, with approximately half occurring before or during birth and half occurring during breastfeeding [1]. Tracking of new HIV infections in individuals > 15 years of age revealed a disproportionate impact on adolescent girls and young women, particularly in sub‐Saharan Africa, which places their future children at risk. New infections during pregnancy and breastfeeding represent the highest risk of vertical transmission. These figures serve as a sobering reminder that pediatric HIV has not disappeared—and in fact, requires continued and focused scientific innovation. More specifically, pediatric HIV remains a pressing global health challenge that merits dedicated research platforms tailored to the unique biology of infants and children.

Significant, although incomplete, investigation has underscored the biological distinctiveness of HIV infection in early life. Perinatal transmission of HIV occurs across a range of time points—during pregnancy, delivery, and breastfeeding—with the immune environment of the fetus and neonate differing profoundly from that of adults [2, 3, 4, 5]. At birth, the immune system is skewed toward regulatory and anti‐inflammatory states, with elevated levels of cytokines supporting Th17 development and reduced type I interferon responses [6, 7]. Adaptive immune function is comparatively immature, while innate immune mechanisms (including NK cells and macrophages) play outsized roles in antiviral defense [2, 8]. These differences impact not only viral pathogenesis but also the efficacy and safety of interventions—including antiretroviral therapy (ART), vaccines and other immunomodulatory therapies.

The typical timeline for approval of new therapeutics for children is protracted due to the standard approach of clinical studies that start with adults and then proceed in succession to younger age groups (i.e., ≥ 18 years, 12–17 years, 2–11 years, 1 month–1 year, neonate). There is also often a higher bar regarding the risk: benefit analysis for pediatric trials. Given the profound immunological, physiological, and ethical complexities of conducting pediatric clinical studies—particularly in neonates and infants—a faithful model system that can provide initial safety and efficacy data provides high value. Rhesus macaques ( Macaca mulatta ) are widely used for studies of HIV pathogenesis, vaccines, and therapeutics [9]. Their immune response to infection with simian immunodeficiency virus (SIV) is very similar to that of people with HIV. The rhesus macaques used for HIV research are typically born in controlled settings at the National Primate Research Centers (NPRCs) under the care of highly skilled veterinarians and, when used for early life research studies, are raised in specialized nurseries designed to foster health and well‐being. The rhesus macaque gestation (164 days), timeline to puberty (~3 years), dietary exposures, and responses to environmental stressors recapitulate many aspects of pediatric human biology and they undergo immune development that mirrors that of human infants [10, 11, 12, 13]. Crucially, the model allows for intensive tissue sampling and experimental manipulation that would be infeasible in pediatric clinical trials. Infant rhesus macaques thus serve as a relevant and versatile model system.

Experimental SIV and simian‐human immunodeficiency virus (SHIV) infections in macaques is typically achieved through oral inoculation that recapitulates perinatal HIV infection through swallowed blood and secretions during labor and delivery or breastmilk in the postnatal period [14]. This oral exposure leads to rapid viral dissemination within 48 h [15] with persistent infection in multiple sites—including lymphoid tissues, the gastrointestinal tract, and the central nervous system (CNS) [16, 17]. Access to tissues through elective necropsy during suppressive ART has allowed for extensive, although still incomplete, characterization of anatomic reservoirs. One example is the demonstration of viral nucleic acid both in untreated and ART‐suppressed SIV infection in CNS microglia, myeloid lineage cells that are less well studied compared to CD4+ T cells, which are the primary targets of infection [16]. The infection and replication competence of CNS microglia has been confirmed in adult macaques [18, 19] as well as with rare autopsy specimens from adult donations [19]. Such studies have not been conducted with pediatric autopsy specimens.

There have been multiple landmark studies using the infant macaque model to investigate HIV/SIV transmission, immune responses, and viral persistence under ART [14]. One example of how the infection differs in the pediatric versus adult settings that the macaque model helped to uncover relates to the predominance of naïve CD4+ T cells in infant macaques—mirroring observations in children living with HIV (CLWH). Naïve CD4+ T cells have been shown to be infected with intact and replication competent SIV/SHIV in infant macaques, and their high frequency means that they comprise a large proportion of the persistent reservoir [16, 17]. A recent study in CLWH also found intact HIV proviruses in naïve CD4+ T cells that showed evidence of clonal expansion [20]. There were no common integration sites across naïve and memory CD4+ T cells, likely reflecting differential gene expression patterns and underscoring the need to better understand reservoir dynamics across different T cell subsets early in life.

There is a long history of pediatric NHP studies directly impacting clinical research, informing the design and pharmacokinetics of pediatric antiretroviral formulations and long‐acting delivery strategies. Additionally, pediatric NHP models have enabled preclinical evaluation of a wide array of HIV cure strategies. These include latency‐reversing agents (e.g., AZD5582), IL‐15 superagonists (e.g., N‐803), therapeutic vaccines, and broadly neutralizing antibodies (bNAbs), both passively administered and delivered via adeno‐associated virus (AAV) vectors [21, 22, 23, 24, 25]. These studies have yielded insights not only into the safety and pharmacodynamics of these interventions in infants but also into age‐specific differences in tissue biodistribution, immune activation, and reservoir responsiveness. The detection of adverse events in infant macaques is equally as important as favorable results as this safety signal can prevent potentially harmful agents from being tested in children. A major area of success has been the use of bNAbs for both prevention and treatment [8, 26]. Multiple studies in infant macaques paved the way for subsequent trials in human infants and children [24, 25, 27, 28, 29, 30], with many more planned. It is fair to say that the infant NHP studies accelerated the pace of advances for children at risk for or living with HIV.

Although NHP models have led to significant progress, there are unique challenges associated with pediatric NHP models. These include the high cost of care, limited availability of appropriately aged animals, vulnerability to illness during the early postnatal period, and potential confounding effects of nursery rearing [31]. Methodological considerations—such as selection of virus strain, infection route and dose, host MHC genotypes, and timing of ART or therapeutic interventions—must be carefully calibrated to ensure reproducibility and relevance to human pediatric HIV infection.

In sum, Dr. Chahroudi's presentation provided a foundational framework for understanding why pediatric NHP models are not only scientifically valid but indispensable for advancing HIV prevention and cure strategies tailored to infants and children. She emphasized the need for continued multidisciplinary collaboration and cross‐institutional partnerships to support the development and ethical application of pediatric NHP models. As the field moves forward, these models will remain essential for addressing the unique challenges of pediatric HIV and ensuring that therapeutic innovations reach the youngest and most vulnerable populations.

Funding

This work was supported by National Institutes of Health (NIH) and the Office of Research Infrastructure Programs (ORIP) grants P51OD011132 and U42PDP011023. A.C. receives additional support for infant nonhuman primate studies through NIH grants UM1AI164566, P01HD112217, and R01AI192330. This workshop was organized by the Prevention Sciences Program (PSP) of the Division of AIDS (DAIDS) within the National Institute of Allergy and Infectious Diseases (NIAID) with special assistance from Advanced Biosciences Laboratories (ABL) Inc. (Rockville, Maryland) and the Tulane National Primate Research Center (Covington, Louisiana), and funded by Task Order 75N93024F00004 awarded to ABL under Resources to Advance Pediatric and HIV Prevention Sciences (RAPPS) parent contract 75N93023D00001.

Ethics Statement

This is a review article. All efforts were made to appropriately cite others' work.

Conflicts of Interest

A.C. is a Scientific Advisory Board member for ViiV Healthcare Inc.

Chahroudi A., “The Importance of Pediatric Nonhuman Primate Models in Translational HIV Research,” Journal of Medical Primatology 55, no. 2 (2026): e70069, 10.1111/jmp.70069.

Data Availability Statement

The author has nothing to report.