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1.
Nat Commun ; 14(1): 8051, 2023 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-38052872

RESUMO

Gene editing strategies for cystic fibrosis are challenged by the complex barrier properties of airway epithelia. We previously reported that the amphiphilic S10 shuttle peptide non-covalently combined with CRISPR-associated (Cas) ribonucleoprotein (RNP) enabled editing of human and mouse airway epithelial cells. Here, we derive the S315 peptide as an improvement over S10 in delivering base editor RNP. Following intratracheal aerosol delivery of Cy5-labeled peptide in rhesus macaques, we confirm delivery throughout the respiratory tract. Subsequently, we target CCR5 with co-administration of ABE8e-Cas9 RNP and S315. We achieve editing efficiencies of up-to 5.3% in rhesus airway epithelia. Moreover, we document persistence of edited epithelia for up to 12 months in mice. Finally, delivery of ABE8e-Cas9 targeting the CFTR R553X mutation restores anion channel function in cultured human airway epithelia. These results demonstrate the therapeutic potential of base editor delivery with S315 to functionally correct the CFTR R553X mutation in respiratory epithelia.


Assuntos
Regulador de Condutância Transmembrana em Fibrose Cística , Células Epiteliais , Animais , Humanos , Camundongos , Macaca mulatta/metabolismo , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Regulador de Condutância Transmembrana em Fibrose Cística/metabolismo , Células Epiteliais/metabolismo , Mucosa Respiratória/metabolismo , Ribonucleoproteínas/metabolismo , Peptídeos/genética , Sistemas CRISPR-Cas
2.
PLoS One ; 18(10): e0287377, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37856429

RESUMO

We assessed the humoral immune responses to a COVID-19 vaccine in a well-controlled rhesus macaque model compared to humans immunized with two mRNA vaccines over several months post-second dose. The plasma IgG levels against seven coronaviruses (including SARS-CoV-2) and antibody subtypes (IgG 1-4 and IgM) against SARS-CoV-2 were evaluated using multiplex assays. The neutralization capacity of plasma antibodies against the original SAR-CoV-2 isolate and nine variants was evaluated in vaccinated humans and non-human primates. Immunization of macaques and humans with SARS-CoV-2 vaccines induced a robust neutralizing antibody response. In non-SIV-infected adult macaques immunized with an adenoviral vector expressing S-RBD (n = 7) or N protein (n = 3), elevated levels of IgG and neutralizing antibodies were detected 2 weeks post-second dose. Immune responses to the S-RBD vaccine in SIV-infected adult macaques (n = 2) were similar to the non-SIV-infected animals. Adult humans immunized with Pfizer (n = 35) or Moderna (n = 18) vaccines developed IgG and neutralizing antibodies at 4 weeks post-second dose. In both vaccine groups, IgG 1 was the predominant subtype, followed by IgG 3. The IgG levels, including total and IgG 1,2,3 elicited by the Moderna vaccine, were significantly higher than the corresponding levels elicited by the Pfizer vaccine at 4 weeks post-second dose. A significant correlation was observed between the plasma total IgG antibody levels and neutralization titers in both macaques and humans. Furthermore, broad-spectrum neutralization antibodies against several variants of SARS-CoV-2 were detected in the plasma of both macaques and humans after two vaccinations.


Assuntos
Vacinas contra COVID-19 , COVID-19 , Adulto , Animais , Humanos , Macaca mulatta , COVID-19/prevenção & controle , SARS-CoV-2 , Imunoglobulina G , Anticorpos Neutralizantes , Vacinação , Anticorpos Amplamente Neutralizantes , Imunidade , Anticorpos Antivirais
3.
J Immunol ; 211(3): 443-452, 2023 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-37314415

RESUMO

"Adaptive" NK cells, characterized by FcRγ deficiency and enhanced responsiveness to Ab-bound, virus-infected cells, have been found in certain hCMV-seropositive individuals. Because humans are exposed to numerous microbes and environmental agents, specific relationships between hCMV and FcRγ-deficient NK cells (also known as g-NK cells) have been challenging to define. Here, we show that a subgroup of rhesus CMV (RhCMV)-seropositive macaques possesses FcRγ-deficient NK cells that stably persist and display a phenotype resembling human FcRγ-deficient NK cells. Moreover, these macaque NK cells resembled human FcRγ-deficient NK cells with respect to functional characteristics, including enhanced responsiveness to RhCMV-infected target in an Ab-dependent manner and hyporesponsiveness to tumor and cytokine stimulation. These cells were not detected in specific pathogen-free (SPF) macaques free of RhCMV and six other viruses; however, experimental infection of SPF animals with RhCMV strain UCD59, but not RhCMV strain 68-1 or SIV, led to induction of FcRγ-deficient NK cells. In non-SPF macaques, coinfection by RhCMV with other common viruses was associated with higher frequencies of FcRγ-deficient NK cells. These results support a causal role for specific CMV strain(s) in the induction of FcRγ-deficient NK cells and suggest that coinfection by other viruses further expands this memory-like NK cell pool.


Assuntos
Coinfecção , Infecções por Citomegalovirus , Viroses , Animais , Humanos , Citomegalovirus/genética , Macaca mulatta , Células Matadoras Naturais
4.
Bioengineering (Basel) ; 10(5)2023 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-37237620

RESUMO

Transplantation of allogeneic donor ovarian tissue holds great potential for female cancer survivors who often experience premature ovarian insufficiency. To avoid complications associated with immune suppression and to protect transplanted ovarian allografts from immune-mediated injury, we have developed an immunoisolating hydrogel-based capsule that supports the function of ovarian allografts without triggering an immune response. Encapsulated ovarian allografts implanted in naïve ovariectomized BALB/c mice responded to the circulating gonadotropins and maintained function for 4 months, as evident by regular estrous cycles and the presence of antral follicles in the retrieved grafts. In contrast to non-encapsulated controls, repeated implantations of encapsulated mouse ovarian allografts did not sensitize naïve BALB/c mice, which was confirmed with undetectable levels of alloantibodies. Further, encapsulated allografts implanted in hosts previously sensitized by the implantation of non-encapsulated allografts restored estrous cycles similarly to our results in naïve recipients. Next, we tested the translational potential and efficiency of the immune-isolating capsule in a rhesus monkey model by implanting encapsulated ovarian auto- and allografts in young ovariectomized animals. The encapsulated ovarian grafts survived and restored basal levels of urinary estrone conjugate and pregnanediol 3-glucuronide during the 4- and 5-month observation periods. We demonstrate, for the first time, that encapsulated ovarian allografts functioned for months in young rhesus monkeys and sensitized mice, while the immunoisolating capsule prevented sensitization and protected the allograft from rejection.

5.
bioRxiv ; 2023 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-37205470

RESUMO

Treatment of people with HIV (PWH) with antiretroviral therapy (ART) results in sustained suppression of viremia, but HIV persists indefinitely as integrated provirus in CD4-expressing cells. Intact persistent provirus, the "rebound competent viral reservoir" (RCVR), is the primary obstacle to achieving a cure. Most variants of HIV enter CD4 + T cells by binding to the chemokine receptor, CCR5. The RCVR has been successfully depleted only in a handful of PWH following cytotoxic chemotherapy and bone marrow transplantation from donors with a mutation in CCR5 . Here we show that long-term SIV remission and apparent cure can be achieved for infant macaques via targeted depletion of potential reservoir cells that express CCR5. Neonatal rhesus macaques were infected with virulent SIVmac251, then treated with ART beginning one week after infection, followed by treatment with either a CCR5/CD3-bispecific or a CD4-specific antibody, both of which depleted target cells and increased the rate of plasma viremia decrease. Upon subsequent cessation of ART, three of seven animals treated with CCR5/CD3-bispecific antibody rebounded quickly and two rebounded 3 or 6 months later. Remarkably, the other two animals remained aviremic and efforts to detect replication-competent virus were unsuccessful. Our results show that bispecific antibody treatment can achieve meaningful SIV reservoir depletion and suggest that functional HIV cure might be achievable for recently infected individuals having a restricted reservoir.

6.
J Virol ; 97(2): e0165522, 2023 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-36719240

RESUMO

The implementation and access to combined antiretroviral treatment (cART) have dramatically improved the quality of life of people living with HIV (PLWH). However, some comorbidities, such as neurological disorders associated with HIV infection still represent a serious clinical challenge. Soluble factors in plasma that are associated with control of HIV replication and neurological dysfunction could serve as early biomarkers and as new therapeutic targets for this comorbidity. We used a customized antibody array for determination of blood plasma factors in 40 untreated PLWH with different levels of viremia and found sirtuin-2 (SIRT2), an NAD-dependent deacetylase, to be strongly associated with elevated viral loads and HIV provirus levels, as well as with markers of neurological damage (a-synuclein [SNCA], brain-derived neurotrophic factor [BDNF], microtubule-associated protein tau [MAPT], and neurofilament light protein [NFL]). Also, longitudinal analysis in HIV-infected individuals with immediate (n = 9) or delayed initiation (n = 10) of cART revealed that after 1 year on cART, SIRT2 plasma levels differed between both groups and correlated inversely with brain orbitofrontal cortex involution. Furthermore, targeting SIRT2 with specific small-molecule inhibitors in in vitro systems using J-LAT A2 and primary glial cells led to diminished HIV replication and virus reactivation from latency. Our data thus identify SIRT2 as a novel biomarker of uncontrolled HIV infection, with potential impact on neurological dysfunction and offers a new therapeutic target for HIV treatment and cure. IMPORTANCE Neurocognitive disorders are frequently reported in people living with HIV (PLWH) even with the introduction of combined antiretroviral treatment (cART). To identify biomarkers and potential therapeutic tools to target HIV infection in peripheral blood and in the central nervous system (CNS), plasma proteomics were applied in untreated chronic HIV-infected individuals with different levels of virus control. High plasma levels of sirtuin-2 (SIRT2), an NAD+ deacetylase, were detected in uncontrolled HIV infection and were strongly associated with plasma viral load and proviral levels. In parallel, SIRT2 levels in the peripheral blood and CNS were associated with markers of neurological damage and brain involution and were more pronounced in individuals who initiated cART later in infection. In vitro infection experiments using specific SIRT2 inhibitors suggest that specific targeting of SIRT2 could offer new therapeutic treatment options for HIV infections and their associated neurological dysfunction.


Assuntos
Infecções por HIV , Doenças do Sistema Nervoso , Sirtuína 2 , Humanos , Biomarcadores , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , HIV-1 , Proteínas de Neurofilamentos/metabolismo , Provírus/metabolismo , Qualidade de Vida , Sirtuína 2/metabolismo , Doenças do Sistema Nervoso/tratamento farmacológico , Doenças do Sistema Nervoso/etiologia , Doenças do Sistema Nervoso/virologia , Carga Viral
7.
Front Immunol ; 13: 1027855, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36466823

RESUMO

The contribution of the HLA-E/NKG2X axis in NK-mediated control of HIV infection remains unclear. We have studied the relationship between HLA-E expression and phenotypical as well as functional characteristics of NK cells, in the context of chronic HIV infection and in an in vitro model of acute infection. High viremia in HIV+ individuals was related to increased HLA-E expression, and changes in NK subpopulations, especially a reduction of the CD56bright as well as an increase in adaptive NK subpopulation. Uncontrolled HIV infection was also characterized by a reversion of the NKG2A/NKG2C expression ratio and a loss of positive and negative regulation of NK mediated by HLA-E. This was reflected in a lower cytotoxic, degranulation and cytokine production capacity, especially in CD56bright and adaptive NK. In line with these results, HLA-E expression showed a positive correlation with viral growth inhibition in an in vitro model of acute infection at day 7, which was lost after 14 days of culture. Using HLA-E expressing K562 cells, we determined that only one out of 11 described HIV-derived HLA-E epitopes increased HLA-E surface stability. In spite of that, eight of the 11 epitopes were capable of increasing degranulation and three drove differences in NK-cell mediated cell lysis or cytokine secretion. In conclusion, our results indicate that HLA-E molecules presenting HIV-derived epitopes may sensitize target cells for NK lysis in early HIV infection. However, prolonged exposure to elevated HLA-E expression levels in vivo may lead to NK cell dysfunction and reduced viral control In chronic infection.


Assuntos
Infecções por HIV , Humanos , Viremia , Epitopos , Citocinas , Antígenos HLA-E
8.
Microbiome ; 10(1): 168, 2022 10 10.
Artigo em Inglês | MEDLINE | ID: mdl-36210471

RESUMO

BACKGROUND: Both the gut microbiota and chronic viral infections have profound effects on host immunity, but interactions between these influences have been only superficially explored. Cytomegalovirus (CMV), for example, infects approximately 80% of people globally and drives significant changes in immune cells. Similarly, certain gut-resident bacteria affect T-cell development in mice and nonhuman primates. It is unknown if changes imposed by CMV on the intestinal microbiome contribute to immunologic effects of the infection. RESULTS: We show that rhesus cytomegalovirus (RhCMV) infection is associated with specific differences in gut microbiota composition, including decreased abundance of Firmicutes, and that the extent of microbial change was associated with immunologic changes including the proliferation, differentiation, and cytokine production of CD8+ T cells. Furthermore, RhCMV infection disrupted the relationship between short-chain fatty acid producers and Treg/Th17 balance observed in seronegative animals, showing that some immunologic effects of CMV are due to disruption of previously existing host-microbe relationships. CONCLUSIONS: Gut microbes have an important influence on health and disease. Diet is known to shape the microbiota, but the influence of concomitant chronic viral infections is unclear. We found that CMV influences gut microbiota composition to an extent that is correlated with immunologic changes in the host. Additionally, pre-existing correlations between immunophenotypes and gut microbes can be subverted by CMV infection. Immunologic effects of CMV infection on the host may therefore be mediated by two different mechanisms involving gut microbiota. Video Abstract.


Assuntos
Infecções por Citomegalovirus , Linfócitos T Reguladores , Animais , Linfócitos T CD8-Positivos , Citocinas , Citomegalovirus/genética , Ácidos Graxos Voláteis , Macaca mulatta , Camundongos
9.
Curr Opin HIV AIDS ; 17(6): 333-337, 2022 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-36165078

RESUMO

PURPOSE OF THE REVIEW: Not all T-cell responses against HIV are created equally and responses of certain epitope specificities have been associated with superior control of infection. These insights have spurred the development of a wide range of immunogen sequences, each with particular advantages and limitations. RECENT FINDINGS: We review some of the most advanced designs that have reached or are close to reaching human clinical trials, with a special focus on T-cell immunogen developed for therapeutic use. We also touch upon the importance of how immunogens are delivered and point out the lamentable fact that there is essentially no alignment between different designs and vaccine regimens, which is a major hindrance to accelerated advances in the field. SUMMARY: The design of an immunogen able to induce T-cell responses of adequate specificity and functionality is subject of a wide range of preclinical and clinical studies. Few designs have shown promise to date, but emerging data highlight the critical contribution of specificity to effective antiviral activity in vivo .


Assuntos
Vacinas contra a AIDS , Infecções por HIV , HIV-1 , Antivirais , Epitopos , Infecções por HIV/prevenção & controle , Humanos , Linfócitos T
10.
Front Immunol ; 13: 928039, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35784304

RESUMO

T cell responses are considered critical for the in vivo control of HIV, but the contribution of different T cell subsets to this control remains unclear. Using a boosted flow cytometric approach that is able to differentiate CD4+ and CD8+ T cell Th1/Tc1, Th2/Tc2, Th17/Tc17, Treg and Tfh/Tfc-like HIV-specific T cell populations, we identified CD8+ Tfc responses that were related to HIV plasma viral loads and associated with rate of antibody isotype class switching to IgG. This favorable balance towards IgG responses positively correlated with increased virus neutralization, higher avidity of neutralizing antibodies and more potent antibody-dependent cell cytotoxicity (ADCC) in PBMCs from HIV controllers compared to non-controllers. Our results identified the CD8+ Tfc-like T-cell response as a component of effective virus control which could possibly be exploited therapeutically.


Assuntos
Doença Enxerto-Hospedeiro , Infecções por HIV , Linfócitos T CD8-Positivos , Humanos , Switching de Imunoglobulina , Imunoglobulina G , Infecção Persistente
11.
Front Microbiol ; 13: 836831, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35359743

RESUMO

Human Immunodeficiency Virus-1 (HIV) remains a global health challenge due to the latent HIV reservoirs in people living with HIV (PLWH). Dormant yet replication competent HIV harbored in the resting CD4+ T cells cannot be purged by antiretroviral therapy (ART) alone. One approach of HIV cure is the "Kick and Kill" strategy where latency reversal agents (LRAs) have been implemented to disrupt latent HIV, expecting to eradicate HIV reservoirs by viral cytopathic effect or immune-mediated clearance. Protein Kinase C agonists (PKCa), a family of LRAs, have demonstrated the ability to disrupt latent HIV to an extent. However, the toxicity of PKCa remains a concern in vivo. Early growth response protein 1 (EGR1) is a downstream target of PKCa during latency reversal. Here, we show that PKCa induces EGR1 which directly drives Tat-dependent HIV transcription. Resveratrol, a natural phytoalexin found in grapes and various plants, induces Egr1 expression and disrupts latent HIV in several HIV latency models in vitro and in CD4+ T cells isolated from ART-suppressed PLWH ex vivo. In the primary CD4+ T cells, resveratrol does not induce immune activation at the dosage that it reverses latency, indicating that targeting EGR1 may be able to reverse latency and bypass PKCa-induced immune activation.

12.
PLoS Pathog ; 18(4): e1009925, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35443018

RESUMO

Early in the SARS-CoV-2 pandemic, there was a high level of optimism based on observational studies and small controlled trials that treating hospitalized patients with convalescent plasma from COVID-19 survivors (CCP) would be an important immunotherapy. However, as more data from controlled trials became available, the results became disappointing, with at best moderate evidence of efficacy when CCP with high titers of neutralizing antibodies was used early in infection. To better understand the potential therapeutic efficacy of CCP, and to further validate SARS-CoV-2 infection of macaques as a reliable animal model for testing such strategies, we inoculated 12 adult rhesus macaques with SARS-CoV-2 by intratracheal and intranasal routes. One day later, 8 animals were infused with pooled human CCP with a high titer of neutralizing antibodies (RVPN NT50 value of 3,003), while 4 control animals received normal human plasma. Animals were monitored for 7 days. Animals treated with CCP had detectable but low levels of antiviral antibodies after infusion. In comparison to the control animals, CCP-treated animals had similar levels of viral RNA in upper and lower respiratory tract secretions, similar detection of viral RNA in lung tissues by in situ hybridization, but lower amounts of infectious virus in the lungs. CCP-treated animals had a moderate, but statistically significant reduction in interstitial pneumonia, as measured by comprehensive lung histology. Thus overall, therapeutic benefits of CCP were marginal and inferior to results obtained earlier with monoclonal antibodies in this animal model. By highlighting strengths and weaknesses, data of this study can help to further optimize nonhuman primate models to provide proof-of-concept of intervention strategies, and guide the future use of convalescent plasma against SARS-CoV-2 and potentially other newly emerging respiratory viruses.


Assuntos
COVID-19 , SARS-CoV-2 , Animais , Anticorpos Neutralizantes , Antivirais , COVID-19/terapia , Humanos , Imunização Passiva , Macaca mulatta , RNA Viral , Soroterapia para COVID-19
13.
EBioMedicine ; 78: 103956, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35325780

RESUMO

BACKGROUND: The BCN02-trial combined therapeutic vaccination with a viral latency reversing agent (romidepsin, RMD) in HIV-1-infected individuals and included a monitored antiretroviral pause (MAP) as an efficacy read-out identifying individuals with an early or late (< or > 4weeks) viral-rebound. Integrated -omics analyses were applied prior treatment interruption to identify markers of virus control during MAP. METHODS: PBMC, whole-genome DNA methylation and transcriptomics were assessed in 14 BCN02 participants, including 8 Early and 4 Late viral-rebound individuals. Chromatin state, histone marks and integration analysis (histone-3 acetylation (H3Ac), viral load, proviral levels and HIV-specific T cells responses) were included. REDUC-trial samples (n = 5) were included as a control group for RMD administration alone. FINDINGS: DNA methylation imprints after receiving the complete intervention discriminated Early versus Late viral-rebound individuals before MAP. Also, differential chromatin accessibility and histone marks at DNA methylation level were detected. Importantly, the differential DNA methylation positions (DMPs) between Early and Late rebounders before MAP were strongly associated with viral load, proviral levels as well as the HIV-specific T-cell responses. Most of these DMPs were already present prior to the intervention and accentuated after RMD infusion. INTERPRETATION: This study identifies host DNA methylation profiles and epigenetic cascades that are predictive of subsequent virus control in a kick-and-kill HIV cure strategy. FUNDING: European Union Horizon 2020 Framework Programme for Research and Innovation under Grant Agreement N°681137-EAVI2020 and N°847943-MISTRAL, the Ministerio de Ciencia e Innovación (SAF2017_89726_R), and the National Institutes of Health-National Institute of Allergy and Infectious Diseases Program Grant P01-AI131568.


Assuntos
Infecções por HIV , Vacinas , Antirretrovirais/uso terapêutico , Linfócitos T CD4-Positivos , Cromatina , Epigênese Genética , Infecções por HIV/tratamento farmacológico , Infecções por HIV/genética , Humanos , Leucócitos Mononucleares , Provírus , Vacinas/uso terapêutico , Carga Viral
14.
Viruses ; 14(3)2022 03 19.
Artigo em Inglês | MEDLINE | ID: mdl-35337045

RESUMO

Idiopathic chronic diarrhea (ICD) is a little understood common clinical problem in captive rhesus macaques claiming 33% of medical culls unrelated to research. The eukaryotic virome in digestive tract tissues collected at necropsy from nine animals with ICD was characterized using viral metagenomics. We compared the distribution of viral reads in tissues and mucosal scrapings from the stomach, duodenum, jejunum, ileum, and the proximal, transverse, and distal colons. In situ hybridization (ISH) using viral probes were performed on fixed tissues. Deep sequencing revealed multiple viruses in the Parvoviridae and Picornaviridae family. Tissues and mucosal scraping from the same locations showed closely related viral reads contents while different gut tissues from the same animal varied widely. ISH showed punctuated staining for both RNA and DNA viruses in the distal colon. Parvovirus staining was also detected in the stomach/duodenum/jejunum in distinct oval-shaped structures. The location of enteric viral nucleic acid differed widely between different viral families and along the length of the digestive tract.


Assuntos
Ácidos Nucleicos , Parvovirus , Vírus , Animais , Diarreia/veterinária , Fezes , Humanos , Íleo , Macaca mulatta , Metagenômica , Vírus/genética
15.
Artigo em Inglês | MEDLINE | ID: mdl-35283343

RESUMO

Nonhuman primates are essential for the study of human disease and to explore the safety of new diagnostics and therapies proposed for human use. They share similar genetic, physiologic, immunologic, reproductive, and developmental features with humans and thus have proven crucial for the study of embryonic/fetal development, organ system ontogeny, and the role of the maternal-placental-fetal interface in health and disease. The fetus may be exposed to a variety of inflammatory stimuli including infectious microbes as well as maternal inflammation, which can result from infections, obesity, or environmental exposures. Growing evidence supports that inflammation is a mediator of fetal programming and that the maternal immune system is tightly integrated with fetal-placental immune responses that may set a postnatal path for future health or disease. This review addresses some of the unique features of the nonhuman primate model system, specifically the rhesus monkey (Macaca mulatta), and importance of the species for studies focused on organ system ontogeny and the impact of viral teratogens in relation to development and congenital disorders.


Assuntos
Inflamação , Placenta , Animais , Feminino , Humanos , Macaca mulatta , Gravidez
16.
Annu Rev Anim Biosci ; 10: 441-468, 2022 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-35167321

RESUMO

Nonhuman primates are critically important animal models in which to study complex human diseases, understand biological functions, and address the safety of new diagnostics and therapies proposed for human use. They have genetic, physiologic, immunologic, and developmental similarities when compared to humans and therefore provide important preclinical models of human health and disease. This review highlights select research areas that demonstrate the importance of nonhuman primates in translational research. These include pregnancy and developmental disorders, infectious diseases, gene therapy, somatic cell genome editing, and applications of in vivo imaging. The power of the immune system and our increasing understanding of the role it plays in acute and chronic illnesses are being leveraged to produce new treatments for a range of medical conditions. Given the importance of the human immune system in health and disease, detailed study of the immune system of nonhuman primates is essential to advance preclinical translational research. The need for nonhuman primates continues to remain a high priority, which has been acutely evident during the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) global pandemic. Nonhuman primates will continue to address key questions and provide predictive models to identify the safety and efficiency of new diagnostics and therapies for human use across the lifespan.


Assuntos
COVID-19 , Primatas , Animais , COVID-19/veterinária , Modelos Animais de Doenças , Humanos , Primatas/genética , SARS-CoV-2 , Pesquisa Translacional Biomédica
17.
PLoS One ; 17(2): e0263129, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35120150

RESUMO

Childhood undernutrition is a major health burden worldwide that increases childhood morbidity and mortality and causes impairment in infant growth and developmental delays that can persist into adulthood. The first weeks and months after birth are critical to the establishment of healthy growth and development during childhood. The World Health Organization recommends immediate and exclusive breastfeeding (EBF). In infants for whom EBF may not meet nutritional and caloric demands, early, daily, small-volume formula supplementation along with breastfeeding may more effectively avoid underweight wasting and stunting in early infancy than breastfeeding alone. The primary objective of this randomized controlled trial is to evaluate the efficacy of formula for 30 days among low birth weight (LBW) infants <6 hours of age and those not LBW with weights <2600 grams at 4 days of age. We will compare breastfeeding and formula (up to 59 milliliters administered daily) through 30 days of infant age vs recommendations for frequent EBF without supplementation, and test the hypothesis that formula increases weight-for-age z-score at 30 days of infant age. The trial will enroll and randomize 324 mother-infant pairs in Guinea-Bissau and Uganda, and follow them for 6 months for outcomes including growth, intestinal microbiota, breastfeeding duration, infant dietary intake, and adverse events. Conservatively estimating 20% loss to follow up, this sample size provides ≥80% power per weight stratum for intervention group comparison to detect a difference of 0.20 with respect to the outcome of WAZ at day 30. This trial was approved by the University of California, San Francisco Institutional Review Board (19-29405); the Guinea-Bissau National Committee on Ethics in Health (Comite Nacional de Etica na Saude, 075/CNES/INASA/2020); the Higher Degrees, Research and Ethics Committee of Makerere University (871); and the Uganda National Council of Science and Technology (HS1226ES). We plan to disseminate study results in peer-reviewed journals and international conferences. Trial registration number: NCT04704076.


Assuntos
Fórmulas Infantis , Suplementos Nutricionais , Feminino , Alimentos Formulados , Microbioma Gastrointestinal , Guiné-Bissau , Humanos , Lactente , Fenômenos Fisiológicos da Nutrição do Lactente , Recém-Nascido de Baixo Peso , Recém-Nascido , Análise de Intenção de Tratamento , Mães , Segurança do Paciente , Estudos Prospectivos , Magreza , Resultado do Tratamento , Uganda
18.
Viruses ; 13(12)2021 12 14.
Artigo em Inglês | MEDLINE | ID: mdl-34960771

RESUMO

While recent changes in treatment have reduced the lethality of idiopathic chronic diarrhea (ICD), this condition remains one of the most common causes of rhesus macaque deaths in non-human primate research centers. We compared the viromes in fecal swabs from 52 animals with late stage ICD and 41 healthy animals. Viral metagenomics targeting virus-like particles was used to identify viruses fecally shed by each animal. Five viruses belonging to the Picornaviridae, one to the Caliciviridae, one to the Parvoviridae, and one to the Adenoviridae families were identified. The fraction of reads matching each viral species was then used to estimate and compare viral loads in ICD cases versus healthy controls. None of the viruses detected in fecal swabs were strongly associated with ICD.


Assuntos
Diarreia/etiologia , Fezes/virologia , Viroses/complicações , Animais , Estudos de Casos e Controles , Doença Crônica , Diarreia/virologia , Macaca mulatta , Metagenômica
19.
Microbiol Spectr ; 9(3): e0139721, 2021 12 22.
Artigo em Inglês | MEDLINE | ID: mdl-34817208

RESUMO

Human clinical studies investigating use of convalescent plasma (CP) for treatment of coronavirus disease 2019 (COVID-19) have produced conflicting results. Outcomes in these studies may vary at least partly due to different timing of CP administration relative to symptom onset. The mechanisms of action of CP include neutralizing antibodies but may extend beyond virus neutralization to include normalization of blood clotting and dampening of inflammation. Unresolved questions include the minimum therapeutic titer in the CP units or CP recipient as well as the optimal timing of administration. Here, we show that treatment of macaques with CP within 24 h of infection does not reduce viral shedding in nasal or lung secretions compared to controls and does not detectably improve any clinical endpoint. We also demonstrate that CP administration does not impact viral sequence diversity in vivo, although the selection of a viral sequence variant in both macaques receiving normal human plasma was suggestive of immune pressure. Our results suggest that CP, administered to medium titers, has limited efficacy, even when given very early after infection. Our findings also contribute information important for the continued development of the nonhuman primate model of COVID-19. These results should inform interpretation of clinical studies of CP in addition to providing insights useful for developing other passive immunotherapies and vaccine strategies. IMPORTANCE Antiviral treatment options for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remain very limited. One treatment that was explored beginning early in the pandemic (and that is likely to be tested early in future pandemics) is plasma collected from people who have recovered from coronavirus disease 2019 (COVID-19), known as convalescent plasma (CP). We tested if CP reduces viral shedding or disease in a nonhuman primate model. Our results demonstrate that administration of CP 1 day after SARS-CoV-2 infection had no significant impact on viral loads, clinical disease, or sequence diversity, although treatment with normal human plasma resulted in selection of a specific viral variant. Our results demonstrate that passive immunization with CP, even during early infection, provided no significant benefit in a nonhuman primate model of SARS-CoV-2 infection.


Assuntos
COVID-19/terapia , Imunização Passiva/métodos , SARS-CoV-2 , Animais , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/sangue , Antivirais/uso terapêutico , COVID-19/imunologia , Modelos Animais de Doenças , Humanos , Imunidade , Pulmão/patologia , Macaca mulatta , Pandemias , Glicoproteína da Espícula de Coronavírus/imunologia , Carga Viral , Replicação Viral
20.
Cell Rep ; 37(5): 109942, 2021 11 02.
Artigo em Inglês | MEDLINE | ID: mdl-34706272

RESUMO

Anti-viral monoclonal antibody (mAb) treatments may provide immediate but short-term immunity from coronavirus disease 2019 (COVID-19) in high-risk populations, such as people with diabetes and the elderly; however, data on their efficacy in these populations are limited. We demonstrate that prophylactic mAb treatment blocks viral replication in both the upper and lower respiratory tracts in aged, type 2 diabetic rhesus macaques. mAb infusion dramatically curtails severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-mediated stimulation of interferon-induced chemokines and T cell activation, significantly reducing development of interstitial pneumonia. Furthermore, mAb infusion significantly dampens the greater than 3-fold increase in SARS-CoV-2-induced effector CD4 T cell influx into the cerebrospinal fluid. Our data show that neutralizing mAbs administered preventatively to high-risk populations may mitigate the adverse inflammatory consequences of SARS-CoV-2 exposure.


Assuntos
Anticorpos Monoclonais/uso terapêutico , COVID-19/prevenção & controle , SARS-CoV-2/imunologia , Envelhecimento/imunologia , Animais , COVID-19/líquido cefalorraquidiano , COVID-19/complicações , COVID-19/imunologia , Complicações do Diabetes/imunologia , Complicações do Diabetes/virologia , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/imunologia , Feminino , Humanos , Ativação Linfocitária , Macaca mulatta , Masculino , Neurite (Inflamação)/imunologia , Neurite (Inflamação)/prevenção & controle , Profilaxia Pré-Exposição , Linfócitos T/imunologia , Replicação Viral/imunologia
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