UMass Center for Clinical and Translational Science: Past, Present and Future

Katherine Luzuriaga, MD, is PI and Director, UMass Center for Clinical and Translational Science and Vice Provost, Clinical and Translational Research at UMass Medical School. Dr. Luzuriaga is also the UMass Memorial Health Care Chair in Biomedical Research and Professor, Program in Molecular Medicine, Pediatrics and Medicine. In her presentation, she reviews the history, goals, programs and achievements of the UMass Center for Clinical and Translational Science

Global Translational Research and Education

Learn about how the UMMS Office of Global Health (OGH) assists researchers to enhance and expand UMMS research and training programs in global health improvement and disease prevention

Determinants of precocious B-cell aging in European adolescents living with perinatally acquired HIV-1 after over 10 years of suppressive therapy [preprint]

HIV infection results in a state of chronic immune activation leading to premature immune aging, B-cells dysfunction, that persists despite prolonged virological suppression. In this scenario, adolescence living with perinatally acquired HIV (PHIV), deserve a peculiar attention since potentially exposed for their entire life to chronic immune activation. Here we identified determinants of precocious aging B cells in 40 PHIV undergoing suppressive antiretroviral therapy (ART) for median 13.5 years. All individuals started ART by 2nd year of life and achieved virus suppression within the 1st year of ART, with majority of patient maintaining suppression until analysis and 5/40 experiencing viral Spike (transient elevation of HIV-1 VL, 50-999 copies/ml). We employed a multiomics approach including deep immunological B and T cell phenotype in PBMC, with aging B cells defined by the expression of T-bet and CD11c; plasma proteomics analysis by mass spectrometry and serum level of anti-measles antibodies as correlates of humoral response. We found that individuals with expansion of aging B cell, defined by the expression of T-bet+CD11c+, were those starting treatment later, presenting detectable levels of cell-associated HIV-1 RNA, history of Spikes, and a higher frequency of exhausted T-cells, including those expressing PD-1, LAG3, TIGIT. Accordingly, the proteomic analysis revealed that subjects with expansion of aging B cells and exhausted T cells had enrichment of proteins involved in immune inflammation and complement activation pathways, such as CLU and APCS which are also involved in tumor progression. Signs of precocious aging were associated with a reduced capacity to maintain virological memory against measles vaccination. To our knowledge, this is the first study focusing on precocious B-cell aging and dysfunctionality in PHIV with long-term virological suppression. Our experimental strategy enabled identification of clinical, viral, cellular and plasma soluble markers associated with B-cells aging. Our results pave the way to further define risk of disease progression or lymphoproliferative disorders in PHIV

Education and Career Development

This presentation describes educational programs for trainees and faculty that are offered through the UMCCTS

Early HIV-1 Envelope-specific Cytotoxic T Lymphocyte Responses in Vertically Infected Infants

High frequencies of cytotoxic T lymphocyte precursors (CTLp) recognizing HIV-1 laboratory strain gene products have been detected in adults within weeks of primary infection. In contrast, HIV-1–specific CTLp are uncommonly detected in infants younger than 6 mo. To address the hypothesis that the use of target cells expressing laboratory strain env gene products might limit the detection of HIV-1 env-specific CTLp in early infancy, recombinant vaccinia vectors (vv) expressing HIV-1 env genes from early isolates of four vertically infected infants were generated. The frequencies of CTLp recognizing target cells infected with vv-expressing env gene products from early isolates and HIV-1 IIIB were serially measured using limiting dilution followed by in vitro stimulation with mAb to CD3. In one infant, the detection of early isolate env-specific CTLp preceded the detection of IIIB-specific CTLp. CTLp recognizing HIV-1 IIIB and infant isolate env were detected by 6 mo of age in two infants. In a fourth infant, HIV-1 IIIB env and early isolate env-specific CTLp were simultaneously detected at 12 mo of age. These results provide evidence that young infants can generate HIV-1–specific CTL responses and provide support for the concept of neonatal vaccination to prevent HIV-1 transmission. However, the early predominance of type-specific CTL detected in some young infants suggests that the use of vaccines based on laboratory strains of HIV-1 may not protect against vertical infection

Recombination elevates the effective evolutionary rate and facilitates the establishment of HIV-1 infection in infants after mother-to-child transmission

BACKGROUND: Previous studies have demonstrated that single HIV-1 genotypes are commonly transmitted from mother to child, but such analyses primarily used single samples from mother and child. It is possible that in a single sample, obtained early after infection, only the most replication competent virus is detected even when other forms may have been transmitted. Such forms may have advantages later in infection, and may thus be detected in follow-up samples. Because HIV-1 frequently recombines, phylogenetic analyses that ignore recombination may miss transmission of multiple forms if they recombine after transmission. Moreover, recombination may facilitate adaptation, thus providing an advantage in establishing infection. The effect of recombination on viral evolution in HIV-1 infected children has not been well defined. RESULTS: We analyzed full-length env sequences after single genome amplification from the plasma of four subtype B HIV-1 infected women (11-67 env clones from 1 time point within a month prior to delivery) and their non-breastfed, intrapartum-infected children (3-6 longitudinal time points per child starting at the time of HIV-1 diagnosis). To address the potential beneficial or detrimental effects of recombination, we used a recently developed hierarchical recombination detection method based on the pairwise homoplasy index (PHI)-test. Recombination was observed in 9-67% of the maternal sequences and in 25-60% of the child sequences. In the child, recombination only occurred between variants that had evolved after transmission; taking recombination into account, we identified transmission of only 1 or 2 phylogenetic lineages from mother to child. Effective HIV-1 evolutionary rates of HIV-1 were initially high in the child and slowed over time (after 1000 days). Recombination was associated with elevated evolutionary rates. CONCLUSIONS: Our results confirm that 1-2 variants are typically transmitted from mothers to their newborns. They also demonstrate that early abundant recombination elevates the effective evolutionary rate, suggesting that recombination increases the rate of adaptation in HIV-1 evolution

Severity of Infectious Mononucleosis (IM) Correlates with the Frequency of Crossreactive Influenza A Virus (IAV)-M1 and Epstein Barr Virus (EBV)-BMLF-1-specific CD8 T Cells

During EBV-associated IM IAV-specific crossreactive memory T cells are activated and play a role in disease severity. In HLA-A2+ IM patients, influenza M158 (IAV-M1)-specific CD8 memory T cell responses crossreacted with two different EBV lytic epitopes, BMLF1280 (17/29) and BRLF1190 (19/20). Furthermore, 11/22 IM patients demonstrated some intra-viral crossreactivity between EBV-BRLF1 and -BMLF1 responses. Disease severity of IM directly correlated with significantly increased frequencies of crossreactive IAV-M1/EBV-BMLF1, IAV-M1, and EBV-BMLF1 specific CD8 cells, and with mean viral load over the first 5 weeks of infection. Disease severity did not correlate with BRLF1 or M1/BRLF1 crossreactive responses. When severity of IM was scored and patients were assigned to either mild or severe groups, disease severity correlated with specific TCR Vb usage in IAV-M1 population suggesting that TcR selection is driving disease outcome. Consistent with IAV-M1 and EBV-BMLF1 responses driving increased immunopathology was the observation that patients with severe disease had significantly more IAV-M1 and EBV-BMLF1 cells producing IFNg/MIP1-b in response to antigen as compared to patients with mild disease. These results suggest that T cell crossreactivity impacts T cell selection and function and ultimately disease outcome. Insights on these issues are important for the intelligent design of vaccines and to develop therapeutic interventions for virally induced disease (NIHAI49320)

Crossreactive Epstein-Barr Virus (EBV)-Influenza A Virus (IAV) Specific CD8 Memory T Cells During Acute Symptomatic IAV Infection

We previously showed that crossreactivity is common between IAV and EBV in HLA-A2+ patients during infectious mononucleosis. IAV-M1-GIL58-66 specific CD8 T cells, along with expanded populations of IAV-M1-GIL58-66/EBV-BRLF-1109-117 -YVL and IAV-M1-GIL58-66/EBV-BMLF1280-288-GLC double-tetramer+ cells were detected directly ex-vivo in 5 HLA-A2+ patients. Altered IAV-M158-66, EBV-BRLF1119-117 and -BMLF1280-288 TCR repertoires were observed over the course of infection and in comparison to healthy donors. After culture, cells were sorted and analyzed by gene array in order to assess global changes in immune responses following different stimulations, either cognate or crossreactive, in different patient populations. M1-GIL and BRLF1-YVL specific cells had similar immune-response gene signatures, but the -GLC specific CD8 cells were more similar to the two-crossreactive populations. Crossreactive M1-GIL/BRLF1-YVL cells from the BRLF1-YVL line were different in their activation status than the BRLF1-specific cells, consistent with BRLF1-YVL ligand stimulation of different gene activation profiles in these two populations. These results suggest that during symptomatic IAV infection there is an expansion of EBV/IAV crossreactive memory CD8 T cell responses. Ongoing studies are investigating whether EBV-IAV cross-reactive CD8+ T cells may contribute to immunopathology during acute IAV infection (NIH / NIAID PO1 AI 049320)

Genotypic and functional properties of early infant HIV-1 envelopes

<p>Abstract</p> <p>Background</p> <p>Understanding the properties of HIV-1 variants that are transmitted from women to their infants is crucial to improving strategies to prevent transmission. In this study, 162 full-length <it>envelope </it>(<it>env</it>) clones were generated from plasma RNA obtained from 5 HIV-1 Clade B infected mother-infant pairs. Following extensive genotypic and phylogenetic analyses, 35 representative clones were selected for functional studies.</p> <p>Results</p> <p>Infant quasispecies were highly homogeneous and generally represented minor maternal variants, consistent with transmission across a selective bottleneck. Infant clones did not differ from the maternal in <it>env </it>length, or glycosylation. All infant variants utilized the CCR5 co-receptor, but were not macrophage tropic. Relatively high levels (IC₅₀≥ 100 μg/ml) of autologous maternal plasma IgG were required to neutralize maternal and infant viruses; however, all infant viruses were neutralized by pooled sera from HIV-1 infected individuals, implying that they were not inherently neutralization-resistant. All infant viruses were sensitive to the HIV-1 entry inhibitors Enfuvirtide and soluble CD4; none were resistant to Maraviroc. Sensitivity to human monoclonal antibodies 4E10, 2F5, b12 and 2G12 varied.</p> <p>Conclusions</p> <p>This study provides extensive characterization of the genotypic and functional properties of HIV-1 <it>env </it>shortly after transmission. We present the first detailed comparisons of the macrophage tropism of infant and maternal <it>env </it>variants and their sensitivity to Maraviroc, the only CCR5 antagonist approved for therapeutic use. These findings may have implications for improving approaches to prevent mother-to-child HIV-1 transmission.</p

Estudio de Conocimientos, Actitudes y Prácticas (CAP) de las estudiantes y los estudiantes de la Unidad Educativa “Octavio Cordero Palacios”, en Ecuador, respecto a las violencias en el entorno educativo. Un abordaje desde el modelo sistémico. Año 2021

Las violencias dentro del entorno educativo, representan una realidad latente que se vive a diario en las instituciones educativas del Ecuador, vulnerando los derechos y la integridad de las estudiantes y los estudiantes víctimas, pasando desapercibidas, en ocasiones, debido al desconocimiento, desinterés o indiferencia. La investigación, tiene como objetivo general identificar los conocimientos, actitudes y prácticas de las estudiantes y los estudiantes de la Unidad Educativa Octavio Cordero Palacios, en Cuenca - Ecuador, respecto a las violencias, a partir de un enfoque sistémico desde el Trabajo Social. Se aplicó un enfoque de investigación cuantitativo, a través de un censo a 97 estudiantes de 14 a 18 años que cursan el primero, segundo y tercero de bachillerato de las secciones (matutina y vespertina). El diseño de investigación es descriptivo y transversal, usando para la recopilación de datos, el cuestionario, conformado por un módulo sociodemográfico, un segundo aplicado a los sistemas sociales y tres módulos orientados a obtener registros sobre los conocimientos, actitudes y prácticas. Se identificó que, los estudiantes y las estudiantes tienen amplios conocimientos sobre las violencias. Referente a las actitudes, los estudiantes y las estudiantes manifiestan rechazo frente a hechos violentos. En la práctica, muestran conductas en contra de cualquier manifestación de violencia. El confinamiento por Covid-19 provocó un cambio de modalidad para la formación, de la presencialidad a la virtualidad. Los estudiantes y las estudiantes expresaron que el ciberbullying ha surgido durante la pandemia dentro de las clases virtuales. Por medio del modelo sistémico desde la perspectiva de trabajo social, los estudiantes y las estudiantes consideran a la familia y colegio, como un lugar seguro y confiable, mientras que, con el barrio, la mayoría de estudiantes no sienten tal afinidad.Violence within the educational environment represents a latent reality that is experienced daily in educational institutions in Ecuador, violating the rights and integrity of students and student victims, sometimes going unnoticed due to ignorance, disinterest or indifference. The general objective of this research is to identify the knowledge, attitudes and practices of the students of the Octavio Cordero Palacios Educational Unit, in Cuenca - Ecuador, regarding violence, based on a systemic approach from Social Work. A quantitative research approach was applied, through a census of 97 students from 14 to 18 years old, who are in the first, second and third year of high school in the morning and afternoon sections. The research design is descriptive and cross-sectional, using a questionnaire for data collection, consisting of a sociodemographic module, a second one applied to social systems and three modules oriented to obtain records on knowledge, attitudes and practices. It was identified that the students have ample knowledge about violence. Regarding attitudes, most of students express rejection of violent acts. In practice, most students show behaviors against any manifestation of violence. The confinement by Covid-19 caused a change in the training modality, from face-to-face to virtual. Students expressed that cyberbullying has emerged during the pandemic within virtual classes. Through the systemic model from the perspective of social work, students consider the family and school as a safe and reliable place, while with the neighborhood, most students do not feel such affinity.0000-0003-0704-2580Licenciada en Trabajo SocialCuenc