Priming B cell-mediated anti-HIV envelope responses by vaccination allows for the long-term control of infection in macaques exposed to a R5-tropic SHIV

The potential of vaccine-elicited anti-HIV envelope antibodies to control HIV-infection was evaluated by immunizing macaques with the HIV envelope protein and transiently depleting them of their CD8+ cells before intravenous challenge with the pathogenic CCR5-tropic SIV/HIV chimeric virus, SHIV(SF162P4). Although sterilizing immunity was not achieved, all vaccinated animals effectively controlled infection and remained free of disease for the duration of observation (over 3 years). In contrast, during the same period, the control animals progressed to disease. Both the vaccinees and the controls developed robust cell-mediated antiviral and neutralizing antibody responses following infection. A comparative analysis of these responses suggests that the more effective long-term control of infection by the vaccinated animals is due to the more rapid development of anti-HIV envelope antibodies. These studies suggest that priming by vaccination of B cell anti-HIV envelope responses maybe crucial for the long-term control of HIV infection.     

Effects of social factors on adrenal weight and related physiology of Macaca fascicularis

Increased adrenal cortical activity and hypertrophy of adrenal glands associated with defeat and social subordination have been reported frequently in small mammals; these adrenal changes have been linked to impairments in immune response, glucose metabolism and reproductive performance. Similar studies in primates have produced variable results. The current study was undertaken to illuminate the effects of social status on the adrenal gland and to examine concurrent effects of social variables on other physiological systems in Macaca fascicularis, in an initial exploration of the hypothesis that high and low social status have different physiological consequences. Sixty adult male M. fascicularis were housed in social groups of n = 5, under either stable or unstable social conditions. It was found that subordinate animals had heavier adrenal glands and somewhat higher plasma glucose concentrations than dominants. In contrast, dominants had higher blood pressure and worsened atherosclerosis, under some conditions, than subordinates. These data appear to offer preliminary support for Henry and Stephen's hypothesis of differential arousal of dominant and subordinate animals.     

皮下注射MPTP诱导猕猴双侧慢性帕金森病模型的制作

目的探讨猕猴双侧慢性不可逆性帕金森病（PD）模型的制作方法。方法 4只猕猴分别采用不同剂量（0.1 mg/kg/d和0.4 mg/kg/d）和不同频率（每天一次和隔天一次）及不同次数皮下注射1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）制作PD模型,注射MPTP前后观察行为学表现并进行非人类灵长类PD评分量表（PPRS）评分。结果猕猴注射MPTP一段时间后开始出现PD症状,主要表现为倦怠、迟缓;继续给药PD症状会出现进行性快速加重导致后续动物因进食困难而死亡;若过早停止给药,则导致PD模型不稳定,动物症状可自愈。采用剂量为0.1 mg/kg/d的MPTP连续皮下注射14 d后,猕猴出现中度PD症状（PPRS评分为6~8分）时,改隔日注射一次,共4次,猕猴出现不可逆性PD症状,且可自主摄食并长期存活,是一个成功的模型。结论适量皮下注射MPTP可制作猕猴慢性、不可逆性、双侧PD模型,其更接近人PD的临床特征,且无需鼻饲喂养可长期存活。     

Four-gene-combination DNA vaccine protects mice against a lethal vaccinia virus challenge and elicits appropriate antibody responses in nonhuman primates

Two major infectious forms of vaccinia virus (VACV) have been described: the intracellular mature virion (IMV), and the extracellular enveloped virion (EEV). Due to their stability in the environment, IMVs play a predominant role in host-to-host transmission, whereas EEVs play an important role in dissemination within the host. In a previous report, we demonstrated that mice vaccinated with VACV L1R (IMV immunogen) and A33R (EEV immunogen) were protected from a lethal poxvirus challenge. Vaccination with a combination of both genes conferred greater protection than either gene alone, suggesting that an immune response against both IMV and EEV is advantageous. Here, we report that in mice individually administered DNA vaccines with two different VACV immunogens, A27L (IMV immunogen) or B5R (EEV immunogen), failed to significantly protect; however, vaccination with a combination of both genes conferred a high level of protection. Mice were completely protected when vaccinated with a combination of four VACV genes (A27L + A33R + L1R + B5R). Rhesus macaques vaccinated with this four-gene-combination developed appropriate antibody responses to each protein. Antibody responses elicited by this vaccine cross-reacted with monkeypox virus orthologous proteins. These data indicate that a gene-based vaccine comprised of the VACV A27L + A33R + L1R + B5R genes may be a useful candidate to protect against other orthopoxviruses, including those that cause monkeypox and smallpox.     

Rearing experiences and stress-induced plasma cortisol as early risk factors for excessive alcohol consumption in nonhuman primates

BACKGROUND: The purpose of this study was to assess the impact of early rearing and stress-induced rise of plasma cortisol collected during infancy as a biological predictors of adult alcohol consumption in nonhuman primates. METHODS: Ninety-seven female and male rhesus macaques (Macaca mulatta) were investigated. They were reared for their first 6 months of life either without mothers or other adults but with constant access to same-aged peers (peer-reared), or as controls with their mothers (mother-reared). When subjects reached 6 months of age, they underwent a series of four sequential weeks of 4-day social separations. Blood was drawn 1 and 2 hr after initiation of the 4-day separation periods, and the plasma was assayed for plasma cortisol concentrations. When the subjects were young adults (approximately 50 months of age), they were tested for voluntary intake of alcohol for 1 hr per day, 4 days a week, during a period of 5 to 7 weeks under normal living conditions. RESULTS: The social separation challenge increased infant plasma cortisol concentrations, with peer-reared subjects exhibiting higher stress-induced cortisol concentrations than mother-reared animals. Subjects that responded to the social separation challenge with high cortisol levels consumed significantly more alcohol per kilogram of body weight as adults than subjects with a low cortisol response to the separation challenge, regardless of rearing condition. In addition, male and peer-reared subjects consumed significantly more alcohol than female and mother-reared subjects, respectively. CONCLUSIONS: These findings suggest that early rearing experiences, such as adult absence, and high plasma cortisol concentrations early in life after a social separation stressor, are useful psychobiological predictors of future high alcohol consumption among nonhuman primates.     

Mechanisms of Visual Perceptual Learning in Macaque Visual Cortex

The neural mechanisms underlying behavioral improvement in the detection or discrimination of visual stimuli following learning are still ill understood. Studies in nonhuman primates have shown relatively small and, across studies, variable effects of fine discrimination learning in primary visual cortex when tested outside the context of the learned task. At later stages, such as extrastriate area V4, extensive practice in fine discrimination produces more consistent effects upon responses and neural tuning. In V1 and V4, the effects of learning were most prominent in those neurons that can contribute the most reliable information about the trained stimuli. I suggest that, depending on the particulars of the task demands, neurons at various stages of stimulus and task processing can change their tuning and responses, so that execution of the task will produce a higher frequency of reward. I speculate that the sort of changes that will occur depend on the task and on stimulus analysis requirements, and they may vary from changes in bottom‐up stimulus processing/tuning within early visual areas or more efficient readout of early visual areas to top‐down driven changes in response properties of these areas.     

Long peptides induce polyfunctional T cells against conserved regions of HIV‐1 with superior breadth to single‐gene vaccines in macaques

A novel T‐cell vaccine strategy designed to deal with the enormity of HIV‐1 variation is described and tested for the first time in macaques to inform and complement approaching clinical trials. T‐cell immunogen HIVconsv, which directs vaccine‐induced responses to the most conserved regions of the HIV‐1, proteome and thus both targets diverse clades in the population and reduces the chance of escape in infected individuals, was delivered using six different vaccine modalities: plasmid DNA (D), attenuated human (A) and chimpanzee (C) adenoviruses, modified vaccinia virus Ankara (M), synthetic long peptides, and Semliki Forest virus replicons. We confirmed that the initial DDDAM regimen, which mimics one of the clinical schedules (DDDCM), is highly immunogenic in macaques. Furthermore, adjuvanted synthetic long peptides divided into sub‐pools and delivered into anatomically separate sites induced T‐cell responses that were markedly broader than those elicited by traditional single‐open‐reading‐frame genetic vaccines and increased by 30% the overall response magnitude compared with DDDAM. Thus, by improving both the HIV‐1‐derived immunogen and vector regimen/delivery, this approach could induce stronger, broader, and theoretically more protective T‐cell responses than vaccines previously used in humans.     

Differential effects of ovarian steroids and raloxifene on serotonin 1A and 2C receptor protein expression in macaques

To further understand the role of ovarian hormones in the function of the serotonin neural system, we investigated the effects of estradiol (E), progesterone (P), and raloxifene on 5HT 1A and 2C receptor protein expression in the dorsal raphe region using Western blot analysis. Adult rhesus macaques (Macaca mulatta) were ovariectomized (Ovx) and implanted with Silastic capsules containing E or P. In the first paradigm, animals that had been Ovx for 6–16 months were treated for 1 month with E (E1) or E + P (EP1) and compared to animals that were untreated and Ovx for 5 months (n = 4 per group). In the second paradigm, comparisons were made between animals that were Ovx and untreated for 5 months, or Ovx and immediately implanted with Silastic capsules containing E or E + P for 5 months (E5, EP5), or administered raloxifene in the diet for 5 months (Ral5) (n = 4 per group). The dorsal raphe region was harvested, homogenized and a crude membrane fraction was obtained for examination of receptor proteins. In the first paradigm, 5HT1A receptor protein expression was significantly lower in E1 and EP1 treatment groups compared to the Ovx-control group (ANOVA P = 0.01; posthoc P < 0.03), but 5HT2C receptor expression was unaffected by 1 month of E or EP treatment. In the second paradigm, there was no difference in 5HT1A receptor expression between the Ovx-control group and the E5 group, but 5HT1A receptor expression was significantly suppressed in the EP5 group (ANOVA P = 0.04; posthoc P < 0.05). In addition, 5HT2C expression increased in the E5 treatment group relative to the Ovx-control group. Addition of P to the E5 regimen prevented the E5-induced increase in 5HT2C receptor expression and significantly reduced 5HT2C receptor expression to a level below that observed in the Ovx-control group (ANOVA P = 0.001; posthoc P < 0.05). Thus, 5HT1A receptor may lose sensitivity to the suppressive effect of E after 5 months, whereas the 5HT2C receptor increases. However, addition of P in the EP5 regimen maintains the regulatory effects observed with 1 month of treatment. 5HT1A receptor protein levels were higher with raloxifene treatment than in Ovx-control animals (P < 0.01), suggesting that raloxifene may antagonize residual E in Ovx animals.     

ATLANTO-OCCIPITAL CEREBROSPINAL FLUID COLLECTION IN MACAQUES

Cerebrospinal fluid (CSF) evaluation can yield important information in behavioral, pharmacologic, and toxic assessment of the nervous system. Recently identified neurotransmitters are available and quantifiable in CSF. CSF collection in macaques is easy to perform and extremely safe for the monkeys. This paper outlines a simple, harmless, and reliable method to collect CSF from the atlanto-occipital cistern of macaques.