Nancy Schultz-Darken

Glycerol monolaurate prevents mucosal SIV transmission

Although there has been great progress in treating human immunodeficiency virus 1 (HIV-1) infection, preventing transmission has thus far proven an elusive goal. Indeed, recent trials of a candidate vaccine and microbicide have been disappointing, both for want of efficacy and concerns about increased rates of transmission. Nonetheless, studies of vaginal transmission in the simian immunodeficiency virus (SIV)–rhesus macaque (Macacca mulatta) model point to opportunities at the earliest stages of infection in which a vaccine or microbicide might be protective, by limiting the expansion of infected founder populations at the portal of entry. Here we show in this SIV–macaque model, that an outside-in endocervical mucosal signalling system, involving MIP-3α (also known as CCL20), plasmacytoid dendritic cells and CCR5+ cell-attracting chemokines produced by these cells, in combination with the innate immune and inflammatory responses to infection in both cervix and vagina, recruits CD4+ T cells to fuel this obligate expansion. We then show that glycerol monolaurate—a widely used antimicrobial compound with inhibitory activity against the production of MIP-3α and other proinflammatory cytokines—can inhibit mucosal signalling and the innate and inflammatory response to HIV-1 and SIV in vitro, and in vivo it can protect rhesus macaques from acute infection despite repeated intra-vaginal exposure to high doses of SIV. This new approach, plausibly linked to interfering with innate host responses that recruit the target cells necessary to establish systemic infection, opens a promising new avenue for the development of effective interventions to block HIV-1 mucosal transmission.

A rhesus macaque model of Asian-lineage Zika virus infection

Infection with Asian-lineage Zika virus (ZIKV) has been associated with Guillain–Barré syndrome and fetal abnormalities, but the underlying mechanisms remain poorly understood. Animal models of infection are thus urgently needed. Here we show that rhesus macaques are susceptible to infection by an Asian-lineage ZIKV closely related to strains currently circulating in the Americas. Following subcutaneous inoculation, ZIKV RNA is detected in plasma 1 day post infection (d.p.i.) in all animals (N=8, including 2 pregnant animals), and is also present in saliva, urine and cerebrospinal fluid. Non-pregnant and pregnant animals remain viremic for 21 days and for up to at least 57 days, respectively. Neutralizing antibodies are detected by 21 d.p.i. Rechallenge 10 weeks after the initial challenge results in no detectable virus replication, indicating protective immunity against homologous strains. Therefore, Asian-lineage ZIKV infection of rhesus macaques provides a relevant animal model for studying pathogenesis and evaluating potential interventions against human infection, including during pregnancy.

Social and reproductive influences on plasma cortisol in female marmoset monkeys

Subordinate female common marmosets (Callithrix jacchus) undergo ovulation suppression and exhibit low plasma cortisol levels compared to the dominant, breeding female. To determine whether this cortisol difference is mediated by the differential reproductive consequences of social status, we monitored plasma progesterone and cortisol in 32 adult female marmosets while they were housed in heterosexual pairs, during the first 3 days of heterosexual group formation, and while animals were housed in established social groups. Cortisol levels prior to group formation were significantly higher in females exhibiting cyclic ovulatory activity than in anovulatory females but were not predictive of social status. Subsequently, when animals were housed in established social groups, dominant (cyclic) females had significantly higher cortisol levels than did subordinate (anovulatory) females. Cortisol levels differed between the pre and postgroup formation conditions only in animals that underwent a corresponding onset or termination of ovulatory cyclicity. Cortisol differences between dominant and subordinate female marmosets therefore appear to be associated with differences in reproductive function rather than with social status per se.

Suppression of Cortisol Levels in Subordinate Female Marmosets: Reproductive and Social Contributions

Socially subordinate female common marmosets (Callithrix jacchus) have markedly lower plasma cortisol levels than dominant females. Subordinate females also undergo hypoestrogenemic anovulation, and estrogen can elevate glucocorticoid levels. Therefore, we previously hypothesized that this cortisol difference is mediated by rank-related differences in reproductive hormones, probably estradiol. To test this possibility, we characterized the effects of the ovarian cycle and ovariectomy on plasma cortisol concentrations. Beginning in the early follicular phase, basal blood samples were collected from seven cycling female marmosets daily for 16 days and at 2- to 3-day intervals for another 16 days. Samples were collected identically from seven anovulatory subordinate females and seven long-term ovariectomized females. Cortisol levels changed reliably across the ovarian cycle, with levels in the mid- to late follicular, peri-ovulatory, and early luteal phases higher than those in the remainder of the cycle. Cortisol levels of cycling females were significantly higher than those of subordinates at all parts of the cycle, but were significantly higher than those of ovariectomized females only during the midcycle elevation. Unexpectedly, subordinates had significantly lower cortisol levels than ovariectomized females, as well as higher estradiol and estrone levels and lower progesterone and luteinizing hormone (LH) levels. These results confirm that circulating cortisol concentrations are modulated by reproductive function in female marmosets but also indicate that low cortisol levels in subordinate females cannot be attributed simply to hypoestrogenemia. Instead, other factors, such as direct effects of social subordination or suppression of LH levels, contribute to suppression of cortisol in subordinates.

Activation of Neural Pathways Associated with Sexual Arousal in Non-Human Primates

To evaluate brain activity associated with sexual arousal, fully conscious male marmoset monkeys were imaged during presentation of odors that naturally elicit high levels of sexual activity and sexual motivation.

Functional imaging of brain activity in conscious monkeys responding to sexually arousing cues

Olfactory cues can elicit intense emotional responses. This study used fMRI in male common marmoset monkeys to identify brain areas associated with sexual arousal in response to odors of ovulating female monkeys. Under light anesthesia, monkeys were secured in a specially designed restrainer and positioned in a 9.4 T magnetic resonance spectrometer. When fully conscious, they were presented with the scents of both ovariectomized and ovulating monkeys. The sexually arousing odors of the ovulating monkeys enhanced signal intensity in the preoptic area and anterior hypothalamus compared to the odors of ovariectomized monkeys. These data corroborate previous findings in monkeys based on invasive electrical lesion and stimulation techniques and demonstrate the feasibility of using non-invasive functional imaging on fully conscious common marmosets to study cue-elicited emotional responses.

Neuroendocrine response to female ovulatory odors depends upon social condition in male common marmosets, Callithrix jacchus

Male mammals show rapid behavioral and hormonal responses to signals from sexually receptive females. However, rapid endocrine responses to female signals have not been observed in a nonhuman primate. Here, we tested the behavioral and hormonal response of male common marmosets (Callithrix jacchus) to isolated scent secretions from ovulatory females or to vehicle control scent. Fifteen males were tested in their home cage for behavioral and hormonal responses. These males showed increased investigative and arousal behaviors to the ovulatory scent compared to the vehicle scent. Time sniffing the scent substrate and the duration of erections were significantly elevated in relation to the vehicle scent. Thirty minutes after presentation of ovulatory scent, males showed a significant increase in testosterone compared to the vehicle, but there was no difference in cortisol values. To better control for scent presentation, 15 additional males were tested under a controlled scent exposure. Current social housing condition influenced the males testosterone response to the ovulatory scent. Single and paired males showed significant increases in testosterone levels with the ovulatory scent but did not increase cortisol levels. Single males also showed the highest change in testosterone with the ovulatory scent, but fathers showed no changes. These results indicate that a rapid hormonal response to sexually arousing cues occurs in marmosets, and the data suggest that a males social condition influences how he responds to sexually relevant cues.

Adaptations to subordinate status in female marmoset monkeys

In singular cooperatively breeding mammals, social status is a key determinant of female reproductive success. Usually only one dominant female breeds in a social group. In the common marmoset (Callithrix jacchus), a cooperatively breeding primate, adaptations to nonbreeding subordinate status appear to parallel those found in social insect societies which demonstrate similar skew to the marmoset in female reproductive success. Female marmosets exhibit rank-related polyethism in behavior, reproductive neuroendocrinology and non-reproductive physiology, and subordinates participate in alloparental care and territory defense. Olfactory, visual and behavioral cues from dominant female marmosets provide important proximate cues regulating ovarian inhibition in female subordinates. Cooperatively breeding marmosets, therefore, appear to have developed specific neural and neuroendocrine adaptations to subordinate social status analogous to those found in social insects such as the lower wasps, bees and termites. Such parallel developments probably reflect the outcome of repeated convergent evolutionary attempts at adapting to environmental conditions not readily conducive to dispersal and independent breeding.

Highly efficient maternal-fetal Zika virus transmission in pregnant rhesus macaques

Infection with Zika virus (ZIKV) is associated with human congenital fetal anomalies. To model fetal outcomes in nonhuman primates, we administered Asian-lineage ZIKV subcutaneously to four pregnant rhesus macaques. While non-pregnant animals in a previous study contemporary with the current report clear viremia within 10–12 days, maternal viremia was prolonged in 3 of 4 pregnancies. Fetal head growth velocity in the last month of gestation determined by ultrasound assessment of head circumference was decreased in comparison with biparietal diameter and femur length within each fetus, both within normal range. ZIKV RNA was detected in tissues from all four fetuses at term cesarean section. In all pregnancies, neutrophilic infiltration was present at the maternal-fetal interface (decidua, placenta, fetal membranes), in various fetal tissues, and in fetal retina, choroid, and optic nerve (first trimester infection only). Consistent vertical transmission in this primate model may provide a platform to assess risk factors and test therapeutic interventions for interruption of fetal infection. The results may also suggest that maternal-fetal ZIKV transmission in human pregnancy may be more frequent than currently appreciated.

Behavioral and social correlates of escape from suppression of ovulation in female common marmosets housed with the natal family.

Although female common marmosets typically do not breed while housed with their natal families, up to half ovulate at least once while housed with the intact natal family, and a similar proportion conceive if an unrelated adult male is present in the group. In this study, we investigated the behavioral and social correlates of escape from suppression of ovulation by daughters housed in intact natal families or in families in which the father had been replaced by an unrelated adult male. Focal‐animal behavioral data were collected from daughters that were (N = 7) or were not (N = 10) undergoing ovulatory cycles while housed with the natal family and from daughters that were (N = 5) or were not (N = 3) cycling or pregnant in families containing an unrelated male. Additionally, four cyclic and six acyclic females housed in intact natal families underwent simulated “prospecting” tests. Cyclic and acyclic daughters in intact natal families did not engage in sexual interactions with the father and showed few differences from one another in their interactions with the parents. Moreover, cyclic and acyclic daughters did not differ in their willingness to leave the family for short periods or to investigate an unfamiliar family in “prospecting” tests. However, daughters that underwent ovarian cycles in the presence of an unrelated male showed numerous behavioral differences from those in intact natal families, including frequent courtship and sexual behaviors with the male, reduced affiliative interactions with the mother, and elevated frequencies of aggressive display behavior. Moreover, these females were less likely to behave submissively towards the mother or the adult male. These findings suggest that both suppression of ovulation and inhibition of sexual behavior normally contribute to reproductive failure in female marmosets living with their natal families, and that the two components of suppression may become dissociated under specific social conditions. Am J Primatol 41:1–21, 1997.