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  • 1
    In: Journal of Virology, American Society for Microbiology, Vol. 86, No. 12 ( 2012-06-15), p. 6835-6846
    Abstract: CD8-mediated virus inhibition can be detected in HIV-1-positive subjects who naturally control virus replication. Characterizing the inhibitory function of CD8 + T cells during acute HIV-1 infection (AHI) can elucidate the nature of the CD8 + responses that can be rapidly elicited and that contribute to virus control. We examined the timing and HIV-1 antigen specificity of antiviral CD8 + T cells during AHI. Autologous and heterologous CD8 + T cell antiviral functions were assessed longitudinally during AHI in five donors from the CHAVI 001 cohort using a CD8 + T cell-mediated virus inhibition assay (CD8 VIA) and transmitted/founder (T/F) viruses. Potent CD8 + antiviral responses against heterologous T/F viruses appeared during AHI at the first time point sampled in each of the 5 donors (Fiebig stages 1/2 to 5). Inhibition of an autologous T/F virus was durable to 48 weeks; however, inhibition of heterologous responses declined concurrent with the resolution of viremia. HIV-1 viruses from 6 months postinfection were more resistant to CD8 + -mediated virus inhibition than cognate T/F viruses, demonstrating that the virus escapes early from CD8 + T cell-mediated inhibition of virus replication. CD8 + T cell antigen-specific subsets mediated inhibition of T/F virus replication via soluble components, and these soluble responses were stimulated by peptide pools that include epitopes that were shown to drive HIV-1 escape during AHI. These data provide insights into the mechanisms of CD8-mediated virus inhibition and suggest that functional analyses will be important for determining whether similar antigen-specific virus inhibition can be induced by T cell-directed vaccine strategies.
    Type of Medium: Online Resource
    ISSN: 0022-538X , 1098-5514
    Language: English
    Publisher: American Society for Microbiology
    Publication Date: 2012
    detail.hit.zdb_id: 1495529-5
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  • 2
    In: Clinical Trials, SAGE Publications, Vol. 20, No. 5 ( 2023-10), p. 457-462
    Abstract: The clinical and translational research enterprise is recognized by many as the “evidence generation system.” While there have been several calls to revolutionize this enterprise to more effectively deliver the fruits of biomedical science to patients and society, significant issues across the clinical research workforce are pervasive. Perhaps the most visible sign is the widening gap between supply and demand for competent staff. Underpinning this, is a perfect storm of complex issues. Now reaching crisis point, this problem is far bigger than a staffing issue and ultimately jeopardizes the “engine” of drug and device development. With the current perilous state of the workforce, proposed enterprise fixes are likely to languish far out of reach, given that even “business as usual” is under threat. In fact, a glaring disconnect is evident between the visionary discourse on how to revolutionize the clinical research enterprise and the sober recognition that operationalization of any such vision rests on the shoulders of a workforce that’s in dire straits. In this article, we provide a brief forensic analysis of the workforce problem and an initial indication of where solutions may lie.
    Type of Medium: Online Resource
    ISSN: 1740-7745 , 1740-7753
    Language: English
    Publisher: SAGE Publications
    Publication Date: 2023
    detail.hit.zdb_id: 2159773-X
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  • 3
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 104, No. 31 ( 2007-07-31), p. 12772-12777
    Abstract: Enfuvirtide (ENF), the first approved fusion inhibitor (FI) for HIV, is a 36-aa peptide that acts by binding to the heptad repeat 1 (HR1) region of gp41 and preventing the interaction of the HR1 and HR2 domains, which is required for virus–cell fusion. Treatment-acquired resistance to ENF highlights the need to create FI therapeutics with activity against ENF-resistant viruses and improved durability. Using rational design, we have made a series of oligomeric HR2 peptides with increased helical structure and with exceptionally high HR1/HR2 bundle stability. The engineered peptides are found to be as much as 3,600-fold more active than ENF against viruses that are resistant to the HR2 peptides ENF, T-1249, or T-651. Passaging experiments using one of these peptides could not generate virus with decreased sensitivity, even after 〉 70 days in culture, suggesting superior durability as compared with ENF. In addition, the pharmacokinetic properties of the engineered peptides were improved up to 100-fold. The potent antiviral activity against resistant viruses, the difficulty in generating resistant virus, and the extended half-life in vivo make this class of fusion inhibitor peptide attractive for further development.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    RVK:
    RVK:
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2007
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
    SSG: 11
    SSG: 12
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  • 4
    In: Journal of Clinical Investigation, American Society for Clinical Investigation, Vol. 130, No. 3 ( 2020-2-10), p. 1058-1061
    Type of Medium: Online Resource
    ISSN: 0021-9738 , 1558-8238
    Language: English
    Publisher: American Society for Clinical Investigation
    Publication Date: 2020
    detail.hit.zdb_id: 2018375-6
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  • 5
    In: Journal of Virology, American Society for Microbiology, Vol. 75, No. 10 ( 2001-05-15), p. 4936-4940
    Abstract: The gp120 V3-encoding region of human immunodeficiency virus type 1 (HIV-1) RNA derived from the saliva and blood plasma of 11 individuals was characterized by heteroduplex tracking assay and sequence analyses. R5-like viral variants were identified in both fluids of all subjects. X4-like variants were detected in the plasma and/or saliva of three subjects, indicating that X4-like variants are not excluded from the saliva compartment. Viral subpopulations were similar in both fluids of most subjects, suggesting that HIV-1 in oral fluids and blood may stem from a common source. These findings raise the possibility of using saliva as a noninvasive fluid for evaluating and monitoring viral evolution in infected persons.
    Type of Medium: Online Resource
    ISSN: 0022-538X , 1098-5514
    Language: English
    Publisher: American Society for Microbiology
    Publication Date: 2001
    detail.hit.zdb_id: 1495529-5
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  • 6
    In: Journal of Virology, American Society for Microbiology, Vol. 88, No. 17 ( 2014-09), p. 9514-9528
    Abstract: The ability of CD8 + T cells to effectively limit HIV-1 replication and block HIV-1 acquisition is determined by the capacity to rapidly respond to HIV-1 antigens. Understanding both the functional properties and regulation of an effective CD8 + response would enable better evaluation of T cell-directed vaccine strategies and may inform the design of new therapies. We assessed the antigen specificity, cytokine signature, and mechanisms that regulate antiviral gene expression in CD8 + T cells from a cohort of HIV-1-infected virus controllers (VCs) ( 〈 5,000 HIV-1 RNA copies/ml and CD4 + lymphocyte counts of 〉 400 cells/μl) capable of soluble inhibition of HIV-1. Gag p24 and Nef CD8 + T cell-specific soluble virus inhibition was common among the VCs and correlated with substantial increases in the abundance of mRNAs encoding the antiviral cytokines macrophage inflammatory proteins MIP-1α, MIP-1αP (CCL3L1), and MIP-1β; granulocyte-macrophage colony-stimulating factor (GM-CSF); lymphotactin (XCL1); tumor necrosis factor receptor superfamily member 9 (TNFRSF9); and gamma interferon (IFN-γ). The induction of several of these mRNAs was driven through a coordinated response of both increased transcription and stabilization of mRNA, which together accounted for the observed increase in mRNA abundance. This coordinated response allows rapid and robust induction of mRNA messages that can enhance the CD8 + T cells' ability to inhibit virus upon antigen encounter. IMPORTANCE We show that mRNA stability, in addition to transcription, is key in regulating the direct anti-HIV-1 function of antigen-specific memory CD8 + T cells. Regulation at the level of RNA helps enable rapid recall of memory CD8 + T cell effector functions for HIV-1 inhibition. By uncovering and understanding the mechanisms employed by CD8 + T cell subsets with antigen-specific anti-HIV-1 activity, we can identify new strategies for comprehensive identification of other important antiviral genes. This will, in turn, enhance our ability to inhibit virus replication by informing both cure strategies and HIV-1 vaccine designs that aim to reduce transmission and can aid in blocking HIV-1 acquisition.
    Type of Medium: Online Resource
    ISSN: 0022-538X , 1098-5514
    Language: English
    Publisher: American Society for Microbiology
    Publication Date: 2014
    detail.hit.zdb_id: 1495529-5
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  • 7
    In: AIDS, Ovid Technologies (Wolters Kluwer Health), Vol. 17, No. 14 ( 2003-09), p. 2025-2033
    Type of Medium: Online Resource
    ISSN: 0269-9370
    RVK:
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2003
    detail.hit.zdb_id: 2012212-3
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  • 8
    In: Journal of Virology, American Society for Microbiology, Vol. 84, No. 10 ( 2010-05-15), p. 4998-5006
    Abstract: Control of HIV-1 replication following nonsterilizing HIV-1 vaccination could be achieved by vaccine-elicited CD8 + T-cell-mediated antiviral activity. To date, neither the functional nor the phenotypic profiles of CD8 + T cells capable of this activity are clearly understood; consequently, little is known regarding the ability of vaccine strategies to elicit them. We used multiparameter flow cytometry and viable cell sorts from phenotypically defined CD8 + T-cell subsets in combination with a highly standardized virus inhibition assay to evaluate CD8 + T-cell-mediated inhibition of viral replication. Here we show that vaccination against HIV-1 Env and Gag-Pol by DNA priming followed by recombinant adenovirus type 5 (rAd5) boosting elicited CD8 + T-cell-mediated antiviral activity against several viruses with either lab-adapted or transmitted virus envelopes. As it did for chronically infected virus controllers, this activity correlated with HIV-1-specific CD107a or macrophage inflammatory protein 1β (MIP-1β) expression from HIV-1-specific T cells. Moreover, for vaccinees or virus controllers, purified memory CD8 + T cells from a wide range of differentiation stages were capable of significantly inhibiting virus replication. Our data define attributes of an antiviral CD8 + T-cell response that may be optimized in the search for an efficacious HIV-1 vaccine.
    Type of Medium: Online Resource
    ISSN: 0022-538X , 1098-5514
    Language: English
    Publisher: American Society for Microbiology
    Publication Date: 2010
    detail.hit.zdb_id: 1495529-5
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  • 9
    Online Resource
    Online Resource
    Cambridge University Press (CUP) ; 2019
    In:  Journal of Clinical and Translational Science Vol. 3, No. s1 ( 2019-03), p. 77-78
    In: Journal of Clinical and Translational Science, Cambridge University Press (CUP), Vol. 3, No. s1 ( 2019-03), p. 77-78
    Abstract: OBJECTIVES/SPECIFIC AIMS: 1.Assess changes in clinical research workforce landscape at Duke 2.Optimize and evaluate efficacy of a tier advancement process for clinical research career progression at Duke 3.Implement CRP engagement as a change management mechanism for workforce innovation METHODS/STUDY POPULATION: We evaluated 857 clinical research positions at Duke to understand changes in the workforce (demographics, numbers in each position and tier) since implementing the tier advancement process in 2016. To understand the efficacy of the tier assessment process, data from a subset of this population (n=84) who underwent the advancement process was examined for success rate. Individual employees and their managers were surveyed to understand their perception of the advancement process and identify areas for improvement. We also describe implementation of multiple mechanisms of community engagement to manage expectations around the tier advancement process and to provide opportunities for employees to self-manage their career planning, including portfolio planning and leadership opportunities. RESULTS/ANTICIPATED RESULTS: Whereas the clinical research workforce has grown by 5.5% since tiering began (2016, n=810; 2018 n=857). Nearly 13% of that growth has been in managerial or senior positions (2016, n=111; 2018 n=127). Distributions across job classifications changed only slightly, representing realignment of positions with study-level responsibilities over department-level responsibilities. Notably, clinical research nurses (CRNC & CRNC Sr.) was the only category including tiered and non-tiered positions to drop overall numbers between 2016 (n = 136) and 2018 (n=115), representing a shift in the workforce from research nurses to research coordinators. General demographics (gender, age) remained largely the same. A total of 359 positions have been hired during this time frame, nearly half of which were entry-level positions (175/359): 47 of these positions represent expansion of the workforce. Of 359 new hires since 2016, 271 currently still work in one of the research roles. Of the 84 employees who underwent the tier advancement process, 84% (43/51) succeeded in tier 2 advancement, 70% (14/20) succeeded in tier 3 advancement (CRC, CRNC, and regulatory coordinators), and 77% (10/13) of research program leaders (RPLs) succeeded in achieving tier two, which is the highest tier for this group. Fifty-five employees (65%) and 32 managers responded to a voluntary feedback survey. Overall confidence in the process improved in both groups from 2016 to 2018, most notably with managers. Both groups indicated a 10 hour reduction (employees = 35hr, 2016 and 25hr 2018; managers 25hr, 2016 and 15hr 2018) in time required to complete the tier advancement process. DISCUSSION/SIGNIFICANCE OF IMPACT: The use of objectively-assessed competencies is an important step in the development of a workforce. By 1) maintaining alignment with industry standards for competencies, 2) upholding high standards, and 3) offering a consistent approach to career growth, Duke is working to develop and maintain a workforce that supports high quality research. Since the implementation of standardized job classifications and competency-based tier advancement, the positions have undergone rigorous competency-based needs evaluation. This leads to better matched jobs to study needs as well as increased standardization across the clinical research workforce. We believe that the subtle workforce shifts represent alignment of our positions with the business needs of our clinical research enterprise. Additionally, approximately 15% of our clinical research workforce has taken advantage of the opportunity to advance their own careers. We have made significant improvements in the following tier advancement processes: standardization of assessments, scoring guides, and modes; changes from LMS to a REDCap delivery of the knowledge assessments; streamlined the utilization of electronic documentation; and additional guidance for employees and managers regarding portfolio inclusions. These improvements have increased satisfaction and acceptance with the advancement process and were made possible through strategic communication across the workforce. Regular town hall meetings and focus group feedback sessions have included the clinical research community in discussions of WE-R initiatives and provided a much-needed feedback loop for process improvement and change management. Moreover, inclusion of WE-R discussion in our Research Professional Network events has provided opportunities to discuss career advancement strategies as well as volunteer opportunities to grow and demonstrate leadership competencies.
    Type of Medium: Online Resource
    ISSN: 2059-8661
    Language: English
    Publisher: Cambridge University Press (CUP)
    Publication Date: 2019
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  • 10
    Online Resource
    Online Resource
    Cambridge University Press (CUP) ; 2019
    In:  Journal of Clinical and Translational Science Vol. 3, No. s1 ( 2019-03), p. 67-68
    In: Journal of Clinical and Translational Science, Cambridge University Press (CUP), Vol. 3, No. s1 ( 2019-03), p. 67-68
    Abstract: OBJECTIVES/SPECIFIC AIMS: 1.Identify barriers to pursuing research for physician trainees 2.Develop a sustainable pipeline of physician-scientists at Duke 3.Coordinate physician-scientist development programs across the School of Medicine under one central Office 4.Provide infrastructure and resources for all physician-scientists 5.Increase the number of MDs and MD/PhDs who pursue, succeed, and are retained in research METHODS/STUDY POPULATION: To establish a baseline understanding of the needs and concerns of physician-scientist trainees at Duke, we conducted focus groups using a standardized interview guide and thematic analysis. Findings from these focus groups were used to develop a framework for support, leading to the creation of the Office of Physician-Scientist Development (OPSD) housed centrally within the Duke School of Medicine. The OPSD integrates programs and resources for multiple populations including medical students, residents, fellows, junior faculty, and faculty mentors. Pipeline programs will also be developed to enhance research engagement in targeted student populations prior to medical school. RESULTS/ANTICIPATED RESULTS: A total of 45 students and faculty participated in the focus groups and structured interviews (1 st year medical student, n=11; 4 th year medical students, n=11; residents/fellows, n=13; junior faculty, n=11). While participants raised a number of specific issues, one key message emerged: non-PhD MDs in basic research felt they lacked opportunities for directed training. Moreover, they felt the need to teach themselves many critical skills through trial and error. This has led to perceptions that they cannot compete effectively with PhDs and MD-PhD scientists for research funding and positions. Consensus recommendations included: better guidance in choosing mentors, labs, and projects; central resource for information relevant to physician scientists; training specifically tailored to physician scientists conducting laboratory-based research; improved infrastructure and well-defined training pathways; and assistance with grant preparation. To-date, over 90 students, residents, and fellows have been identified who identify as laboratory-based physician scientists. Additional efforts are underway to identify and characterize the broader range of physician-scientist students and trainees at Duke. DISCUSSION/SIGNIFICANCE OF IMPACT: Our planning study revealed specific steps forward toward developing a robust community of physician-scientists at Duke. As a first step, the Dean of the School of Medicine has appointed an Associate Dean of Physician-Scientist Development to oversee a new Office of Physician-Scientist Development (OPSD) being launched in December of 2018. The OPSD will offer four primary programs. 1) A concierge mentoring program will assist new trainees in identifying research areas of interest and mentors. Trainees will receive periodic contact to provide additional support as needed and promote success. 2) A physician-scientist training program is being created to provide training specific to laboratory research skills as well as career and professional development training to complement existing clinical and translational research programs. 3) Integrated training pathways will provide additional mentored research training for those pursuing research careers. Pathways will capitalize on existing resources from R38 programs, while pursuing additional R38 and R25 support. 4) An MD-Scientist funding program has been developed to provide additional research funding and protected time for students pursuing a second research year. Through the support and programming offered by the OPSD, we anticipate decreased perceptions of barriers to pursuing a physician-scientist career and increased satisfaction with training opportunities. Over time, we expect such support to increase the number of MD students pursuing research as a career and the number of residents, fellows, and MD junior faculty remaining in research careers.
    Type of Medium: Online Resource
    ISSN: 2059-8661
    Language: English
    Publisher: Cambridge University Press (CUP)
    Publication Date: 2019
    detail.hit.zdb_id: 2898186-8
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