Infant Macaques Research Articles

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

Globally, 1.8 million children are living with HIV-1. While antiretroviral therapy (ART) has improved disease outcomes, it does not eliminate the latent HIV-1 reservoir. Interventions to delay or prevent viral rebound in the absence of ART would be highly beneficial for HIV-1-infected children who now must remain on daily ART throughout their lifespan. Here, we evaluated therapeutic Ad48-SIV prime, MVA-SIV boost immunization in combination with the TLR-7 agonist GS-986 in rhesus macaque (RM) infants orally infected with SIVmac251 at 4 weeks of age and treated with a triple ART regimen beginning 4 weeks after infection. We hypothesized immunization would enhance SIV-specific T cell responses during ART-mediated suppression of viremia. Compared to controls, vaccinated infants had greater magnitude SIV-specific T cell responses (mean of 3475 vs 69 IFN-γ spot forming cells (SFC) per 106 PBMCs, respectively, P = 0.01) with enhanced breadth of epitope recognition and increased CD8+ and CD4+ T cell polyfunctionality (P = 0.004 and P = 0.005, respectively). Additionally, SIV-specific gp120 antibodies against challenge and vaccine virus strains were significantly elevated following MVA boost (P = 0.02 and P < 0.001, respectively). GS-986 led to expected immune stimulation demonstrated by activation of monocytes and T cells 24 hours post-dose. Despite the vaccine-induced immune responses, levels of SIV DNA in peripheral and lymph node CD4+ T cells were not significantly different from controls and a similar time to viral rebound and viral load set point were observed following ART interruption in both groups. We demonstrate infant RMs mount a robust immunological response to this immunization, but vaccination alone was not sufficient to impact viral reservoir size or modulate rebound dynamics following ART release. Our findings hold promise for therapeutic vaccination as a part of a combination cure approach in children and highlight the importance of a pediatric model to evaluate HIV-1 cure interventions in this unique setting of immune development.

Higher early life mortality with lower infant body mass in a free-ranging primate.

Traits that reflect the amount of energy allocated to offspring by mothers, such as infant body mass, are predicted to have long-lasting effects on offspring fitness. In very long-lived species, such as anthropoid primates, where long-lasting and obligate parental care is required for successful recruitment of offspring, there are few studies on the fitness implications of low body mass among infants. Using body mass data collected from 253 free-ranging rhesus macaque Macaca mulatta infants on Cayo Santiago, Puerto Rico, we examined if lower infant body mass predicts lower chance of survival through to reproductive maturation (4th year of life). We also used data on inter-birth intervals and suckling behaviours to determine whether the duration of maternal care was adjusted to infant body mass. Rhesus macaque infants experienced on average 5% reduced hazard of death for an increase in body mass of 0.1 SD (~100g) above the mean within their age-sex class. The positive association between body mass and early life survival was most pronounced in the 1st year of life. Infant body mass tended to be lower if mothers were young or old, but the link between infant body mass and early life survival remained after controlling for maternal age. This finding suggests that maternal effects on early life survival such as maternal age may act through their influence on infant body mass. Mothers of heavier infants were less likely to be delayed in subsequent reproduction, but the estimated association slightly overlapped with zero. The timing of the last week of suckling did not differ by infant body mass. Using infant body mass data that has been rarely available from free-ranging primates, our study provides comparative evidence to strengthen the existing body of literature on the fitness implications of variation in infant body mass.

Long-term alterations in brain and behavior after postnatal Zika virus infection in infant macaques

Zika virus (ZIKV) infection has a profound impact on the fetal nervous system. The postnatal period is also a time of rapid brain growth, and it is important to understand the potential neurobehavioral consequences of ZIKV infection during infancy. Here we show that postnatal ZIKV infection in a rhesus macaque model resulted in long-term behavioral, motor, and cognitive changes, including increased emotional reactivity, decreased social contact, loss of balance, and deficits in visual recognition memory at one year of age. Structural and functional MRI showed that ZIKV-infected infant rhesus macaques had persistent enlargement of lateral ventricles, smaller volumes and altered functional connectivity between brain areas important for socioemotional behavior, cognitive, and motor function (e.g. amygdala, hippocampus, cerebellum). Neuropathological changes corresponded with neuroimaging results and were consistent with the behavioral and memory deficits. Overall, this study demonstrates that postnatal ZIKV infection in this model may have long-lasting neurodevelopmental consequences.

Early developmental changes in visual social engagement in infant rhesus monkeys

Impairments in social interaction in Autism Spectrum Disorder (ASD) differ greatly across individuals and vary throughout an individual’s lifetime. Yet, an important marker of ASD in infancy is deviations in social-visual engagement, such as the reliably detectable early deviations in attention to the eyes or to biological movement (Klin et al., 2015). Given the critical nature of these early developmental periods, understanding its neurobehavioral underpinnings by means of a nonhuman primate model will be instrumental to understanding the pathophysiology of ASD. Like humans, rhesus macaques 1) develop in rich and complex social behaviors, 2) progressively develop social skills throughout infancy, and 3) have high similarities with humans in brain anatomy and cognitive functions (Machado and Bachevalier, 2003). In this study, male infant rhesus macaques living with their mothers in complex social groups were eye-tracked longitudinally from birth to 6 months while viewing full-faced videos of unfamiliar rhesus monkeys differing in age and sex. The results indicated a critical period for the refinement of social skills around 4–8 weeks of age in rhesus macaques. Specifically, infant monkeys’ fixation to the eyes shows an inflection in developmental trajectory, increasing from birth to 8 weeks, decreasing slowly to a trough between 14–18 weeks, before increasing again. These results parallel the developmental trajectory of social visual engagement published in human infants (Jones & Klin, 2013) and suggest the presence of a switch in the critical networks supporting these early developing social skills that is highly conserved between rhesus macaque and human infant development.

A new look at neurobehavioral development in rhesus monkey neonates (Macaca mulatta).

The Brazelton Neonatal Behavioral Assessment Scale (NBAS) evaluates a newborn infant's autonomic, motor, state, temperament, and social-attentional systems, which can help to identify infants at risk of developmental problems. Given the prevalence of rhesus monkeys being used as an animal model for human development, here we aimed to validate a standardized test battery modeled after the NBAS for use with nonhuman primates called the Infant Behavioral Assessment Scale (IBAS), employing exploratory structural equation modeling using a large sample of rhesus macaque neonates (n = 1,056). Furthermore, we examined the repeated assessments of the common factors within the same infants to describe any changes in performance over time, taking into account two independent variables (infant sex and rearing condition) that can potentially affect developmental outcomes. Results revealed three factors (Orientation, State Control, and Motor Activity) that all increased over the 1st month of life. While infant sex did not have an effect on any factor, nursery-rearing led to higher scores on Orientation but lower scores on State Control and Motor Activity. These results validate the IBAS as a reliable and valuable research tool for use with rhesus macaque infants and suggest that differences in rearing conditions can affect developmental trajectories and potentially pre-expose infants to heightened levels of cognitive and emotional deficiencies.

Functional Perturbation of Mucosal Group 3 Innate Lymphoid and Natural Killer Cells in Simian-Human Immunodeficiency Virus/Simian Immunodeficiency Virus-Infected Infant Rhesus Macaques.

Mother-to-child transmission of human immunodeficiency virus type 1 (HIV-1) via breastfeeding is responsible for nearly half of new infections of children with HIV. Although innate lymphoid cells (ILC) and natural killer (NK) cells are found throughout the oral mucosae, the effects of HIV/simian-human immunodeficiency virus (SHIV) in these tissues are largely unknown. To better understand the mechanics of postnatal transmission, we performed a comprehensive study of simian immunodeficiency virus (SIV)/SHIV-infected infant rhesus macaques (RM) and tracked changes in frequency, trafficking, and function of group 3 ILC (ILC3) and NK cells using polychromatic flow cytometry and cell stimulation assays in colon, tonsil, and oral lymph node samples. Infection led to a 3-fold depletion of ILC3 in the colon and an increase in the levels of NK cells in tonsils and oral lymph nodes. ILC3 and NK cells exhibited alterations in their trafficking repertoires as a result of infection, with increased expression of CD103 in colon NK cells and curtailment of CXCR3, and a significant decrease in α4β7 expression in colon ILC3. SPICE analyses revealed that ILC3 and NK cells displayed distinct functional profiles by tissue in naive samples. Infection perturbed these profiles, with a nearly total loss of interleukin-22 (IL-22) production in the tonsil and colon; an increase in the levels of CD107a, gamma interferon (IFN-γ), and tumor necrosis factor alpha (TNF-α) from ILC3; and an increase in the levels of CD107a, macrophage inflammatory protein 1 beta (MIP-1β), and TNF-α from NK cells. Collectively, these data reveal that lentivirus infection alters the frequencies, receptor repertoires, and functions of innate cells in the oral and gut mucosa of infants. Further study will be required to delineate the full extent of the effect that these changes have on oral and gut homeostasis, SHIV/SIV pathogenesis, and oral opportunistic disease.IMPORTANCE Vertical transmission of HIV from mother to child accounts for many of the new cases seen worldwide. There is currently no vaccine to mitigate this transmission, and there has been limited research on the effects that lentiviral infection has on the innate immune system in oral tissues of infected children. To fill this knowledge gap, our laboratory studied infant rhesus macaques to evaluate how acute SIV/SHIV infections impacted ILC3 and NK cells, which are immune cells critical for mucosal homeostasis and antimicrobial defense. Our data revealed that SIV/SHIV infection led to a depletion of ILC3 and an increase of NK cells and to a functional shift from a homeostatic to a multifunctional proinflammatory state. Taking the results together, we describe how lentiviral infection perturbs the oral and gastrointestinal mucosae of infant macaques through alterations of resident innate immune cells giving rise to chronic inflammation and potentially exacerbating morbidity and mortality in children living with HIV.

Single-dose bNAb cocktail or abbreviated ART post-exposure regimens achieve tight SHIV control without adaptive immunity

Vertical transmission accounts for most human immunodeficiency virus (HIV) infection in children, and treatments for newborns are needed to abrogate infection or limit disease progression. We showed previously that short-term broadly neutralizing antibody (bNAb) therapy given 24 h after oral exposure cleared simian-human immunodeficiency virus (SHIV) in a macaque model of perinatal infection. Here, we report that all infants given either a single dose of bNAbs at 30 h, or a 21-day triple-drug ART regimen at 48 h, are aviremic with almost no virus in tissues. In contrast, bNAb treatment beginning at 48 h leads to tight control without adaptive immune responses in half of animals. We conclude that both bNAbs and ART mediate effective post-exposure prophylaxis in infant macaques within 30–48 h of oral SHIV exposure. Our findings suggest that optimizing the treatment regimen may extend the window of opportunity for preventing perinatal HIV infection when treatment is delayed.

Long-term alterations in brain and behavior after postnatal Zika virus infection in infant macaques

Long-term alterations in brain and behavior after postnatal Zika virus infection in infant macaques

Perivascular macrophages in the neonatal macaque brain undergo massive necroptosis after simian immunodeficiency virus infection.

We previously showed that rhesus macaques neonatally infected with simian immunodeficiency virus (SIV) do not develop SIV encephalitis (SIVE) and maintain low brain viral loads despite having similar plasma viral loads compared to SIV-infected adults. We hypothesize that differences in myeloid cell populations that are the known target of SIV and HIV in the brain contribute to the lack of neonatal susceptibility to lentivirus-induced encephalitis. Using immunohistochemistry and immunofluorescence microscopy, we examined the frontal cortices from uninfected and SIV-infected infant and adult macaques (n=8/ea) as well as adults with SIVE (n=4) to determine differences in myeloid cell populations. The number of CD206+ brain perivascular macrophages (PVMs) was significantly greater in uninfected infants than in uninfected adults and was markedly lower in SIV-infected infants while microglia numbers were unchanged across groups. CD206+ PVMs, which proliferate after infection in SIV-infected adults, did not undergo proliferation in infants. While virtually all CD206+ cells in adults are also CD163+, infants have a distinct CD206 single-positive population in addition to the double-positive population commonly seen in adults. Notably, we found that more than 60% of these unique CD206+CD163- PVMs in SIV-infected infants were positive for cleaved caspase-3, an indicator of apoptosis, and that nearly 100% of this subset were concomitantly positive for the necroptosis marker receptor-interacting protein kinase-3 (RIP3). These findings show that distinct subpopulations of PVMs found in infants undergo programmed cell death instead of proliferation following SIV infection, which may lead to the absence of PVM-dependent SIVE and the limited size of the virus reservoir in the infant brain.

Infant rhesus macaque (Macaca mulatta) personality and subjective well-being.

Infant temperament is theorized to lay the foundation for adult personality; however, many questions remain regarding personality in infancy, including the number of dimensions, extent to which they are adult-like, and their relation to other outcomes, such as mental and physical health. Here we tested whether adult-like personality dimensions are already present in infancy in a nonhuman primate species. We measured personality and subjective well-being in 7-month-old rhesus macaques (N = 55) using the Hominoid Personality Questionnaire and Subjective Well-Being Questionnaire, both of which were developed for adult primates based on human measures. Multiple human raters, who provided infants with daily care since birth, independently rated each infant. We found high interrater reliability. Results from a parallel analysis and scree plot indicated a five component structure, which, using principal components analysis, we found to be comprised of dimensions relating to Openness (e.g., curiosity, inquisitive, playfulness), Assertiveness (e.g., dominance, bullying, aggressive), Anxiety (e.g., vigilance, fearful), Friendliness (e.g., sociable, affectionate, sympathetic), and Intellect (e.g., organized, not erratic). These components are largely analogous to those in adult macaques, suggesting remarkably stable structural personality components across the lifespan. Infant macaques' subjective well-being positively correlates with Openness and Assertiveness and negatively correlated with Anxiety, similar to findings in adult macaques and other primates. Together, these findings suggest that, in macaques, infant personality dimensions may be conceptually related to adult personality and challenge the view that infant temperament may be disorganized and not as meaningful as adult personality. Further research is necessary to explore the antecedents, predictive validity, and stability of these personality components across situations and with development.

Do young rhesus macaques know what others see?: A comparative developmental perspective.

Humans undergo robust ontogenetic shifts in the theory of mind capabilities. Are these developmental changes unique to human development or are they shared with other closely related non-human species? To explore this issue, we tested the development of the theory of mind capacities in a population of 236 infant and juvenile rhesus macaques (Macaca mulatta). Using a looking-time method, we examined what developing monkeys know about others' perceptions. Specifically, we tested whether younger monkeys predict that a person will reach for an object where she last saw it. Overall, we found a significant interaction between a monkey's age and performance on this task (p = .014). Juvenile monkeys (between two and 5 years of age) show a nonsignificant trend towards human infant-like patterns of performance, looking longer during the unexpected condition as compared to the expected condition, though this difference is nonsignificant (p = .09). However, contrary to findings in human infants, infant rhesus macaques show a different trend. Infant monkeys on average look slightly longer on average during the expected condition than the unexpected condition, though this pattern was not significant (p = .06). Our developmental results in monkeys provide some hints about the development of the theory of mind capacities in non-humans. First, young rhesus macaques appear to show some interest in the perception of other agents. Second, young rhesus seems able to make predictions based on the visual perspective of another agent, though the developmental pattern of this ability is not as clear nor as robust as in humans. As such, though an understanding of others' perceptions is early-emerging in human infants, it may require more experience interacting with other social agents in our non-human relatives.

Social touch alters newborn monkey behavior

In humans, infants respond positively to slow, gentle stroking—processed by C-tactile (CT) nerve fibers—by showing reductions in stress and increases in eye contact, smiling, and positive vocalizations. More frequent maternal touch is linked to greater activity and connectivity strength in social brain regions, and increases children’s attention to and learning of faces. It has been theorized that touch may prime children for social interactions and set them on a path towards healthy social cognitive development. However, less is known about the effects of touch on young infants’ psychological development, especially in the newborn period, a highly sensitive period of transition with rapid growth in sensory and social processing. It remains untested whether newborns can distinguish CT-targeted touch from other types of touch, or whether there are benefits of touch for newborns’ social, emotional, or cognitive development. In the present study, we experimentally investigated the acute effects of touch in newborn monkeys, a common model for human social development. Rhesus macaques (Macaca mulatta), like humans, are highly social, have complex mother-infant interactions with frequent body contact for the first weeks of life, making them an excellent model of infant sociality. Infant monkeys in the present study were reared in a neonatal nursery, enabling control over their early environment, including all caregiver interactions. One-week-old macaque infants (N = 27) participated in three 5-minute counter-balanced caregiver interactions, all with mutual gaze: stroking head and shoulders (CT-targeted touch), stroking palms of hands and soles of feet (Non-CT touch), or no stroking (No-touch). Immediately following the interaction, infants watched social and nonsocial videos and picture arrays including faces and objects, while we tracked their visual attention with remote eye tracking. We found that, during the caregiver interactions, infants behaved differently while being touched compared to the no-touch condition, irrespective of the body part touched. Most notably, in both touch conditions, infants exhibited fewer stress-related behaviors—self-scratching, locomotion, and contact time with a comfort object—compared to when they were not touched. Following CT-targeted touch, infants were faster to orient to the picture arrays compared to the other interaction conditions, suggesting CT-targeted touch may activate or prime infants’ attentional orienting system. In the No-touch condition infants attended longer to the nonsocial compared to the social video, possibly reflecting a baseline preference for nonsocial stimuli. In contrast, in both touch conditions, infants’ looked equally to the social and nonsocial videos, suggesting that touch may influence the types of visual stimuli that hold infants’ attention. Collectively, our results reveal that newborn macaques responded positively to touch, and touch appeared to influence some aspects of their subsequent attention, although we found limited evidence that these effects are mediated by CT fibers. These findings suggest that newborn touch may broadly support infants’ psychological development, and may have early evolutionary roots, shared across primates. This study illustrates the unique insight offered by nonhuman primates for exploring early infant social touch, revealing that touch may positively affect emotional and attentional development as early as the newborn period.

Neonatal temperament and neuromotor differences are predictive of adolescent alcohol intake in rhesus monkeys (Macaca mulatta).

Identifying predictors of teenage alcohol use disorder (AUDs) is a major health initiative, with studies suggesting that there are distinct personality-related traits that underlie patterns of alcohol intake. As temperament is biologically based, identifiable early in life, and stable across time, it is considered the foundation of personality. As such, we hypothesized that neonatal temperament traits would predict anxiety-mediated adolescent alcohol consumption. To test this, N = 145 rhesus macaque (Macaca mulatta) infants (14 days of age), reared in a neonatal nursery (n = 82) or in a control condition with their mothers (n = 63) were assessed with a widely used standardized nonhuman primate testing battery, the Infant Behavioral Assessment Scale (IBAS), modeled after the Brazelton Neonatal Assessment Scale, evaluating visual orienting, temperament, motor maturity and, more recently, sensory sensitivity. As adolescents (3-4 years of age), these same subjects were allowed unfettered access to a sweetened-alcohol solution for 1 hr/day, 4 days/week, over 5-7 weeks. Subjects were allowed to self-administer alcohol while housed alone (n = 70) or socially in their home cage (n = 55). Linear regressions showed that alcohol intake was predicted by neonatal orienting ability (β = -.35; p = .01), state control (β = -.19; p = .04), and motor maturity (β = -.24; p = .01). Poor neonatal orienting, state control (ease of consolability), and motor maturity were associated with higher adolescent alcohol intake in rhesus monkeys. These findings suggest that neonatal temperament is predictive of patterns of adolescent alcohol intake. To the extent that these results generalize to humans, they provide evidence that early-life temperament and neurodevelopment may be important risk factors for adolescent AUDs and that the IBAS may be used as an assessment tool for identifying such risk.

Simian-Human Immunodeficiency Virus SHIV.CH505-Infected Infant and Adult Rhesus Macaques Exhibit Similar Env-Specific Antibody Kinetics, despite Distinct T-Follicular Helper and Germinal Center B Cell Landscapes.

Global elimination of pediatric human immunodeficiency virus (HIV) infections will require the development of novel immune-based approaches, and understanding infant immunity to HIV is critical to guide the rational design of these intervention strategies. Despite their immunological immaturity, chronically HIV-infected children develop broadly neutralizing antibodies (bnAbs) more frequently and earlier than adults do. However, the ontogeny of humoral responses during acute HIV infection is poorly defined in infants and challenging to study in human cohorts due to the presence of maternal antibodies. To further our understanding of age-related differences in the development of HIV-specific immunity during acute infection, we evaluated the generation of virus-specific humoral immune responses in infant (n = 6) and adult (n = 12) rhesus macaques (RMs) infected with a transmitted/founder (T/F) simian-human immunodeficiency virus (SHIV) (SHIV.C.CH505 [CH505]). The plasma HIV envelope-specific IgG antibody kinetics were similar in SHIV-infected infant and adult RMs, with no significant differences in the magnitude or breadth of these responses. Interestingly, autologous tier 2 virus neutralization responses also developed with similar frequencies and kinetics in infant and adult RMs, despite infants exhibiting significantly higher follicular T helper cell (Tfh) and germinal center B cell frequencies than adults. Finally, we show that plasma viral load was the strongest predictor of the development of autologous virus neutralization in both age groups. Our results indicate that the humoral immune response to SHIV infection develops with similar kinetics among infant and adult RMs, suggesting that the early-life immune system is equipped to respond to HIV-1 and promote the production of neutralizing HIV antibodies.IMPORTANCE There is a lack of understanding of how the maturation of the infant immune system influences immunity to HIV infection or how these responses differ from those of adults. Improving our knowledge of infant HIV immunity will help guide antiviral intervention strategies that take advantage of the unique infant immune environment to successfully elicit protective immune responses. We utilized a rhesus macaque model of SHIV infection as a tool to distinguish the differences in HIV humoral immunity in infants versus adults. Here, we demonstrate that the kinetics and quality of the infant humoral immune response to HIV are highly comparable to those of adults during the early phase of infection, despite distinct differences in their Tfh responses, indicating that slightly different mechanisms may drive infant and adult humoral immunity.

A Meningococcal Outer Membrane Vesicle Vaccine with Overexpressed Mutant FHbp Elicits Higher Protective Antibody Responses in Infant Rhesus Macaques than a Licensed Serogroup B Vaccine.

MenB-4C (Bexsero; GlaxoSmithKline Biologicals) is a licensed meningococcal vaccine for capsular B strains. The vaccine contains detergent-extracted outer membrane vesicles (dOMV) and three recombinant proteins, of which one is factor H binding protein (FHbp). In previous studies, overexpression of FHbp in native OMV (NOMV) with genetically attenuated endotoxin (LpxL1) and/or by the use of mutant FHbp antigens with low factor H (FH) binding increased serum bactericidal antibody (SBA) responses. In this study, we immunized 13 infant macaques with 2 doses of NOMV with overexpressed mutant (R41S) FHbp with low binding to macaque FH (NOMV-FHbp). Control macaques received MenB-4C (n = 13) or aluminum hydroxide adjuvant alone (n = 4). NOMV-FHbp elicited a 2-fold higher IgG anti-FHbp geometric mean titer (GMT) than MenB-4C (P = 0.003), and the anti-FHbp repertoire inhibited binding of FH to FHbp, whereas anti-FHbp antibodies to MenB-4C enhanced FH binding. MenB-4C elicited a 10-fold higher GMT against strain NZ98/254, which was used to prepare the dOMV component, whereas NOMV-FHbp elicited an 8-fold higher GMT against strain H44/76, which was the parent of the mutant NOMV-FHbp vaccine strain. Against four strains with PorA mismatched to both of the vaccines and different FHbp sequence variants, NOMV-FHbp elicited 6- to 14-fold higher SBA GMTs than MenB-4C (P ≤ 0.0002). Two of 13 macaques immunized with MenB-4C but 0 of 17 macaques immunized with NOMV-FHbp or adjuvant developed serum anti-FH autoantibodies (P = 0.18). Thus, the mutant NOMV-FHbp approach has the potential to elicit higher and broader SBA responses than a licensed group B vaccine that contains wild-type FHbp that binds FH. The mutant NOMV-FHbp also might pose less of a risk of eliciting anti-FH autoantibodies.IMPORTANCE There are two licensed meningococcal capsular B vaccines. Both contain recombinant factor H binding protein (FHbp), which can bind to host complement factor H (FH). The limitations of these vaccines include a lack of protection against some meningococcal strains and the potential to elicit autoantibodies to FH. We immunized infant macaques with a native outer membrane vesicle (NOMV) vaccine with genetically attenuated endotoxin and overproduced mutant FHbp with low binding to FH. The NOMV-FHbp vaccine stimulated higher levels of protective serum antibodies than a licensed meningococcal group B vaccine against five of six genetically diverse meningococcal strains tested. Two of 13 macaques immunized with the licensed vaccine, which contains FHbp that binds macaque FH, but 0 of 17 macaques given NOMV-FHbp or the negative control developed serum anti-FH autoantibodies Thus, in a relevant nonhuman primate model, the NOMV-FHbp vaccine elicited greater protective antibodies than the licensed vaccine and may pose less of a risk of anti-FH autoantibody.

CHARTING DEVELOPMENT-BASED JOINT PARCELLATION MAPS OF HUMAN AND MACAQUE BRAINS DURING INFANCY.

Comparative characterization of early brain development between human and macaque using neuroimaging data is crucial to understand the mechanisms of brain development and evolution. To this end, joint cortical parcellation maps of human and macaque infant brains with corresponding regions are highly desirable, since they provide basic cortical parcels for both region-based and network-based studies of two closely-related species. To address this issue, we propose to leverage developmental patterns of cortical properties of both human and macaque infants for creating joint parcellation maps with inter-species comparability. The motivation is that the developmental patterns of cortical properties indicate underlying rapid changes of microstructures, which determine the molecular and functional principles of the cortex. Thus, developmental patterns are well suitable for defining distinct cortical regions in both structures and functions. To comprehensively capture the similarities of developmental patterns of vertices on cortical surfaces, for each species, we first construct two complementary similarity matrices: a low-order matrix and a high-order matrix. Then, we non-linearly fuse these four matrices together as a single matrix in a hierarchical manner, thus capturing the common and complementary information of both human and macaque infants. Finally, based on the fused similarity matrix, we apply the spectral clustering to derive the joint parcellation maps. By applying our method to 210 longitudinal human infant MRI scans and 140 longitudinal macaque infant MRI scans, we generate the first biologically-meaningful joint parcellation maps of human and macaque infants.

Behavioral effects of postnatal ketamine exposure in rhesus macaque infants are dependent on MAOA-LPR genotype.

Ketamine is an N-methyl-D-aspartate (NMDA) receptor antagonist widely used in pediatric anesthetic and therapeutic practices and veterinary medicine. Previous evidence suggests that exposure to ketamine during sensitive periods of development results in neural apoptosis and atypical behavior. Since monoamine neurotransmitters play important roles in prenatal and early postnatal neural development, and since previous work suggests ketamine can inhibit monoamine transporters, we hypothesized that there would be behavioral consequences of prenatal and early postnatal exposure to ketamine moderated by genotype of the promoter in the monoamine oxidase-A (MAOA) gene. From a large sample of animals (N=408), we compared groups of rhesus monkeys that had experienced a single exposure to ketamine during prenatal development, an exposure during prenatal development and one postnatal exposure, a postnatal exposure with no prenatal exposure, and no exposures. Animals were classified by putative activity levels for the MAOA genotype and were tested between 3 and 4 months of age on a battery of behavioral tests. Results suggested that animals exposed to ketamine postnatally, at a dose typically used for sedative effects that also had the low-activity variant of MAOA performed poorly on a visual memory test compared to animals with the high-activity variant of the MAOA gene.

Coadministration of CH31 Broadly Neutralizing Antibody Does Not Affect Development of Vaccine-Induced Anti-HIV-1 Envelope Antibody Responses in Infant Rhesus Macaques.

Prevention of mother-to-child transmission (MTCT) is an indispensable component in combatting the global AIDS epidemic. A combination of passive broadly neutralizing antibody (bnAb) infusion and active vaccination promises to provide protection of infants against MTCT from birth through the breastfeeding period and could prime the immune system for lifelong immunity. In this study, we investigate the impact of a single infusion of CD4 binding site (CD4bs) bnAb administered at birth on de novo antibody responses elicited by concurrent active HIV envelope vaccination. Four groups of infant macaques received active immunizations with subunit Env protein or modified vaccinia Ankara (MVA)-vectored Env and subunit Env protein, with or without a single intravenous coadministration of CH31 bnAb at birth. Vaccinated animals were monitored to evaluate binding and functional antibody responses elicited by the active vaccinations. Despite achieving plasma concentrations that were able to neutralize tier 2 viruses, coadministration of CH31 did not have a large impact on the kinetics, magnitude, specificity, or avidity of vaccine-elicited binding or functional antibody responses, including epitope specificity, the development of CD4bs antibodies, neutralization, binding to infected cells, or antibody-dependent cell-mediated cytotoxicity (ADCC). We conclude that infusion of CD4bs bnAb CH31 at birth does not interfere with de novo antibody responses to active vaccination and that a combination of passive bnAb infusion and active HIV-1 Env vaccination is a viable strategy for immediate and prolonged protection against MTCT.IMPORTANCE Our study is the first to evaluate the impact of passive infusion of a broadly neutralizing antibody in newborns on the de novo development of antibody responses following active vaccinations in infancy. We demonstrated the safety and the feasibility of bnAb administration to achieve biologically relevant levels of the antibody and showed that the passive infusion did not impair the de novo antibody production following HIV-1 Env vaccination. Our study paves the way for further investigations of the combination strategy using passive plus active immunization to provide protection of infants born to HIV-1-positive mothers over the entire period of risk for mother-to-child transmission.

Performance on the Operant Test Battery in young children exposed to procedures requiring general anaesthesia: the MASK study

BackgroundIt is not known whether the neurotoxicity produced by anaesthetics administered to young animals can also occur in children. Exposure of infant macaques to ketamine impairs performance in selected domains of the Operant Test Battery (OTB), which can also be administered to children. This study determined whether a similar pattern of results on the OTB is found in children exposed to procedures requiring general anaesthesia before age 3 yr. MethodsWe analysed data from the Mayo Anesthesia Safety in Kids (MASK) study, in which unexposed, singly-exposed, and multiply-exposed children born in Olmsted County, MN, USA, from 1994 to 2007 were sampled using a propensity-guided approach and prospectively underwent OTB testing at ages 8–12 or 15–20 yr, using five tasks that generated 15 OTB test scores. ResultsIn primary analysis, none of the OTB test scores depended upon anaesthesia exposure status when corrected for multiple comparisons. Cluster analysis identified four clusters of subjects, with cluster membership determined by relative performance on the OTB tasks. There was no evidence of association between exposure status and cluster membership. Exploratory factor analysis showed that the OTB scores loaded onto four factors. The score for one factor was significantly less in multiply-exposed children (mean standardised difference –0.28 [95% confidence interval, –0.55 to –0.01; P=0.04]), but significance did not survive a sensitivity analysis accounting for outlying values. ConclusionsThese findings provide little evidence to support the hypothesis that children exposed to procedures requiring anaesthesia show deficits on OTB tasks that are similar to those observed in non-human primates.

Multimodal imaging of the retina and choroid in healthy Macaca fascicularis at different ages

PurposeThe aim of this study was to identify the morphological features of the retina and choroid in Macaca fascicularis of different ages using multimodal imaging.MethodsA total of 27 Macaca fascicularis with no ocular diseases were studied (mean age, 104.2 months; range, 1.2–223.6 months). Multimodal imaging was obtained from each subject. The morphological features were compared within four subgroups according to age.ResultsOn spectrum-domain optical coherence tomography (SD-OCT), four hyper-reflective bands could be observed in the outer retina in non-infant macaques (21/21, 100%), while the interdigitation zone could not be observed in the six infant macaques. A narrow hypo-reflective band just posterior to the retinal pigment epithelium (RPE) was noted in most eyes (25/27, 92.6%). The choroidal–scleral junction (CSJ) was visible in 83.3% of infants but only in 12.5% of adults and 14.3% of the geriatric population, and it could not be seen in juveniles. There was a significant difference in CSJ visibility between the infant group and the other three groups (P < 0.001). Tessellated fundus, in which the choroidal vessels are visible through the retina, could be observed clearly with near-infrared reflectance imaging (NIR). Some granular spots were noted in juveniles, and they accumulated dramatically with age, but were absent in infants.ConclusionNotable morphological features can be observed in the Macaca fascicularis subjects using multimodal imaging, and these features vary distinctly according to their age. It is important to note that infant macaques had no interdigitation zone, while the other macaques had no visible CSJ but did have well-defined choroidal capillaries. Age and the features should be considered seriously in future animal studies.