The common marmoset genome provides insight into primate biology and evolution

We report the whole-genome sequence of the common marmoset (Callithrix jacchus). The 2.26-Gb genome of a female marmoset was assembled using Sanger read data (6×) and a whole-genome shotgun strategy. A first analysis has permitted comparison with the genomes of apes and Old World monkeys and the identification of specific features that might contribute to the unique biology of this diminutive primate, including genetic changes that may influence body size, frequent twinning and chimerism. We observed positive selection in growth hormone/insulin-like growth factor genes (growth pathways), respiratory complex I genes (metabolic pathways), and genes encoding immunobiological factors and proteases (reproductive and immunity pathways). In addition, both protein-coding and microRNA genes related to reproduction exhibited evidence of rapid sequence evolution. This genome sequence for a New World monkey enables increased power for comparative analyses among available primate genomes and facilitates biomedical research application. © 2014 Nature America, Inc

Global disparities in surgeons’ workloads, academic engagement and rest periods: the on-calL shIft fOr geNEral SurgeonS (LIONESS) study

: The workload of general surgeons is multifaceted, encompassing not only surgical procedures but also a myriad of other responsibilities. From April to May 2023, we conducted a CHERRIES-compliant internet-based survey analyzing clinical practice, academic engagement, and post-on-call rest. The questionnaire featured six sections with 35 questions. Statistical analysis used Chi-square tests, ANOVA, and logistic regression (SPSS® v. 28). The survey received a total of 1.046 responses (65.4%). Over 78.0% of responders came from Europe, 65.1% came from a general surgery unit; 92.8% of European and 87.5% of North American respondents were involved in research, compared to 71.7% in Africa. Europe led in publishing research studies (6.6 ± 8.6 yearly). Teaching involvement was high in North America (100%) and Africa (91.7%). Surgeons reported an average of 6.7 ± 4.9 on-call shifts per month, with European and North American surgeons experiencing 6.5 ± 4.9 and 7.8 ± 4.1 on-calls monthly, respectively. African surgeons had the highest on-call frequency (8.7 ± 6.1). Post-on-call, only 35.1% of respondents received a day off. Europeans were most likely (40%) to have a day off, while African surgeons were least likely (6.7%). On the adjusted multivariable analysis HDI (Human Development Index) (aOR 1.993) hospital capacity > 400 beds (aOR 2.423), working in a specialty surgery unit (aOR 2.087), and making the on-call in-house (aOR 5.446), significantly predicted the likelihood of having a day off after an on-call shift. Our study revealed critical insights into the disparities in workload, access to research, and professional opportunities for surgeons across different continents, underscored by the HDI

Recombinant Yellow Fever Vaccine Virus 17D Expressing Simian Immunodeficiency Virus SIVmac239 Gag Induces SIV-Specific CD8+ T-Cell Responses in Rhesus Macaques ▿

Here we describe a novel vaccine vector for expressing human immunodeficiency virus (HIV) antigens. We show that recombinant attenuated yellow fever vaccine virus 17D expressing simian immunodeficiency virus SIVmac239 Gag sequences can be used as a vector to generate SIV-specific CD8+ T-cell responses in the rhesus macaque. Priming with recombinant BCG expressing SIV antigens increased the frequency of these SIV-specific CD8+ T-cell responses after recombinant YF17D boosting. These recombinant YF17D-induced SIV-specific CD8+ T cells secreted several cytokines, were largely effector memory T cells, and suppressed viral replication in CD4+ T cells

Vaccine-Induced Simian Immunodeficiency Virus-Specific CD8 +

Certain major histocompatibility complex class I (MHC-I) alleles (e.g., HLA-B*27) are enriched among human immunodeficiency virus type 1 (HIV-1)-infected individuals who suppress viremia without treatment (termed “elite controllers” [ECs]). Likewise, Mamu-B*08 expression also predisposes rhesus macaques to control simian immunodeficiency virus (SIV) replication. Given the similarities between Mamu-B*08 and HLA-B*27, SIV-infected Mamu-B*08(+) animals provide a model to investigate HLA-B*27-mediated elite control. We have recently shown that vaccination with three immunodominant Mamu-B*08-restricted epitopes (Vif RL8, Vif RL9, and Nef RL10) increased the incidence of elite control in Mamu-B*08(+) macaques after challenge with the pathogenic SIVmac239 clone. Furthermore, a correlate analysis revealed that CD8(+) T cells targeting Nef RL10 was correlated with improved outcome. Interestingly, this epitope is conserved between SIV and HIV-1 and exhibits a delayed and atypical escape pattern. These features led us to postulate that a monotypic vaccine-induced Nef RL10-specific CD8(+) T-cell response would facilitate the development of elite control in Mamu-B*08(+) animals following repeated intrarectal challenges with SIVmac239. To test this, we vaccinated Mamu-B*08(+) animals with nef inserts in which Nef RL10 was either left intact (group 1) or disrupted by mutations (group 2). Although monkeys in both groups mounted Nef-specific cellular responses, only those in group 1 developed Nef RL10-specific CD8(+) T cells. These vaccine-induced effector memory CD8(+) T cells did not prevent infection. Escape variants emerged rapidly in the group 1 vaccinees, and ultimately, the numbers of ECs were similar in groups 1 and 2. High-frequency vaccine-induced CD8(+) T cells focused on a single conserved epitope and therefore did not prevent infection or increase the incidence of elite control in Mamu-B*08(+) macaques. IMPORTANCE Since elite control of chronic-phase viremia is a classic example of an effective immune response against HIV/SIV, elucidating the basis of this phenomenon may provide useful insights into how to elicit such responses by vaccination. We have previously established that vaccine-induced CD8(+) T-cell responses against three immunodominant epitopes can increase the incidence of elite control in SIV-infected Mamu-B*08(+) rhesus macaques—a model of HLA-B*27-mediated elite control. Here, we investigated whether a monotypic vaccine-induced CD8(+) T-cell response targeting the conserved “late-escaping” Nef RL10 epitope can increase the incidence of elite control in Mamu-B*08(+) monkeys. Surprisingly, vaccine-induced Nef RL10-specific CD8(+) T cells selected for variants within days after infection and, ultimately, did not facilitate the development of elite control. Elite control is, therefore, likely to involve CD8(+) T-cell responses against more than one epitope. Together, these results underscore the complexity and multidimensional nature of virologic control of lentivirus infection

The Frequency of Vaccine-Induced T-Cell Responses Does Not Predict the Rate of Acquisition after Repeated Intrarectal SIVmac239 Challenges in Mamu-B08 + Rhesus Macaques

Approximately 50% of rhesus macaques (RMs) expressing the major histocompatibility complex class I (MHC-I) allele spontaneously control chronic-phase viremia after infection with the pathogenic simian immunodeficiency virus mac239 (SIVmac239) clone. CD8 T-cell responses in these animals are focused on immunodominant Mamu-B*08-restricted SIV epitopes in Vif and Nef, and prophylactic vaccination with these epitopes increases the incidence of elite control in SIVmac239-infected -positive ( ) RMs. Here we evaluated if robust vaccine-elicited CD8 T-cell responses against Vif and Nef can prevent systemic infection in RMs following mucosal SIV challenges. Ten RMs were vaccinated with a heterologous prime/boost/boost regimen encoding Vif and Nef, while six sham-vaccinated MHC-I-matched RMs served as the controls for this experiment. Vaccine-induced CD8 T cells against Mamu-B*08-restricted SIV epitopes reached high frequencies in blood but were present at lower levels in lymph node and gut biopsy specimens. Following repeated intrarectal challenges with SIVmac239, all control RMs became infected by the sixth SIV exposure. By comparison, four vaccinees were still uninfected after six challenges, and three of them remained aviremic after 3 or 4 additional challenges. The rate of SIV acquisition in the vaccinees was numerically lower (albeit not statistically significantly) than that in the controls. However, peak viremia was significantly reduced in infected vaccinees compared to control animals. We found no T-cell markers that distinguished vaccinees that acquired SIV infection from those that did not. Additional studies will be needed to validate these findings and determine if cellular immunity can be harnessed to prevent the establishment of productive immunodeficiency virus infection. It is generally accepted that the antiviral effects of vaccine-induced classical CD8 T-cell responses against human immunodeficiency virus (HIV) are limited to partial reductions in viremia after the establishment of productive infection. Here we show that rhesus macaques (RMs) vaccinated with Vif and Nef acquired simian immunodeficiency virus (SIV) infection at a lower (albeit not statistically significant) rate than control RMs following repeated intrarectal challenges with a pathogenic SIV clone. All animals in the present experiment expressed the elite control-associated major histocompatibility complex class I (MHC-I) molecule Mamu-B*08 that binds immunodominant epitopes in Vif and Nef. Though preliminary, these results provide tantalizing evidence that the protective efficacy of vaccine-elicited CD8 T cells may be greater than previously thought. Future studies should examine if vaccine-induced cellular immunity can prevent systemic viral replication in RMs that do not express MHC-I alleles associated with elite control of SIV infection

Vaccine-Induced Simian Immunodeficiency Virus-Specific CD8 TCell Responses Focused on a Single Nef Epitope Select for Escape Variants Shortly after Infection

Submitted by sandra infurna ([email protected]) on 2016-05-24T12:52:58Z No. of bitstreams: 1 noemia_lima_etal_IOC_2015.pdf: 4329443 bytes, checksum: 07ae819d17aad8154e81d4a63ea57ee2 (MD5)Approved for entry into archive by sandra infurna ([email protected]) on 2016-06-02T13:02:47Z (GMT) No. of bitstreams: 1 noemia_lima_etal_IOC_2015.pdf: 4329443 bytes, checksum: 07ae819d17aad8154e81d4a63ea57ee2 (MD5)Made available in DSpace on 2016-06-02T13:02:47Z (GMT). No. of bitstreams: 1 noemia_lima_etal_IOC_2015.pdf: 4329443 bytes, checksum: 07ae819d17aad8154e81d4a63ea57ee2 (MD5) Previous issue date: 2015Made available in DSpace on 2016-06-03T12:34:19Z (GMT). No. of bitstreams: 2 noemia_lima_etal_IOC_2015.pdf: 4329443 bytes, checksum: 07ae819d17aad8154e81d4a63ea57ee2 (MD5) license.txt: 2991 bytes, checksum: 5a560609d32a3863062d77ff32785d58 (MD5) Previous issue date: 2015University of Miami. Department of Pathology. Miami, Florida, USA.Ragon Institute of MGH. MIT. Harvard. Cambridge. Massachusetts, USA.University of Miami. Department of Pathology. Miami, Florida, USA.Ragon Institute of MGH. MIT. Harvard. Cambridge. Massachusetts, USA.University of Miami. Department of Pathology. Miami, Florida, USA.Ragon Institute of MGH. MIT. Harvard. Cambridge. Massachusetts, USA.Ragon Institute of MGH. MIT. Harvard. Cambridge. Massachusetts, USA.Ragon Institute of MGH. MIT. Harvard. Cambridge. Massachusetts, USA.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Molecular de Flavivírus. Rio de Janeiro, RJ, Brasil.University of Miami. Department of Pathology. Miami, Florida, USA.University of Alabama. Department of Biostatistics. Section on Statistical Genetics. Birmingham, Alabama, USA.University of Alabama. Department of Biostatistics. Section on Statistical Genetics. Birmingham, Alabama, USA.Frederick National Laboratory. Leidos Biomedical Research, Inc. AIDS and Cancer Virus Program. Frederick, Maryland, USA.Emory University. Department of Microbiology and Immunology. Atlanta, Georgia, USA.Brooklyn Army Terminal. AIDS Vaccine Design and Development Laboratory. International AIDS Vaccine Initiative. Brooklyn, New York, USA.University of Wisconsin—Madison. Wisconsin National Primate Research Center. Madison, Wisconsin, USA.University of Wisconsin—Madison. Wisconsin National Primate Research Center. Madison, Wisconsin, USA.Fundação Oswaldo Cruz. Instituto de Tecnologia em Imunobiológicos. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Molecular de Flavivírus. Rio de Janeiro, RJ, Brasil.Frederick National Laboratory. Leidos Biomedical Research, Inc. AIDS and Cancer Virus Program. Frederick, Maryland, USA.Ragon Institute of MGH. MIT. Harvard. Cambridge. Massachusetts, USA.University of Miami. Department of Pathology. Miami, Florida, USA.Certain major histocompatibility complex class I (MHC-I) alleles (e.g., HLA-B*27) are enriched among human immunodeficiency virus type 1 (HIV-1)-infected individuals who suppress viremia without treatment (termed "elite controllers" [ECs]). Likewise, Mamu-B*08 expression also predisposes rhesus macaques to control simian immunodeficiency virus (SIV) replication. Given the similarities between Mamu-B*08 and HLA-B*27, SIV-infected Mamu-B*08(+) animals provide a model to investigate HLA-B*27-mediated elite control. We have recently shown that vaccination with three immunodominant Mamu-B*08-restricted epitopes (Vif RL8, Vif RL9, and Nef RL10) increased the incidence of elite control in Mamu-B*08(+) macaques after challenge with the pathogenic SIVmac239 clone. Furthermore, a correlate analysis revealed that CD8(+) T cells targeting Nef RL10 was correlated with improved outcome. Interestingly, this epitope is conserved between SIV and HIV-1 and exhibits a delayed and atypical escape pattern. These features led us to postulate that a monotypic vaccine-induced Nef RL10-specific CD8(+) T-cell response would facilitate the development of elite control in Mamu-B*08(+) animals following repeated intrarectal challenges with SIVmac239. To test this, we vaccinated Mamu-B*08(+) animals with nef inserts in which Nef RL10 was either left intact (group 1) or disrupted by mutations (group 2). Although monkeys in both groups mounted Nef-specific cellular responses, only those in group 1 developed Nef RL10-specific CD8(+) T cells. These vaccine-induced effector memory CD8(+) T cells did not prevent infection. Escape variants emerged rapidly in the group 1 vaccinees, and ultimately, the numbers of ECs were similar in groups 1 and 2. High-frequency vaccine-induced CD8(+) T cells focused on a single conserved epitope and therefore did not prevent infection or increase the incidence of elite control in Mamu-B*08(+) macaques. IMPORTANCE: Since elite control of chronic-phase viremia is a classic example of an effective immune response against HIV/SIV, elucidating the basis of this phenomenon may provide useful insights into how to elicit such responses by vaccination. We have previously established that vaccine-induced CD8(+) T-cell responses against three immunodominant epitopes can increase the incidence of elite control in SIV-infected Mamu-B*08(+) rhesus macaques—a model of HLA-B*27-mediated elite control. Here, we investigated whether a monotypic vaccine-induced CD8(+) T-cell response targeting the conserved "late-escaping" Nef RL10 epitope can increase the incidence of elite control in Mamu-B*08(+) monkeys. Surprisingly, vaccine-induced Nef RL10-specific CD8(+) T cells selected for variants within days after infection and, ultimately, did not facilitate the development of elite control. Elite control is, therefore, likely to involve CD8(+) T-cell responses against more than one epitope. Together, these results underscore the complexity and multidimensional nature of virologic control of lentivirus infection

Vaccine-induced CD8+ T cells control AIDS virus replication

Developing a vaccine for HIV may be aided by a complete understanding of those rare cases where some HIV-infected individuals control replication of the virus 1 – 3 . The majority of these elite controllers (ECs) express HLA-B*57 or HLA-B*27 3 . These alleles remain by far the most robust associations with low concentrations of plasma virus 4 , 5 , yet the mechanism of control in these individuals is not entirely clear. Here we vaccinated Indian rhesus macaques that express Mamu-B*08 , an animal model for HLA-B*27 - mediated elite control 6 , with three Mamu-B*08-restricted CD8 + T cell epitopes and demonstrate that these vaccinated animals controlled replication of the highly pathogenic SIVmac239 clonal virus. High frequencies of CD8 + T cells against these Vif and Nef epitopes in the blood, lymph nodes and colon, were associated with viral control. Moreover, the frequency of the Nef RL10-specific response correlated significantly with reduced acute phase viremia. Finally, two of the eight vaccinees lost control of viral replication in the chronic phase, concomitant with escape in all three targeted epitopes, further implicating these three CD8 + T cell responses in control of viral replication. Our findings indicate that narrowly targeted vaccine-induced virus-specific CD8 + T cell responses can control replication of the AIDS virus

Mamu-B*17+ rhesus macaques vaccinated with env, vif, and nef manifest early control of SIVmac239 replication

Lima, Noemia S. e Bonaldo, Myrna C. - Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Molecular de Flavivírus. Rio de Janeiro, RJ, Brasil.AUTHORS - Mauricio A. Martins1*, Damien C. Tully2, Núria Pedreño-Lopez1, Benjamin von Bredow3, Matthias G. Pauthner4, Young C. Shin1, Maoli Yuan5, Noemia S. Lima6, David J. Bean2 , Lucas Gonzalez-Nieto1, Aline Domingues1, Martin J. Gutman1, Helen S. Maxwell1, Diogo M. Magnani1, Michael J. Ricciardi1, Varian K. Bailey1, John D. Altman7, Dennis R. Burton2,4, Keisuke Ejima8, David B. Allison8, David T. Evans3,9, Eva G. Rakasz9, Christopher L. Parks5, Myrna C. Bonaldo6, Saverio Capuano III9, Jeffrey D. Lifson10, Ronald C. Desrosiers1, Todd M. Allen2 , David I. Watkins1 - AFFILIATIONS - 1 Department of Pathology, University of Miami, Miami, Florida, USA. 2 Ragon Institute of MGH, MIT and Harvard, Cambridge, Massachusetts, USA 3 Department of Pathology and Laboratory Medicine, University of Wisconsin, Madison, Wisconsin, USA 4 Department of Immunology and Microbiology; IAVI Neutralizing Antibody Center; Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery (CHAVI-ID); The Scripps Research Institute, La Jolla, California, USA., 5 International AIDS Vaccine Initiative, AIDS Vaccine Design and Development Laboratory,Brooklyn, New York, USA, 6 Laboratório de Biologia Molecular de Flavivirus, Instituto Oswaldo Cruz–FIOCRUZ, Rio de Janeiro, Brazil 7 Department of Microbiology and Immunology, Emory University, Atlanta, Georgia, USA 8 School of Public Health, 24 Indiana University-Bloomington, Bloomington, Indiana, USA 9 Wisconsin National Primate Research Center, University of Wisconsin–Madison, Madison, Wisoncin, USA 10 AIDS and Cancer Virus Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.Submitted by Sandra Infurna ([email protected]) on 2018-10-01T15:19:11Z No. of bitstreams: 1 myrna2_bonaldo_etal_IOC_2018.pdf: 3441325 bytes, checksum: 778f5a9626115435750b11a4747107c5 (MD5)Approved for entry into archive by Sandra Infurna ([email protected]) on 2018-10-01T16:46:44Z (GMT) No. of bitstreams: 1 myrna2_bonaldo_etal_IOC_2018.pdf: 3441325 bytes, checksum: 778f5a9626115435750b11a4747107c5 (MD5)Made available in DSpace on 2018-10-01T16:46:44Z (GMT). No. of bitstreams: 1 myrna2_bonaldo_etal_IOC_2018.pdf: 3441325 bytes, checksum: 778f5a9626115435750b11a4747107c5 (MD5)Múltipla autoria - ver em Notas.Certain major histocompatibility complex class-I (MHC-I) alleles are associated with spontaneous control of viral replication in human immunodeficiency virus (HIV)-infected people and simian immunodeficiency virus (SIV)-infected rhesus macaques (RMs). These cases of “elite” control of HIV/SIV replication are often immune-mediated, thereby providing a framework for studying anti-lentiviral immunity. Here we examined how vaccination impacts SIV replication in RMs expressing the MHC-I allele Mamu-B*17. Approximately 21% of Mamu-B*17+ and 50% of Mamu-B*08+ RMs control chronic phase viremia after SIVmac239 infection. Because CD8+ T-cells targeting Mamu-B*08-restricted SIV epitopes have been implicated in virologic suppression in Mamu-B*08+ RMs, we investigated whether this might also be true for Mamu-B*17+ RMs. Two groups of Mamu-B*17+ RMs were vaccinated with genes encoding Mamu-B*17-restricted epitopes in Vif and Nef. These genes were delivered by themselves (Group 1) or together with env (Group 2). Group 3 included MHC-I-matched RMs and served as the control group. Surprisingly, the Group 1 vaccine regimen had little effect on viral replication compared to Group 3, suggesting that, unlike Mamu-B*08+ RMs, pre-existing SIV-specific CD8+ T-cells alone do not facilitate long term virologic suppression in Mamu-B*17+ RMs. Remarkably, however, 5/8 Group 2 vaccinees controlled viremia to <15 viral RNA copies/mL soon after infection. No serological neutralizing activity against SIVmac239 was detected in Group 2, although vaccine-elicited gp140-binding antibodies correlated inversely with nadir viral loads. Collectively, these data shed new light into the unique mechanism of elite control in Mamu-B*17+ RMs and implicate vaccine-induced, non-neutralizing anti-Env antibodies in the containment of immunodeficiency virus infection

Vaccine-induced immune responses against both Gag and Env improve control of simian immunodeficiency virus replication in rectally challenged rhesus macaques

<div><p>The ability to control lentivirus replication may be determined, in part, by the extent to which individual viral proteins are targeted by the immune system. Consequently, defining the antigens that elicit the most protective immune responses may facilitate the design of effective HIV-1 vaccines. Here we vaccinated four groups of rhesus macaques with a heterologous vector prime/boost/boost/boost (PBBB) regimen expressing the following simian immunodeficiency virus (SIV) genes: <i>env</i>, <i>gag</i>, <i>vif</i>, <i>rev</i>, <i>tat</i>, and <i>nef</i> (Group 1); <i>env</i>, <i>vif</i>, <i>rev</i>, <i>tat</i>, and <i>nef</i> (Group 2); <i>gag</i>, <i>vif</i>, <i>rev</i>, <i>tat</i>, and <i>nef</i> (Group 3); or <i>vif</i>, <i>rev</i>, <i>tat</i>, and <i>nef</i> (Group 4). Following repeated intrarectal challenges with a marginal dose of the neutralization-resistant SIVmac239 clone, vaccinees in Groups 1–3 became infected at similar rates compared to control animals. Unexpectedly, vaccinees in Group 4 became infected at a slower pace than the other animals, although this difference was not statistically significant. Group 1 exhibited the best post-acquisition virologic control of SIV infection, with significant reductions in both peak and chronic phase viremia. Indeed, 5/8 Group 1 vaccinees had viral loads of less than 2,000 vRNA copies/mL of plasma in the chronic phase. Vaccine regimens that did not contain <i>gag</i> (Group 2), <i>env</i> (Group 3), or both of these inserts (Group 4) were largely ineffective at decreasing viremia. Thus, vaccine-induced immune responses against both Gag and Env appeared to maximize control of immunodeficiency virus replication. Collectively, these findings are relevant for HIV-1 vaccine design as they provide additional insights into which of the lentiviral proteins might serve as the best vaccine immunogens.</p></div

Quantitative definition of neurobehavior, vision, hearing and brain volumes in macaques congenitally exposed to Zika virus.

Congenital Zika virus (ZIKV) exposure results in a spectrum of disease ranging from severe birth defects to delayed onset neurodevelopmental deficits. ZIKV-related neuropathogenesis, predictors of birth defects, and neurodevelopmental deficits are not well defined in people. Here we assess the methodological and statistical feasibility of a congenital ZIKV exposure macaque model for identifying infant neurobehavior and brain abnormalities that may underlie neurodevelopmental deficits. We inoculated five pregnant macaques with ZIKV and mock-inoculated one macaque in the first trimester. Following birth, growth, ocular structure/function, brain structure, hearing, histopathology, and neurobehavior were quantitatively assessed during the first week of life. We identified the typical pregnancy outcomes of congenital ZIKV infection, with fetal demise and placental abnormalities. We estimated sample sizes needed to define differences between groups and demonstrated that future studies quantifying brain region volumes, retinal structure, hearing, and visual pathway function require a sample size of 14 animals per group (14 ZIKV, 14 control) to detect statistically significant differences in at least half of the infant exam parameters. Establishing the parameters for future studies of neurodevelopmental outcomes following congenital ZIKV exposure in macaques is essential for robust and rigorous experimental design