The role of Zika virus (ZIKV) immunity on subsequent dengue virus (DENV) infections is relevant to anticipate the dynamics of forthcoming DENV epidemics in areas with previous ZIKV exposure. We study the effect of ZIKV infection with... more
The role of Zika virus (ZIKV) immunity on subsequent dengue virus (DENV) infections is relevant to anticipate the dynamics of forthcoming DENV epidemics in areas with previous ZIKV exposure. We study the effect of ZIKV infection with various strains on subsequent DENV immune response after 10 and 2 months of ZIKV infection in rhesus macaques. Our results show that a subsequent DENV infection in animals with early- and middle-convalescent periods to ZIKV do not promote an increase in DENV viremia nor pro-inflammatory status. Previous ZIKV exposure increases the magnitude of the antibody and T cell responses against DENV, and different time intervals between infections alter the magnitude and durability of such responses—more after longer ZIKV pre-exposure. Collectively, we find no evidence of a detrimental effect of ZIKV immunity in a subsequent DENV infection. This supports the implementation of ZIKV vaccines that could also boost immunity against future DENV epidemics.
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The four dengue virus serotypes co-circulate globally and cause significant human disease. Dengue vaccine development is challenging because some virus-specific antibodies are protective, while others are implicated in enhanced viral... more
The four dengue virus serotypes co-circulate globally and cause significant human disease. Dengue vaccine development is challenging because some virus-specific antibodies are protective, while others are implicated in enhanced viral replication and more severe disease. Current dengue tetravalent vaccines contain four live attenuated serotypes formulated to theoretically induce balanced protective immunity. Among the number of vaccine candidates in clinical trials, only Dengvaxia is licensed for use in DENV seropositive individuals. To simplify live-virus vaccine design, we identify co-evolutionary constraints inherent in flavivirus virion assembly and design chimeric viruses to replace domain II (EDII) of the DENV2 envelope (E) glycoprotein with EDII from DENV4. The chimeric DENV2/4EDII virus replicates efficiently in vitro and in vivo. In male macaques, a single inoculation of DENV2/4EDII induces type-specific neutralizing antibodies to both DENV2 and DENV4, thereby providing a st...
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Increasing age is associated with dysregulated immune function and increased inflammation– patterns that are also observed in individuals exposed to chronic social adversity. Yet we still know little about how social adversity impacts the... more
Increasing age is associated with dysregulated immune function and increased inflammation– patterns that are also observed in individuals exposed to chronic social adversity. Yet we still know little about how social adversity impacts the immune system and how it might promote age-related diseases. Here, we investigated how immune cell diversity varied with age, sex and social adversity (operationalized as low social status) in free-ranging rhesus macaques. We found age-related signatures of immunosenescence, including lower proportions of CD20+ B cells, CD20+/CD3+ ratio, and CD4+/CD8+ T cell ratio – all signs of diminished antibody production. Age was associated with higher proportions of CD3+/CD8+ Cytotoxic T cells, CD16+/CD3-Natural Killer cells, CD3+/CD4+/CD25+ and CD3+/CD8+/CD25+ T regulatory cells, and CD14+/CD16+/HLA-DR+ intermediate monocytes, and lower levels of CD14+/CD16-/HLA-DR+ classical monocytes, indicating greater amounts of inflammation and immune dysregulation. We ...
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Reproduction and survival in most primate species reflects management of both competitive and cooperative relationships. Here, we investigated the links between neuroanatomy and sociality in free-ranging rhesus macaques. In adults, the... more
Reproduction and survival in most primate species reflects management of both competitive and cooperative relationships. Here, we investigated the links between neuroanatomy and sociality in free-ranging rhesus macaques. In adults, the number of social partners predicted the volume of the mid–superior temporal sulcus and ventral-dysgranular insula, implicated in social decision-making and empathy, respectively. We found no link between brain structure and other key social variables such as social status or indirect connectedness in adults, nor between maternal social networks or status and dependent infant brain structure. Our findings demonstrate that the size of specific brain structures varies with the number of direct affiliative social connections and suggest that this relationship may arise during development. These results reinforce proposed links between social network size, biological success, and the expansion of specific brain circuits.
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Purpose: Rhesus macaques (Macaca mulatta) are the premier nonhuman primate model for studying human health and disease. We aimed to investigate if age was associated with ocular features of clinical relevance in a large cohort of... more
Purpose: Rhesus macaques (Macaca mulatta) are the premier nonhuman primate model for studying human health and disease. We aimed to investigate if age was associated with ocular features of clinical relevance in a large cohort of free-ranging rhesus macaques from Cayo Santiago, Puerto Rico. Methods: We evaluated 120 rhesus macaques (73 males, 47 females) aged from 0 to 29 years old (mean±SD: 12.6/6.4) from September to December, 2021. The ophthalmic evaluation included IOP assessment, corneal pachymetry, anterior segment biomicroscopy, A-Scan biometry, automated refraction, and fundus photography after pupil dilation. The effects of age on the outcome variables were investigated through multilevel mixed-effects models adjusted for sex and weight. Results: On average, IOP, pachymetry, axial length, and automated refraction spherical equivalent were 15.47±2.47 mmHg, 474.43±32.21 micras, 19.49±1.24 mm, and 0.30±1.70 D, respectively. Age was significantly associated with pachymetry (Coe...
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Prior exposure to a single serotype of dengue virus (DENV) predisposes individuals to severe disease upon secondary heterologous DENV infection. Here we show that the length of time between DENV/Zika (ZIKV) infections has a qualitative... more
Prior exposure to a single serotype of dengue virus (DENV) predisposes individuals to severe disease upon secondary heterologous DENV infection. Here we show that the length of time between DENV/Zika (ZIKV) infections has a qualitative impact on controlling ZIKV replication. We identified limited but significant differences in the magnitude of the early humoral immune response associated with a period of twelve months but not three months of DENV convalescence. However, their role limiting ZIKV replication is not conclusive. There was no evidence of in vivo antibody-dependent amplification of ZIKV by DENV immunity in any group. We are also showing that the significant differences among groups may be linked to a pre-existing polyfunctional CD4+ T cells response (increased IFN-g and Cd107a before ZIKV infection) and to an early and continuous expansion of the CD4+ effector memory cells early on after ZIKV infection. Those significant differences were associated with a period of 12 mon...
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OBJECTIVE Milk is the first and continued source of ingested Vitamin D. Extensive studies have been carried out in humans measuring Vitamin D in lactating mothers but to date few values have been obtained for milk of non-human primates... more
OBJECTIVE Milk is the first and continued source of ingested Vitamin D. Extensive studies have been carried out in humans measuring Vitamin D in lactating mothers but to date few values have been obtained for milk of non-human primates and none for rhesus monkeys. Consequently. we have determined Vitamin D and antirachitic activity (ARA) in milk samples obtained from 21 rhesus monkeys. METHODS Lactating dams were sampled by hand-stripping. 25(OH)D2, Vitamin D2, 25(OH)D3, Vitamin D3 and ARA were assessed in foremilk using LC-MS/MS techniques. RESULTS 25(OH)D2 and Vitamin D2 were below detectible limits (<0.5 ng/g), 25(OH) D3 =4.2 ± 1.8 ng/ml, Vitamin D3 = 6.1 ± 3.1 ng/ml and ARA = 1080 ± 480 IU/L. CONCLUSION This is the first report of content of Vitamin D and ARA activity in foremilk of the rhesus monkey and can serve as a reference for future studies.
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Research in the basic biology of ageing is increasingly identifying mechanisms and modifiers of ageing in short-lived organisms such as worms and mice. The ultimate goal of such work is to improve human health, particularly in the growing... more
Research in the basic biology of ageing is increasingly identifying mechanisms and modifiers of ageing in short-lived organisms such as worms and mice. The ultimate goal of such work is to improve human health, particularly in the growing segment of the population surviving into old age. Thus far, few interventions have robustly transcended species boundaries in the laboratory, suggesting that changes in approach are needed to avoid costly failures in translational human research. In this review, we discuss both well-established and alternative model organisms for ageing research and outline how research in nonhuman primates is sorely needed, first, to translate findings from shorter-lived organisms to humans, and second, to understand key aspects of ageing that are unique to primate biology. We focus on rhesus macaques as a particularly promising model organism for ageing research due to their social and physiological similarity to humans as well as the existence of key resources t...
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Knowledge of major histocompatibility complex (MHC) composition and distribution in rhesus macaque colonies is critical for management strategies that maximize the utility of this model for biomedical research. Variation within the Mamu-A... more
Knowledge of major histocompatibility complex (MHC) composition and distribution in rhesus macaque colonies is critical for management strategies that maximize the utility of this model for biomedical research. Variation within the Mamu-A and Mamu-B (class I) and DRB, DQA/B, and DPA/B (class II) regions of 379 animals from the Caribbean Primate Research Center's (CPRC) specific pathogen free (SPF) colony was examined using massively parallel sequencing. Analyses of the 7 MHC loci revealed a background of Indian origin with high levels of variation despite past genetic bottlenecks. All loci exhibited mutual linkage disequilibria while conforming to Hardy-Weinberg expectations suggesting the achievement of mutation-selection balance. The CPRC's SPF colony is a significant resource for research on AIDS and other infectious agents. Characterizing colony-wide MHC variability facilitates the breeding and selection of animals bearing desired haplotypes and increases the investigato...
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P. gingivalis (Pg) is an oral pathogen with the ability to induce oral dysbiosis and periodontal disease. Nevertheless, the mechanisms by which mucosal responses to the oral microbiota in the presence of specific pathogens such as Pg... more
P. gingivalis (Pg) is an oral pathogen with the ability to induce oral dysbiosis and periodontal disease. Nevertheless, the mechanisms by which mucosal responses to the oral microbiota in the presence of specific pathogens such as Pg could abrogate the host-microbe symbiotic relationship leading to periodontitis remain unclear. Herein, we identified the Notch-1/PLA-IIA axis as a new molecular pathway through which Pg could be specifically modulating oral epithelial antimicrobial and inflammatory responses. Pg activated Notch-1, and inhibition or silencing of Notch-1 completely abrogated Pg-induced PLA-IIA in oral epithelial cells (OECs). Activation of Notch-1 and PLA-IIA production were associated with Pg-produced gingipains. Other oral Gram-positive and Gram-negative species failed to induce similar responses. Pg enhanced OEC antimicrobial activity through PLA-IIA. Increased Notch-1 activation correlated with higher PLA-IIA gingival expression and changes in the abundance of specif...
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The rhesus macaque population at Cayo Santiago increases annually and is in urgent need of control. In-depth assessments of the colony's population genetic and pedigree structures provide a starting point for improving the... more
The rhesus macaque population at Cayo Santiago increases annually and is in urgent need of control. In-depth assessments of the colony's population genetic and pedigree structures provide a starting point for improving the colony's long-term management program. We evaluated the degree of genetic variation and coefficients of inbreeding and kinship of the Cayo Santiago colony by using pedigree and short tandem repeat (STR) data from 4738 rhesus macaques, which represent 7 extant social groups and a group of migrant males. Information on each animal's parentage, sex, birth date, and date of death or removal from the island were used to generate estimates of mean kinship, kinship value, gene value, genome uniqueness (GU), founder equivalents (fe), and founder genome equivalents (fg). Pedigree and STR analyses revealed that the social groups have not differentiated genetically from each other due to male-mediated gene flow (that is, FST estimates were in the negative range) ...
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Zika virus (ZIKV) is a re-emerging virus that has recently spread into dengue virus (DENV) endemic regions and cross-reactive antibodies (Abs) could potentially affect ZIKV pathogenesis. Using DENV-immune serum, it has been shown in vitro... more
Zika virus (ZIKV) is a re-emerging virus that has recently spread into dengue virus (DENV) endemic regions and cross-reactive antibodies (Abs) could potentially affect ZIKV pathogenesis. Using DENV-immune serum, it has been shown in vitro that antibody-dependent enhancement (ADE) of ZIKV infection can occur. Here we study the effects of pre-existing DENV immunity on ZIKV infection in vivo. We infect two cohorts of rhesus macaques with ZIKV; one cohort has been exposed to DENV 2.8 years earlier and a second control cohort is naïve to flaviviral infection. Our results, while confirming ADE in vitro, suggest that pre-existing DENV immunity does not result in more severe ZIKV disease. Rather our results show a reduction in the number of days of ZIKV viremia compared to naïve macaques and that the previous exposure to DENV may result in modulation of the immune response without resulting in enhancement of ZIKV pathogenesis.
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The SPF breeding program at the Caribbean Primate Research Center supplies Indian-origin rhesus macaques of known genetic and virologic background for biomedical research. In this study, population genetic analyses using 14 short... more
The SPF breeding program at the Caribbean Primate Research Center supplies Indian-origin rhesus macaques of known genetic and virologic background for biomedical research. In this study, population genetic analyses using 14 short tandemrepeat sequences showed that the SPF colony has remained genetically homogenous over time, with sufficient amounts of heterozygosity and minimal stratification from its founders. Intergenerational studies indicated that an average of 7 alleles have been retained, inbreeding levels have remained low, and the degree of Indian ancestry is one of the highest among several national primate research centers. The relative low genetic diversity in the free-ranging population as well as in the captive SPF and conventional colonies when compared with that of other primate centers indicates that the free-ranging population, from which the captive-colony animals were derived, has experienced significant founder effects and genetic drift during the years after its...
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The goal of this study was to characterize acute neuronal injury in a novel nonhuman primate (NHP) ischemic stroke model by using multiple outcome measures. Silk sutures were inserted into the M1 segment of the middle cerebral artery of... more
The goal of this study was to characterize acute neuronal injury in a novel nonhuman primate (NHP) ischemic stroke model by using multiple outcome measures. Silk sutures were inserted into the M1 segment of the middle cerebral artery of rhesus macaques to achieve permanent occlusion of the vessel. The sutures were introduced via the femoral artery by using endovascular microcatheterization techniques. Within hours after middle cerebral artery occlusion (MCAO), infarction was detectable by using diffusion-weighted MRI imaging. The infarcts expanded by 24 h after MCAO and then were detectable on T2-weighted images. The infarcts seen by MRI were consistent with neuronal injury demonstrated histologically. Neurobehavioral function after MCAO was determined by using 2 neurologic testing scales. Neurologic assessments indicated that impairment after ischemia was limited to motor function in the contralateral arm; other neurologic and behavioral parameters were largely unaffected. We also ...
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Magnetic Resonance Imaging, Cytokines, Comparative Medicine, Catheterization, Western blotting, and 10 moreBiological Sciences, Stroke, Animals, Neurons, Microarray Analysis, Macaca Mulatta, Psychomotor Disorders, Enzyme Linked Immunosorbent Assay, Gene expression profiling, and Medical and Health Sciences
We reported previously the absence of systemic infection in a subset of macaques vaccinated with an HIV-1 DNA/MVA vaccine after 18 or more rectal challenges with low (physiologically relevant) doses of SHIV162P3. To further study the... more
We reported previously the absence of systemic infection in a subset of macaques vaccinated with an HIV-1 DNA/MVA vaccine after 18 or more rectal challenges with low (physiologically relevant) doses of SHIV162P3. To further study the apparent protection, we looked for sequestered virus in gut tissues, lymph nodes, spleen, and testes obtained at necropsy using virus co-culture and nested PCR for SIV Gag, Pol and LTR. There was no evidence of sequestered virus in tissues obtained from the four protected macaques. In contrast, at least one tissue from each of 11 infected animals scored positive by one of these sensitive procedures. Activated PBMC from the protected macaques were not inherently resistant to in vitro infection by the challenge virus. These findings demonstrate that some vaccinated macaques appeared to be free from the challenge virus. Therefore, such T cell-based vaccines may provide some protection when challenge virus doses approach physiological equivalencies.
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Flow Cytometry, HIV, Biological Sciences, Animals, Vaccine, and 15 moreDigestive System, Monocytes, Rhesus Monkey, Macaca Mulatta, Simian Immunodeficiency Virus, Lymphocytes, Lymph Node, Enzyme Linked Immunosorbent Assay, Nested PCR, Lymphoid Tissue, Lymph nodes, reverse transcriptase polymerase chain reaction, coculture techniques, Medical and Health Sciences, and Rectum
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Cellular immune responses, particularly those associated with CD3+ CD8+ cytotoxic T lymphocytes (CTL), play a primary role in controlling viral infection, including persistent infection with human immunodeficiency virus type 1 (HIV-1).... more
Cellular immune responses, particularly those associated with CD3+ CD8+ cytotoxic T lymphocytes (CTL), play a primary role in controlling viral infection, including persistent infection with human immunodeficiency virus type 1 (HIV-1). Accordingly, recent HIV-1 vaccine research efforts have focused on establishing the optimal means of eliciting such antiviral CTL immune responses. We evaluated several DNA vaccine formulations, a modified vaccinia virus Ankara vector, and a replication-defective adenovirus serotype 5 (Ad5) vector, each expressing the same codon-optimized HIV-1 gag gene for immunogenicity in rhesus monkeys. The DNA vaccines were formulated with and without one of two chemical adjuvants (aluminum phosphate and CRL1005). The Ad5-gag vector was the most effective in eliciting anti-Gag CTL. The vaccine produced both CD4+ and CD8+ T-cell responses, with the latter consistently being the dominant component. To determine the effect of existing antiadenovirus immunity on Ad5-...
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Immune response, HIV, Biological Sciences, High Frequency, Cell line, and 15 moreHumans, Kidney, Animals, Male, Immunization, DNA vaccines, Human immunodeficiency virus, Genetic Recombination, Macaca Mulatta, DNA vaccine, Epitopes, Enzyme Linked Immunosorbent Assay, Humoral Immunity, Medical and Health Sciences, and HIV infections
Six rhesus macaques were adapted to morphine dependence by injecting three doses of morphine (5 mg/kg of body weight) for a total of 20 weeks. These animals along with six control macaques were infected intravenously with mixture of... more
Six rhesus macaques were adapted to morphine dependence by injecting three doses of morphine (5 mg/kg of body weight) for a total of 20 weeks. These animals along with six control macaques were infected intravenously with mixture of simian-human immunodeficiency virus KU-1B (SHIVKU-1B), SHIV89.6P, and simian immunodeficiency virus 17E-Fr. Levels of circulating CD4+ T cells and viral loads in the plasma and the cerebrospinal fluid were monitored in these macaques for a period of 12 weeks. Both morphine and control groups showed precipitous loss of CD4+ T cells. However this loss was more prominent in the morphine group at week 2 (P = 0.04). Again both morphine and control groups showed comparable peak plasma viral load at week 2, but the viral set points were higher in the morphine group than that in the control group. Likewise, the extent of virus replication in the cerebral compartment was more pronounced in the morphine group. These results provide a definitive evidence for a posi...
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Alcohol abuse constitutes a major cohort among HIV-infected individuals. The precise effect of alcohol addiction on HIV pathogenesis remains inconclusive, however. This study was designed to determine the effect of alcohol dependence on... more
Alcohol abuse constitutes a major cohort among HIV-infected individuals. The precise effect of alcohol addiction on HIV pathogenesis remains inconclusive, however. This study was designed to determine the effect of alcohol dependence on virus replication and CD4 profiles in simian immunodeficiency virus/simian-HIV-infected rhesus macaques. A group of 3 male Indian rhesus macaques was adapted to a self-drinking model of alcohol consumption, whereas another group of 3 macaques was provided a Nutrasweet solution. After 7 weeks of alcohol consumption, the alcohol-dependent animals along with controls were intravenously inoculated with a mixture of SHIV(KU), SHIV(89.6)P, and SIV/17E-Fr. These animals were followed for a period of 24 weeks for complete blood cell counts, CD4 cell profiles, and viral loads in the blood and cerebral compartments. The alcohol and control groups showed comparable peak viral loads in the blood. The plasma viral load in the alcohol group was 31- to 85-fold higher than that in the control group at weeks 18 through 24 after infection, however. The pattern of cerebrospinal fluid viral replication was also comparable during the acute phase; however, the virus continued to replicate in the brain of alcohol-dependent animals, whereas it became undetectable in the controls. The extent of CD4 cell loss in the alcohol group was significantly higher than that in the control animals at week 1 after infection.