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1.
PLoS Pathog ; 20(4): e1012171, 2024 Apr.
Article in English | MEDLINE | ID: mdl-38683864

ABSTRACT

Researchers and clinicians often rely on molecular assays like PCR to identify and monitor viral infections, instead of the resource-prohibitive gold standard of viral culture. However, it remains unclear when (if ever) PCR measurements of viral load are reliable indicators of replicating or infectious virus. The recent popularity of PCR protocols targeting subgenomic RNA for SARS-CoV-2 has caused further confusion, as the relationships between subgenomic RNA and standard total RNA assays are incompletely characterized and opinions differ on which RNA type better predicts culture outcomes. Here, we explore these issues by comparing total RNA, subgenomic RNA, and viral culture results from 24 studies of SARS-CoV-2 in non-human primates (including 2167 samples from 174 individuals) using custom-developed Bayesian statistical models. On out-of-sample data, our best models predict subgenomic RNA positivity from total RNA data with 91% accuracy, and they predict culture positivity with 85% accuracy. Further analyses of individual time series indicate that many apparent prediction errors may arise from issues with assay sensitivity or sample processing, suggesting true accuracy may be higher than these estimates. Total RNA and subgenomic RNA showed equivalent performance as predictors of culture positivity. Multiple cofactors (including exposure conditions, host traits, and assay protocols) influence culture predictions, yielding insights into biological and methodological sources of variation in assay outcomes-and indicating that no single threshold value applies across study designs. We also show that our model can accurately predict when an individual is no longer infectious, illustrating the potential for future models trained on human data to guide clinical decisions on case isolation. Our work shows that meta-analysis of in vivo data can overcome longstanding challenges arising from limited sample sizes and can yield robust insights beyond those attainable from individual studies. Our analytical pipeline offers a framework to develop similar predictive tools in other virus-host systems, including models trained on human data, which could support laboratory analyses, medical decisions, and public health guidelines.


Subject(s)
COVID-19 , RNA, Viral , SARS-CoV-2 , Viral Load , Animals , SARS-CoV-2/genetics , COVID-19/virology , COVID-19/diagnosis , RNA, Viral/genetics , Primates/virology , Bayes Theorem , Humans , Polymerase Chain Reaction/methods , COVID-19 Nucleic Acid Testing/methods
2.
Nature ; 624(7992): 630-638, 2023 Dec.
Article in English | MEDLINE | ID: mdl-38093012

ABSTRACT

The COVID-19 pandemic has fostered major advances in vaccination technologies1-4; however, there are urgent needs for vaccines that induce mucosal immune responses and for single-dose, non-invasive administration4-6. Here we develop an inhalable, single-dose, dry powder aerosol SARS-CoV-2 vaccine that induces potent systemic and mucosal immune responses. The vaccine encapsulates assembled nanoparticles comprising proteinaceous cholera toxin B subunits displaying the SARS-CoV-2 RBD antigen within microcapsules of optimal aerodynamic size, and this unique nano-micro coupled structure supports efficient alveoli delivery, sustained antigen release and antigen-presenting cell uptake, which are favourable features for the induction of immune responses. Moreover, this vaccine induces strong production of IgG and IgA, as well as a local T cell response, collectively conferring effective protection against SARS-CoV-2 in mice, hamsters and nonhuman primates. Finally, we also demonstrate a mosaic iteration of the vaccine that co-displays ancestral and Omicron antigens, extending the breadth of antibody response against co-circulating strains and transmission of the Omicron variant. These findings support the use of this inhaled vaccine as a promising multivalent platform for fighting COVID-19 and other respiratory infectious diseases.


Subject(s)
COVID-19 Vaccines , Immunity, Mucosal , Animals , Cricetinae , Humans , Mice , Administration, Inhalation , Aerosols , Antibodies, Viral/immunology , Antigen-Presenting Cells/immunology , Antigen-Presenting Cells/metabolism , Antigens, Viral/immunology , Cholera Toxin , COVID-19/immunology , COVID-19/prevention & control , COVID-19 Vaccines/administration & dosage , Immunity, Mucosal/immunology , Immunoglobulin A/immunology , Immunoglobulin G/immunology , Nanoparticles , Powders , Primates/virology , SARS-CoV-2/classification , SARS-CoV-2/immunology , T-Lymphocytes/immunology , Vaccination , Capsules
3.
J Virol ; 97(10): e0083023, 2023 10 31.
Article in English | MEDLINE | ID: mdl-37796130

ABSTRACT

IMPORTANCE: Herpesviruses present a major global disease burden. Understanding the host cell mechanisms that block viral infections, as well as how viruses can evolve to counteract these host defenses, is critically important for understanding viral disease pathogenesis. This study reveals that the major human variant of the antiviral protein myxovirus resistance protein B (MxB) inhibits the human pathogen herpes simplex virus (HSV-1), whereas a minor human variant and orthologous MxB genes from even closely related primates do not. Thus, in contrast to the many antagonistic virus-host interactions in which the virus is successful in thwarting the host's defense systems, here the human gene appears to be at least temporarily winning at this interface of the primate-herpesvirus evolutionary arms race. Our findings further show that a polymorphism at amino acid 83 in a small fraction of the human population is sufficient to abrogate MxB's ability to inhibit HSV-1, which could have important implications for human susceptibility to HSV-1 pathogenesis.


Subject(s)
Herpesvirus 1, Human , Host Microbial Interactions , Myxovirus Resistance Proteins , Polymorphism, Genetic , Animals , Humans , Herpesvirus 1, Human/pathogenicity , Herpesvirus 1, Human/physiology , Host Microbial Interactions/genetics , Myxovirus Resistance Proteins/genetics , Myxovirus Resistance Proteins/metabolism , Primates/genetics , Primates/virology , Species Specificity
4.
Nature ; 615(7953): 678-686, 2023 03.
Article in English | MEDLINE | ID: mdl-36922586

ABSTRACT

Dengue is a major health threat and the number of symptomatic infections caused by the four dengue serotypes is estimated to be 96 million1 with annually around 10,000 deaths2. However, no antiviral drugs are available for the treatment or prophylaxis of dengue. We recently described the interaction between non-structural proteins NS3 and NS4B as a promising target for the development of pan-serotype dengue virus (DENV) inhibitors3. Here we present JNJ-1802-a highly potent DENV inhibitor that blocks the NS3-NS4B interaction within the viral replication complex. JNJ-1802 exerts picomolar to low nanomolar in vitro antiviral activity, a high barrier to resistance and potent in vivo efficacy in mice against infection with any of the four DENV serotypes. Finally, we demonstrate that the small-molecule inhibitor JNJ-1802 is highly effective against viral infection with DENV-1 or DENV-2 in non-human primates. JNJ-1802 has successfully completed a phase I first-in-human clinical study in healthy volunteers and was found to be safe and well tolerated4. These findings support the further clinical development of JNJ-1802, a first-in-class antiviral agent against dengue, which is now progressing in clinical studies for the prevention and treatment of dengue.


Subject(s)
Antiviral Agents , Dengue Virus , Dengue , Primates , Viral Nonstructural Proteins , Animals , Humans , Mice , Antiviral Agents/adverse effects , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , Clinical Trials, Phase I as Topic , Dengue/drug therapy , Dengue/prevention & control , Dengue/virology , Dengue Virus/classification , Dengue Virus/drug effects , Dose-Response Relationship, Drug , Drug Resistance, Viral , In Vitro Techniques , Molecular Targeted Therapy , Primates/virology , Protein Binding/drug effects , Viral Nonstructural Proteins/antagonists & inhibitors , Viral Nonstructural Proteins/metabolism , Virus Replication
5.
Nature ; 615(7953): 728-733, 2023 03.
Article in English | MEDLINE | ID: mdl-36754086

ABSTRACT

The APOBEC3 (A3) proteins are host antiviral cellular proteins that hypermutate the viral genome of diverse viral families. In retroviruses, this process requires A3 packaging into viral particles1-4. The lentiviruses encode a protein, Vif, that antagonizes A3 family members by targeting them for degradation. Diversification of A3 allows host escape from Vif whereas adaptations in Vif enable cross-species transmission of primate lentiviruses. How this 'molecular arms race' plays out at the structural level is unknown. Here, we report the cryogenic electron microscopy structure of human APOBEC3G (A3G) bound to HIV-1 Vif, and the hijacked cellular proteins that promote ubiquitin-mediated proteolysis. A small surface explains the molecular arms race, including a cross-species transmission event that led to the birth of HIV-1. Unexpectedly, we find that RNA is a molecular glue for the Vif-A3G interaction, enabling Vif to repress A3G by ubiquitin-dependent and -independent mechanisms. Our results suggest a model in which Vif antagonizes A3G by intercepting it in its most dangerous form for the virus-when bound to RNA and on the pathway to packaging-to prevent viral restriction. By engaging essential surfaces required for restriction, Vif exploits a vulnerability in A3G, suggesting a general mechanism by which RNA binding helps to position key residues necessary for viral antagonism of a host antiviral gene.


Subject(s)
APOBEC-3G Deaminase , HIV-1 , Proteolysis , vif Gene Products, Human Immunodeficiency Virus , Animals , Humans , APOBEC-3G Deaminase/antagonists & inhibitors , APOBEC-3G Deaminase/chemistry , APOBEC-3G Deaminase/metabolism , APOBEC-3G Deaminase/ultrastructure , HIV-1/metabolism , HIV-1/pathogenicity , RNA/chemistry , RNA/metabolism , Ubiquitin/metabolism , vif Gene Products, Human Immunodeficiency Virus/chemistry , vif Gene Products, Human Immunodeficiency Virus/metabolism , vif Gene Products, Human Immunodeficiency Virus/ultrastructure , Cryoelectron Microscopy , Viral Genome Packaging , Primates/virology
6.
J Med Virol ; 95(2): e28513, 2023 02.
Article in English | MEDLINE | ID: mdl-36661039

ABSTRACT

Mpox is caused by the mpox virus, which belongs to the Orthopoxvirus genus and Poxviridae family. Animal hosts, such as African rodents, mice, prairie dogs, and non-human primates, play important roles in the development and transmission of outbreaks. Laboratory animal infection experiments have demonstrated that some animals are susceptible to mpox virus. This review summarizes the current progress on the animal hosts for mpox virus. The surveillance of mpox virus in animal hosts will provide important insights into virus tracing, analysis of mutation evolutionary patterns, transmission mechanisms, and development of control measures.


Subject(s)
Monkeypox virus , Mpox (monkeypox) , Animals , Mice , Host Specificity , Primates/virology , Sciuridae/virology , Mpox (monkeypox)/veterinary
7.
Proc Natl Acad Sci U S A ; 119(35): e2206610119, 2022 08 30.
Article in English | MEDLINE | ID: mdl-35947637

ABSTRACT

The coronavirus disease 19 (COVID-19) pandemic is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a coronavirus that spilled over from the bat reservoir. Despite numerous clinical trials and vaccines, the burden remains immense, and the host determinants of SARS-CoV-2 susceptibility and COVID-19 severity remain largely unknown. Signatures of positive selection detected by comparative functional genetic analyses in primate and bat genomes can uncover important and specific adaptations that occurred at virus-host interfaces. We performed high-throughput evolutionary analyses of 334 SARS-CoV-2-interacting proteins to identify SARS-CoV adaptive loci and uncover functional differences between modern humans, primates, and bats. Using DGINN (Detection of Genetic INNovation), we identified 38 bat and 81 primate proteins with marks of positive selection. Seventeen genes, including the ACE2 receptor, present adaptive marks in both mammalian orders, suggesting common virus-host interfaces and past epidemics of coronaviruses shaping their genomes. Yet, 84 genes presented distinct adaptations in bats and primates. Notably, residues involved in ubiquitination and phosphorylation of the inflammatory RIPK1 have rapidly evolved in bats but not primates, suggesting different inflammation regulation versus humans. Furthermore, we discovered residues with typical virus-host arms race marks in primates, such as in the entry factor TMPRSS2 or the autophagy adaptor FYCO1, pointing to host-specific in vivo interfaces that may be drug targets. Finally, we found that FYCO1 sites under adaptation in primates are those associated with severe COVID-19, supporting their importance in pathogenesis and replication. Overall, we identified adaptations involved in SARS-CoV-2 infection in bats and primates, enlightening modern genetic determinants of virus susceptibility and severity.


Subject(s)
COVID-19 , Chiroptera , Evolution, Molecular , Host Adaptation , Primates , SARS-CoV-2 , Spike Glycoprotein, Coronavirus , Animals , COVID-19/genetics , Chiroptera/virology , Genetic Predisposition to Disease , Host Adaptation/genetics , Humans , Pandemics , Primates/genetics , Primates/virology , SARS-CoV-2/genetics , Selection, Genetic , Spike Glycoprotein, Coronavirus/genetics
8.
J Gen Virol ; 103(1)2022 01.
Article in English | MEDLINE | ID: mdl-35077341

ABSTRACT

Decades after its discovery in East Africa, Zika virus (ZIKV) emerged in Brazil in 2013 and infected millions of people during intense urban transmission. Whether vertebrates other than humans are involved in ZIKV transmission cycles remained unclear. Here, we investigate the role of different animals as ZIKV reservoirs by testing 1723 sera of pets, peri-domestic animals and African non-human primates (NHP) sampled during 2013-2018 in Brazil and 2006-2016 in Côte d'Ivoire. Exhaustive neutralization testing substantiated co-circulation of multiple flaviviruses and failed to confirm ZIKV infection in pets or peri-domestic animals in Côte d'Ivoire (n=259) and Brazil (n=1416). In contrast, ZIKV seroprevalence was 22.2% (2/9, 95% CI, 2.8-60.1) in West African chimpanzees (Pan troglodytes verus) and 11.1% (1/9, 95% CI, 0.3-48.3) in king colobus (Colobus polycomos). Our results indicate that while NHP may represent ZIKV reservoirs in Africa, pets or peri-domestic animals likely do not play a role in ZIKV transmission cycles.


Subject(s)
Animals, Domestic/virology , Primates/virology , Zika Virus Infection/epidemiology , Zika Virus Infection/virology , Zika Virus , Africa , Animals , Brazil , Cote d'Ivoire , Humans , Neutralization Tests , Seroepidemiologic Studies , Zika Virus Infection/transmission
9.
PLoS Negl Trop Dis ; 15(12): e0010016, 2021 12.
Article in English | MEDLINE | ID: mdl-34898602

ABSTRACT

Improving our understanding of Mayaro virus (MAYV) ecology is critical to guide surveillance and risk assessment. We conducted a PRISMA-adherent systematic review of the published and grey literature to identify potential arthropod vectors and non-human animal reservoirs of MAYV. We searched PubMed/MEDLINE, Embase, Web of Science, SciELO and grey-literature sources including PAHO databases and dissertation repositories. Studies were included if they assessed MAYV virological/immunological measured occurrence in field-caught, domestic, or sentinel animals or in field-caught arthropods. We conducted an animal seroprevalence meta-analysis using a random effects model. We compiled granular georeferenced maps of non-human MAYV occurrence and graded the quality of the studies using a customized framework. Overall, 57 studies were eligible out of 1523 screened, published between the years 1961 and 2020. Seventeen studies reported MAYV positivity in wild mammals, birds, or reptiles and five studies reported MAYV positivity in domestic animals. MAYV positivity was reported in 12 orders of wild-caught vertebrates, most frequently in the orders Charadriiformes and Primate. Sixteen studies detected MAYV in wild-caught mosquito genera including Haemagogus, Aedes, Culex, Psorophora, Coquillettidia, and Sabethes. Vertebrate animals or arthropods with MAYV were detected in Brazil, Panama, Peru, French Guiana, Colombia, Trinidad, Venezuela, Argentina, and Paraguay. Among non-human vertebrates, the Primate order had the highest pooled seroprevalence at 13.1% (95% CI: 4.3-25.1%). From the three most studied primate genera we found the highest seroprevalence was in Alouatta (32.2%, 95% CI: 0.0-79.2%), followed by Callithrix (17.8%, 95% CI: 8.6-28.5%), and Cebus/Sapajus (3.7%, 95% CI: 0.0-11.1%). We further found that MAYV occurs in a wide range of vectors beyond Haemagogus spp. The quality of evidence behind these findings was variable and prompts calls for standardization of reporting of arbovirus occurrence. These findings support further risk emergence prediction, guide field surveillance efforts, and prompt further in-vivo studies to better define the ecological drivers of MAYV maintenance and potential for emergence.


Subject(s)
Alphavirus Infections/veterinary , Alphavirus Infections/virology , Alphavirus/physiology , Arthropod Vectors/virology , Disease Reservoirs/virology , Mosquito Vectors/virology , Alphavirus/genetics , Alphavirus Infections/transmission , Animals , Arthropod Vectors/physiology , Birds/virology , Humans , Mammals/virology , Mosquito Vectors/physiology , Primates/virology , Reptiles/virology
10.
Curr Opin Virol ; 51: 179-189, 2021 12.
Article in English | MEDLINE | ID: mdl-34749265

ABSTRACT

Zaire Ebola virus (EBOV) is a member of the Filoviridae family. Infection with EBOV causes Ebola virus disease (EVD) characterized by excessive inflammation, lymphocyte death, coagulopathy, and multi-organ failure. In 2019, the FDA-approved the first anti-EBOV vaccine, rVSV-EBOV-GP (Ervebo® by Merck). This live-recombinant vaccine confers both prophylactic and therapeutic protection to nonhuman primates and humans. While mechanisms conferring prophylactic protection are well-investigated, those underlying protection conferred shortly before and after exposure to EBOV remain poorly understood. In this review, we review data from in vitro and in vivo studies analyzing early immune responses to rVSV-EBOV-GP and discuss the role of innate immune activation in therapeutic protection.


Subject(s)
Ebola Vaccines/immunology , Ebola Vaccines/therapeutic use , Ebolavirus/immunology , Hemorrhagic Fever, Ebola/immunology , Hemorrhagic Fever, Ebola/therapy , Immunity, Innate , Vaccination , Animals , Hemorrhagic Fever, Ebola/prevention & control , Hemorrhagic Fever, Ebola/virology , Humans , Primates/immunology , Primates/virology , United States , United States Food and Drug Administration
11.
Viruses ; 13(10)2021 09 25.
Article in English | MEDLINE | ID: mdl-34696363

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the agent of coronavirus disease 2019 (COVID-19), is responsible for the worst pandemic of the 21st century. Like all human coronaviruses, SARS-CoV-2 originated in a wildlife reservoir, most likely from bats. As SARS-CoV-2 has spread across the globe in humans, it has spilled over to infect a variety of non-human animal species in domestic, farm, and zoo settings. Additionally, a broad range of species, including one neotropical monkey, have proven to be susceptible to experimental infection with SARS-CoV-2. Together, these findings raise the specter of establishment of novel enzootic cycles of SARS-CoV-2. To assess the potential exposure of free-living non-human primates to SARS-CoV-2, we sampled 60 neotropical monkeys living in proximity to Manaus and São José do Rio Preto, two hotspots for COVID-19 in Brazil. Our molecular and serological tests detected no evidence of SAR-CoV-2 infection among these populations. While this result is reassuring, sustained surveillance efforts of wildlife living in close association with human populations is warranted, given the stochastic nature of spillover events and the enormous implications of SARS-CoV-2 spillover for human health.


Subject(s)
COVID-19/epidemiology , Epidemiological Monitoring/veterinary , Primates/virology , Alouatta/virology , Animals , Animals, Wild/virology , Brazil/epidemiology , COVID-19/veterinary , Callicebus/virology , Callithrix/virology , Pandemics , SARS-CoV-2/pathogenicity , Viral Zoonoses/transmission
12.
Viruses ; 13(10)2021 10 01.
Article in English | MEDLINE | ID: mdl-34696408

ABSTRACT

The 2021 re-emergence of yellow fever in non-human primates in the state of Rio Grande do Sul (RS), southernmost Brazil, resulted in the death of many howler monkeys (genus Alouatta) and led the state to declare a Public Health Emergency of State Importance, despite no human cases reported. In this study, near-complete genomes of yellow fever virus (YFV) recovered from the outbreak were sequenced and examined aiming at a better understanding of the phylogenetic relationships and the spatio-temporal dynamics of the virus distribution. Our results suggest that the most likely sequence of events involved the reintroduction of YFV from the state of São Paulo to RS through the states of Paraná and Santa Catarina, by the end of 2020. These findings reinforce the role of genomic surveillance in determining the pathways of distribution of the virus and in providing references for the implementation of preventive measures for populations in high risk areas.


Subject(s)
Yellow Fever/epidemiology , Yellow Fever/genetics , Yellow fever virus/genetics , Alouatta/virology , Animals , Brazil/epidemiology , Disease Outbreaks , Epidemiological Monitoring/veterinary , Genomics , Phylogeny , Primates/virology , Whole Genome Sequencing/methods , Yellow Fever/transmission , Yellow fever virus/pathogenicity , Zoonoses/virology
13.
Emerg Microbes Infect ; 10(1): 1881-1889, 2021 Dec.
Article in English | MEDLINE | ID: mdl-34490832

ABSTRACT

SARS-CoV-2 has been the causative pathogen of the pandemic of COVID-19, resulting in catastrophic health issues globally. It is important to develop human-like animal models for investigating the mechanisms that SARS-CoV-2 uses to infect humans and cause COVID-19. Several studies demonstrated that the non-human primate (NHP) is permissive for SARS-CoV-2 infection to cause typical clinical symptoms including fever, cough, breathing difficulty, and other diagnostic abnormalities such as immunopathogenesis and hyperplastic lesions in the lung. These NHP models have been used for investigating the potential infection route and host immune response to SARS-CoV-2, as well as testing vaccines and drugs. This review aims to summarize the benefits and caveats of NHP models currently available for SARS-CoV-2, and to discuss key topics including model optimization, extended application, and clinical translation.


Subject(s)
COVID-19/virology , Disease Models, Animal , Primates/virology , SARS-CoV-2/physiology , Animals , Antiviral Agents/administration & dosage , COVID-19/immunology , COVID-19/pathology , COVID-19 Vaccines/administration & dosage , COVID-19 Vaccines/immunology , Humans , Primates/immunology , SARS-CoV-2/genetics , COVID-19 Drug Treatment
14.
Viruses ; 13(9)2021 09 02.
Article in English | MEDLINE | ID: mdl-34578335

ABSTRACT

Human T-lymphotropic virus 1 and 2 (HTLV-1/2) belong to the delta group of retroviruses which may cause a life-long infection in humans, HTLV-1 leading to adult T-cell leukemia/lymphoma and other diseases. Different transmission modes have been described, such as breastfeeding, and, as for other blood-borne pathogens, unsafe sexual activity, intravenous drug usage, and blood transfusion and transplantation. The present systematic review was conducted to identify all peer-reviewed studies concerning the work-related infection by HTLV-1/2. A literature search was conducted from January to May 2021, according to the PRISMA methodology, selecting 29 studies: seven related to health care workers (HCWs), five to non-HCWs, and 17 to sex workers (SWs). The findings showed no clear evidence as to the possibility of HTLV-1/2 occupational transmission in HCWs, according to the limited number and quality of the papers. Moreover, non-HCWs showed a higher prevalence in jobs consistent with a lower socioeconomic status or that could represent a familial cluster, and an increased risk of zoonotic transmission from STLV-1-infected non-human primates has been observed in African hunters. Finally, a general increase of HTLV-1 infection was observed in SWs, whereas only one paper described an increased prevalence for HTLV-2, supporting the urgent need for prevention and control measures, including screening, diagnosis, and treatment of HTLV-1/2, to be offered routinely as part of a comprehensive approach to decrease the impact of sexually transmitted diseases in SWs.


Subject(s)
HTLV-I Infections , HTLV-II Infections , Human T-lymphotropic virus 1 , Human T-lymphotropic virus 2 , Occupational Diseases , Animals , Humans , Health Personnel/statistics & numerical data , HTLV-I Infections/epidemiology , HTLV-I Infections/etiology , HTLV-I Infections/transmission , HTLV-II Infections/epidemiology , HTLV-II Infections/etiology , HTLV-II Infections/transmission , Human T-lymphotropic virus 1/pathogenicity , Human T-lymphotropic virus 2/pathogenicity , Occupational Diseases/epidemiology , Occupational Diseases/virology , Phylogeny , Prevalence , Primates/virology , Sex Workers/statistics & numerical data , Viral Zoonoses/epidemiology , Viral Zoonoses/transmission
15.
Nat Immunol ; 22(10): 1294-1305, 2021 10.
Article in English | MEDLINE | ID: mdl-34556879

ABSTRACT

Development of effective human immunodeficiency virus 1 (HIV-1) vaccines requires synergy between innate and adaptive immune cells. Here we show that induction of the transcription factor CREB1 and its target genes by the recombinant canarypox vector ALVAC + Alum augments immunogenicity in non-human primates (NHPs) and predicts reduced HIV-1 acquisition in the RV144 trial. These target genes include those encoding cytokines/chemokines associated with heightened protection from simian immunodeficiency virus challenge in NHPs. Expression of CREB1 target genes probably results from direct cGAMP (STING agonist)-modulated p-CREB1 activity that drives the recruitment of CD4+ T cells and B cells to the site of antigen presentation. Importantly, unlike NHPs immunized with ALVAC + Alum, those immunized with ALVAC + MF59, the regimen in the HVTN702 trial that showed no protection from HIV infection, exhibited significantly reduced CREB1 target gene expression. Our integrated systems biology approach has validated CREB1 as a critical driver of vaccine efficacy and highlights that adjuvants that trigger CREB1 signaling may be critical for efficacious HIV-1 vaccines.


Subject(s)
Cyclic AMP Response Element-Binding Protein/immunology , HIV Infections/immunology , HIV-1/immunology , Immunogenicity, Vaccine/immunology , Viral Vaccines/immunology , AIDS Vaccines/immunology , Adjuvants, Immunologic/pharmacology , Animals , B-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/immunology , Gene Expression/immunology , Genetic Vectors/immunology , HIV Antibodies/immunology , HIV Infections/virology , Humans , Immunization/methods , Primates/immunology , Primates/virology , Vaccination/methods
16.
Nat Immunol ; 22(10): 1306-1315, 2021 10.
Article in English | MEDLINE | ID: mdl-34417590

ABSTRACT

B.1.351 is the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant most resistant to antibody neutralization. We demonstrate how the dose and number of immunizations influence protection. Nonhuman primates received two doses of 30 or 100 µg of Moderna's mRNA-1273 vaccine, a single immunization of 30 µg, or no vaccine. Two doses of 100 µg of mRNA-1273 induced 50% inhibitory reciprocal serum dilution neutralizing antibody titers against live SARS-CoV-2 p.Asp614Gly and B.1.351 of 3,300 and 240, respectively. Higher neutralizing responses against B.1.617.2 were also observed after two doses compared to a single dose. After challenge with B.1.351, there was ~4- to 5-log10 reduction of viral subgenomic RNA and low to undetectable replication in bronchoalveolar lavages in the two-dose vaccine groups, with a 1-log10 reduction in nasal swabs in the 100-µg group. These data establish that a two-dose regimen of mRNA-1273 will be critical for providing upper and lower airway protection against major variants of concern.


Subject(s)
COVID-19 Vaccines/immunology , COVID-19/immunology , Primates/immunology , SARS-CoV-2/immunology , 2019-nCoV Vaccine mRNA-1273 , Animals , Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , COVID-19/virology , Cell Line , Chlorocebus aethiops , Female , Humans , Macaca mulatta , Male , Mesocricetus , Primates/virology , RNA, Viral/immunology , Spike Glycoprotein, Coronavirus/immunology , Vaccination/methods , Vero Cells , Viral Load/methods
17.
Zool Res ; 42(5): 626-632, 2021 Sep 18.
Article in English | MEDLINE | ID: mdl-34410047

ABSTRACT

Viruses can be transmitted from animals to humans (and vice versa) and across animal species. As such, host-virus interactions and transmission have attracted considerable attention. Non-human primates (NHPs), our closest evolutionary relatives, are susceptible to human viruses and certain pathogens are known to circulate between humans and NHPs. Here, we generated global statistics on VI-NHPs based on a literature search and public data mining. In total, 140 NHP species from 12 families are reported to be infected by 186 DNA and RNA virus species, 68.8% of which are also found in humans, indicating high potential for crossing species boundaries. The top 10 NHP species with high centrality in the NHP-virus network include two great apes (Pan troglodytes, Pongo pygmaeus) and eight Old World monkeys (Macaca mulatta, M. fascicularis, M. leonina, Papio cynocephalus, Cercopithecus ascanius, C. erythrotis, Chlorocebus aethiops, and Allochrocebus lhoesti). Given the wide distribution of Old World monkeys and their frequent contact with humans, there is a high risk of virus circulation between humans and such species. Thus, we suggest recurring epidemiological surveillance of NHPs, specifically Old World monkeys that are in frequent contact with humans, and other effective measures to prevent potential circulation and transmission of viruses. Avoidance of false positives and sampling bias should also be a focus in future work.


Subject(s)
Conservation of Natural Resources , Primates/virology , Public Health , Virus Diseases/veterinary , Viruses/classification , Animals , Animals, Wild , Global Health , Virus Diseases/epidemiology , Virus Diseases/virology
18.
Sci Rep ; 11(1): 16277, 2021 08 11.
Article in English | MEDLINE | ID: mdl-34381111

ABSTRACT

We investigated the sylvatic yellow fever (SYF) diffusion process in São Paulo (SP) between 2016 and 2019. We developed an ecological study of SYF through autochthonous human cases and epizootics of non-human primates (NHPs) that were spatiotemporally evaluated. We used kriging to obtain maps with isochrones representative of the evolution of the outbreak and characterized its diffusion pattern. We confirmed 648 human cases of SYF in SP, with 230 deaths and 843 NHP epizootics. Two outbreak waves were identified: one from West to East (2016 and 2017), and another from the Campinas region to the municipalities bordering Rio de Janeiro, Minas Gerais, and Paraná and those of the SP coast (2017-2019). The SYF outbreak diffusion process was by contagion. The disease did not exhibit jumps between municipalities, indicating that the mosquitoes and NHPs were responsible for transmitting the virus. There were not enough vaccines to meet the population at risk; hence, health authorities used information about the epizootic occurrence in NHPs in forest fragments to identify priority populations for vaccination.


Subject(s)
Yellow Fever/epidemiology , Animals , Brazil/epidemiology , Disease Outbreaks/prevention & control , Humans , Primates/virology , Vaccination/methods , Yellow Fever/immunology , Yellow Fever/virology , Yellow fever virus/immunology , Zoonoses/epidemiology , Zoonoses/immunology , Zoonoses/virology
19.
Viruses ; 13(7)2021 06 30.
Article in English | MEDLINE | ID: mdl-34209295

ABSTRACT

Ebolaviruses and marburgviruses are filoviruses that are known to cause severe hemorrhagic fever in humans and nonhuman primates (NHPs). While some bat species are suspected to be natural reservoirs of these filoviruses, wild NHPs often act as intermediate hosts for viral transmission to humans. Using an enzyme-linked immunosorbent assay, we screened two NHP species, wild baboons and vervet monkeys captured in Zambia, for their serum IgG antibodies specific to the envelope glycoproteins of filoviruses. From 243 samples tested, 39 NHPs (16%) were found to be seropositive either for ebolaviruses or marburgviruses with endpoint antibody titers ranging from 100 to 25,600. Interestingly, antibodies reactive to Reston virus, which is found only in Asia, were detected in both NHP species. There was a significant difference in the seropositivity for the marburgvirus antigen between the two NHP species, with baboons having a higher positive rate. These results suggest that wild NHPs in Zambia might be nonlethally exposed to these filoviruses, and this emphasizes the need for continuous monitoring of filovirus infection in wild animals to better understand the ecology of filoviruses and to assess potential risks of outbreaks in humans in previously nonendemic countries.


Subject(s)
Antibodies, Viral/blood , Filoviridae Infections/immunology , Filoviridae Infections/veterinary , Filoviridae/immunology , Primates/virology , Animals , Animals, Wild/virology , Chlorocebus aethiops/virology , Ebolavirus/immunology , Enzyme-Linked Immunosorbent Assay/methods , Female , Filoviridae/classification , Filoviridae/isolation & purification , Filoviridae Infections/epidemiology , Humans , Immunoglobulin G/blood , Male , Marburgvirus/immunology , Papio/virology , Seroepidemiologic Studies , Zambia/epidemiology
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