18 results on '"Kreider, Edward F."'
Search Results
2. Paired quantitative and qualitative assessment of the replication-competent HIV-1 reservoir and comparison with integrated proviral DNA
- Author
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Lorenzi, Julio CC, Cohen, Yehuda Z, Cohn, Lillian B, Kreider, Edward F, Barton, John P, Learn, Gerald H, Oliveira, Thiago, Lavine, Christy L, Horwitz, Joshua A, Settler, Allison, Jankovic, Mila, Seaman, Michael S, Chakraborty, Arup K, Hahn, Beatrice H, Caskey, Marina, and Nussenzweig, Michel C
- Subjects
Medical Microbiology ,Biomedical and Clinical Sciences ,Immunology ,Infectious Diseases ,HIV/AIDS ,Aetiology ,2.2 Factors relating to the physical environment ,Infection ,Good Health and Well Being ,HIV ,reservoir ,replication-competent ,culture ,method - Abstract
HIV-1-infected individuals harbor a latent reservoir of infected CD4+ T cells that is not eradicated by antiretroviral therapy (ART). This reservoir presents the greatest barrier to an HIV-1 cure and has remained difficult to characterize, in part, because the vast majority of integrated sequences are defective and incapable of reactivation. To characterize the replication-competent reservoir, we have combined two techniques, quantitative viral outgrowth and qualitative sequence analysis of clonal outgrowth viruses. Leukapheresis samples from four fully ART-suppressed, chronically infected individuals were assayed at two time points separated by a 4- to 6-mo interval. Overall, 54% of the viruses emerging from the latent reservoir showed gp160 env sequences that were identical to at least one other virus. Moreover, 43% of the env sequences from viruses emerging from the reservoir were part of identical groups at the two time points. Groups of identical expanded sequences made up 54% of proviral DNA, and, as might be expected, the sequences of replication-competent viruses in the active reservoir showed limited overlap with integrated proviral DNA, most of which is known to represent defective viruses. Finally, there was an inverse correlation between proviral DNA clone size and the probability of reactivation, suggesting that replication-competent viruses are less likely to be found among highly expanded provirus-containing cell clones.
- Published
- 2016
3. Longitudinal Antigenic Sequences and Sites from Intra-Host Evolution (LASSIE) Identifies Immune-Selected HIV Variants
- Author
-
Hraber, Peter, Korber, Bette, Wagh, Kshitij, Giorgi, Elena E., Bhattacharya, Tanmoy, Gnanakaran, S., Lapedes, Alan S., Learn, Gerald H., Kreider, Edward F., Li, Yingying, Shaw, George M., Hahn, Beatrice H., Montefiori, David C., Alam, S. Munir, Bonsignori, Mattia, Moody, M. Anthony, Liao, Hua-Xin, Gao, Feng, and Haynes, Barton F.
- Subjects
Quantitative Biology - Populations and Evolution ,Quantitative Biology - Quantitative Methods - Abstract
Within-host genetic sequencing from samples collected over time provides a dynamic view of how viruses evade host immunity. Immune-driven mutations might stimulate neutralization breadth by selecting antibodies adapted to cycles of immune escape that generate within-subject epitope diversity. Comprehensive identification of immune-escape mutations is experimentally and computationally challenging. With current technology, many more viral sequences can readily be obtained than can be tested for binding and neutralization, making down-selection necessary. Typically, this is done manually, by picking variants that represent different time-points and branches on a phylogenetic tree. Such strategies are likely to miss many relevant mutations and combinations of mutations, and to be redundant for other mutations. Longitudinal Antigenic Sequences and Sites from Intrahost Evolution (LASSIE) uses transmitted-founder loss to identify virus "hot-spots" under putative immune selection and chooses sequences that represent recurrent mutations in selected sites. LASSIE favors earliest sequences in which mutations arise. With well-characterized longitudinal Env sequences, we confirmed selected sites were concentrated in antibody contacts and selected sequences represented diverse antigenic phenotypes. Practical applications include rapidly identifying immune targets under selective pressure within a subject, selecting minimal sets of reagents for immunological assays that characterize evolving antibody responses, and for immunogens in polyvalent "cocktail" vaccines., Comment: 73 pages, 10 figures, 8 supplemental figures; 18 full-resolution figures appear at the end of the manuscript. Presented at 22nd International Workshop on HIV Dynamics and Evolution, Budapest, May 2015
- Published
- 2015
4. Early Engagement in HIV Research: Evaluation of the Penn CFAR Scholars Program Aimed at Increasing Diversity of the HIV/AIDS Workforce
- Author
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Kreider, Edward F., primary, Ortega-Burgos, Yohaniz, additional, Dumeng-Rodriguez, Jeriel, additional, Gesualdi, James, additional, O'Brien, Caroline, additional, Bracy, Danny, additional, Johnson, Jeanene, additional, Bowman, Jacqui, additional, Metzger, David, additional, Dine, C. Jessica, additional, Favor, Kevin, additional, Jordan-Sciutto, Kelly L., additional, and Momplaisir, Florence, additional
- Published
- 2023
- Full Text
- View/download PDF
5. HIV-1 therapy with monoclonal antibody 3BNC117 elicits host immune responses against HIV-1
- Author
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Schoofs, Till, Klein, Florian, Braunschweig, Malte, Kreider, Edward F., Feldmann, Anna, Nogueira, Lilian, Oliveira, Thiago, Lorenzi, Julio C. C., Parrish, Erica H., Learn, Gerald H., West, Anthony P., Bjorkman, Pamela J., Schlesinger, Sarah J., Seaman, Michael S., Czartoski, Julie, McElrath, M. Juliana, Pfeifer, Nico, Hahn, Beatrice H., Caskey, Marina, and Nussenzweig, Michel C.
- Published
- 2016
6. Antibody 10-1074 suppresses viremia in HIV-1-infected individuals
- Author
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Caskey, Marina, Schoofs, Till, Gruell, Henning, Settler, Allison, Karagounis, Theodora, Kreider, Edward F, Murrell, Ben, Pfeifer, Nico, Nogueira, Lilian, Oliveira, Thiago Y, Learn, Gerald H, Cohen, Yehuda Z, Lehmann, Clara, Gillor, Daniel, Shimeliovich, Irina, Unson-O'Brien, Cecilia, Weiland, Daniela, Robles, Alexander, Kümmerle, Tim, Wyen, Christoph, Levin, Rebeka, Witmer-Pack, Maggi, Eren, Kemal, Ignacio, Caroline, Kiss, Szilard, West, Anthony P, Jr, Mouquet, Hugo, Zingman, Barry S, Gulick, Roy M, Keler, Tibor, Bjorkman, Pamela J, Seaman, Michael S, Hahn, Beatrice H, Fätkenheuer, Gerd, Schlesinger, Sarah J, Nussenzweig, Michel C, and Klein, Florian
- Subjects
HIV infections -- Genetic aspects -- Development and progression -- Care and treatment ,Viral proteins -- Health aspects ,Monoclonal antibodies -- Patient outcomes ,Biological sciences ,Health - Abstract
Monoclonal antibody 10-1074 targets the V3 glycan supersite on the HIV-1 envelope (Env) protein. It is among the most potent anti-HIV-1 neutralizing antibodies isolated so far. Here we report on its safety and activity in 33 individuals who received a single intravenous infusion of the antibody. 10-1074 was well tolerated and had a half-life of 24.0 d in participants without HIV-1 infection and 12.8 d in individuals with HIV-1 infection. Thirteen individuals with viremia received the highest dose of 30 mg/kg 10-1074. Eleven of these participants were 10-1074-sensitive and showed a rapid decline in viremia by a mean of 1.52 log[sub.10] copies/ml. Virologic analysis revealed the emergence of multiple independent 10-1074-resistant viruses in the first weeks after infusion. Emerging escape variants were generally resistant to the related V3-specific antibody PGT121, but remained sensitive to antibodies targeting nonoverlapping epitopes, such as the anti-CD4-binding-site antibodies 3BNC117 and VRC01. The results demonstrate the safety and activity of 10-1074 in humans and support the idea that antibodies targeting the V3 glycan supersite might be useful for the treatment and prevention of HIV-1 infection., Author(s): Marina Caskey (corresponding author) [1]; Till Schoofs [1]; Henning Gruell [2, 3, 4]; Allison Settler [1]; Theodora Karagounis [1]; Edward F Kreider [5]; Ben Murrell [6]; Nico Pfeifer [7]; [...]
- Published
- 2017
- Full Text
- View/download PDF
7. Staged induction of HIV-1 glycan–dependent broadly neutralizing antibodies
- Author
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Bonsignori, Mattia, Kreider, Edward F., Fera, Daniela, Meyerhoff, R. Ryan, Bradley, Todd, Wiehe, Kevin, Alam, S. Munir, Aussedat, Baptiste, Walkowicz, William E., Hwang, Kwan-Ki, Saunders, Kevin O., Zhang, Ruijun, Gladden, Morgan A., Monroe, Anthony, Kumar, Amit, Xia, Shi-Mao, Cooper, Melissa, Louder, Mark K., McKee, Krisha, Bailer, Robert T., Pier, Brendan W., Jette, Claudia A., Kelsoe, Garnett, Williams, Wilton B., Morris, Lynn, Kappes, John, Wagh, Kshitij, Kamanga, Gift, Cohen, Myron S., Hraber, Peter T., Montefiori, David C., Trama, Ashley, Liao, Hua-Xin, Kepler, Thomas B., Moody, M. Anthony, Gao, Feng, Danishefsky, Samuel J., Mascola, John R., Shaw, George M., Hahn, Beatrice H., Harrison, Stephen C., Korber, Bette T., and Haynes, Barton F.
- Published
- 2017
- Full Text
- View/download PDF
8. HIV-1 antibody 3BNC117 suppresses viral rebound in humans during treatment interruption
- Author
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Scheid, Johannes F., Horwitz, Joshua A., Bar-On, Yotam, Kreider, Edward F., Lu, Ching-Lan, Lorenzi, Julio C.C., Feldmann, Anna, Braunschweig, Malte, Nogueira, Lilian, Oliveira, Thiago, Shimeliovich, Irina, Patel, Roshni, Burke, Leah, Cohen, Yehuda Z., Hadrigan, Sonya, Settler, Allison, Witmer-Pack, Maggi, West, Jr., Anthony P., Juelg, Boris, Keler, Tibor, Hawthorne, Thomas, Zingman, Barry, Gulick, Roy M., Pfeifer, Nico, Learn, Gerald H., Seaman, Michael S., Bjorkman, Pamela J., Klein, Florian, Schlesinger, Sarah J., Walker, Bruce D., Hahn, Beatrice H., Nussenzweig, Michel C., and Caskey, Marina
- Subjects
HIV antibodies -- Health aspects ,Antiviral agents -- Dosage and administration ,Drug therapy, Combination -- Methods ,Host-virus relationships -- Prevention ,HIV infection -- Drug therapy ,Environmental issues ,Science and technology ,Zoology and wildlife conservation - Abstract
Interruption of combination antiretroviral therapy in HIV-1infected individuals leads to rapid viral rebound. Here we report the results of a phase IIa open label clinical trial evaluating 3BNC117, a broad and potent neutralizing antibody against the CD4 binding site of the HIV-1 Env protein (1), during analytical treatment interruption in 13 HIV-1-infected individuals. Participants with 3BNC117-sensitive virus outgrowth cultures were enrolled. Results show that two or four 30 mg [kg.sup.-1] 3BNC117 infusions, separated by 3 or 2 weeks, respectively, are generally well tolerated. Infusions are associated with a delay in viral rebound of 5-9 weeks after two infusions, and up to 19 weeks after four infusions, or an average of 6.7 and 9.9 weeks, respectively, compared with 2.6 weeks for historical controls (P < 0.00001). Rebound viruses arise predominantly from a single provirus. In most individuals, emerging viruses show increased resistance, indicating escape. However, 30% of participants remained suppressed until antibody concentrations waned below 20 µg [ml.sup.-1], and the viruses emerging in all but one of these individuals showed no apparent resistance to 3BCN117, suggesting failure to escape over a period of 9-19 weeks. We conclude that the administration of 3BNC117 exerts strong selective pressure on HIV-1 emerging from latent reservoirs during analytical treatment interruption in humans., A fraction of HIV-1-infected individuals develops broad and potent serologic activity against the virus. Single-cell antibody cloning methods (2) have uncovered the source of this activity as broadly neutralizing antibodies [...]
- Published
- 2016
9. HIV-1 Neutralizing Antibody Signatures and Application to Epitope-Targeted Vaccine Design
- Author
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Bricault, Christine A., primary, Yusim, Karina, additional, Seaman, Michael S., additional, Yoon, Hyejin, additional, Theiler, James, additional, Giorgi, Elena E., additional, Wagh, Kshitij, additional, Theiler, Maxwell, additional, Hraber, Peter, additional, Macke, Jennifer P., additional, Kreider, Edward F., additional, Learn, Gerald H., additional, Hahn, Beatrice H., additional, Scheid, Johannes F., additional, Kovacs, James M., additional, Shields, Jennifer L., additional, Lavine, Christy L., additional, Ghantous, Fadi, additional, Rist, Michael, additional, Bayne, Madeleine G., additional, Neubauer, George H., additional, McMahan, Katherine, additional, Peng, Hanqin, additional, Chéneau, Coraline, additional, Jones, Jennifer J., additional, Zeng, Jie, additional, Ochsenbauer, Christina, additional, Nkolola, Joseph P., additional, Stephenson, Kathryn E., additional, Chen, Bing, additional, Gnanakaran, S., additional, Bonsignori, Mattia, additional, Williams, LaTonya D., additional, Haynes, Barton F., additional, Doria-Rose, Nicole, additional, Mascola, John R., additional, Montefiori, David C., additional, Barouch, Dan H., additional, and Korber, Bette, additional
- Published
- 2019
- Full Text
- View/download PDF
10. Paired quantitative and qualitative assessment of the replication-competent HIV-1 reservoir and comparison with integrated proviral DNA
- Author
-
Institute for Medical Engineering and Science, Massachusetts Institute of Technology. Department of Biological Engineering, Massachusetts Institute of Technology. Department of Chemical Engineering, Massachusetts Institute of Technology. Department of Chemistry, Massachusetts Institute of Technology. Department of Physics, Barton, John P, Chakraborty, Arup K, Lorenzi, Julio C. C., Cohen, Yehuda Z., Cohn, Lillian B., Kreider, Edward F., Learn, Gerald H., Oliveira, Thiago, Lavine, Christy L., Horwitz, Joshua A., Settler, Allison, Jankovic, Mila, Seaman, Michael S., Hahn, Beatrice H., Caskey, Marina, Nussenzweig, Michel C., Institute for Medical Engineering and Science, Massachusetts Institute of Technology. Department of Biological Engineering, Massachusetts Institute of Technology. Department of Chemical Engineering, Massachusetts Institute of Technology. Department of Chemistry, Massachusetts Institute of Technology. Department of Physics, Barton, John P, Chakraborty, Arup K, Lorenzi, Julio C. C., Cohen, Yehuda Z., Cohn, Lillian B., Kreider, Edward F., Learn, Gerald H., Oliveira, Thiago, Lavine, Christy L., Horwitz, Joshua A., Settler, Allison, Jankovic, Mila, Seaman, Michael S., Hahn, Beatrice H., Caskey, Marina, and Nussenzweig, Michel C.
- Abstract
HIV-1-infected individuals harbor a latent reservoir of infected CD4⁺ T cells that is not eradicated by antiretroviral therapy (ART). This reservoir presents the greatest barrier to an HIV-1 cure and has remained difficult to characterize, in part, because the vast majority of integrated sequences are defective and incapable of reactivation. To characterize the replication-competent reservoir, we have combined two techniques, quantitative viral outgrowth and qualitative sequence analysis of clonal outgrowth viruses. Leukapheresis samples from four fully ART-suppressed, chronically infected individuals were assayed at two time points separated by a 4- to 6-mo interval. Overall, 54% of the viruses emerging from the latent reservoir showed gp160 env sequences that were identical to at least one other virus. Moreover, 43% of the env sequences from viruses emerging from the reservoir were part of identical groups at the two time points. Groups of identical expanded sequences made up 54% of proviral DNA, and, as might be expected, the sequences of replication-competent viruses in the active reservoir showed limited overlap with integrated proviral DNA, most of which is known to represent defective viruses. Finally, there was an inverse correlation between proviral DNA clone size and the probability of reactivation, suggesting that replication-competent viruses are less likely to be found among highly expanded provirus-containing cell clones.
- Published
- 2018
11. Completeness of HIV-1 Envelope Glycan Shield at Transmission Determines Neutralization Breadth
- Author
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Wagh, Kshitij, primary, Kreider, Edward F., additional, Li, Yingying, additional, Barbian, Hannah J., additional, Learn, Gerald H., additional, Giorgi, Elena, additional, Hraber, Peter T., additional, Decker, Timothy G., additional, Smith, Andrew G., additional, Gondim, Marcos V., additional, Gillis, Lindsey, additional, Wandzilak, Jamie, additional, Chuang, Gwo-Yu, additional, Rawi, Reda, additional, Cai, Fangping, additional, Pellegrino, Pierre, additional, Williams, Ian, additional, Overbaugh, Julie, additional, Gao, Feng, additional, Kwong, Peter D., additional, Haynes, Barton F., additional, Shaw, George M., additional, Borrow, Persephone, additional, Seaman, Michael S., additional, Hahn, Beatrice H., additional, and Korber, Bette, additional
- Published
- 2018
- Full Text
- View/download PDF
12. Comparing medical, dental, and nursing students’ preparedness to address lesbian, gay, bisexual, transgender, and queer health
- Author
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Greene, Madelyne Z., primary, France, Katherine, additional, Kreider, Edward F., additional, Wolfe-Roubatis, Emily, additional, Chen, Kevin D., additional, Wu, Andy, additional, and Yehia, Baligh R., additional
- Published
- 2018
- Full Text
- View/download PDF
13. Effective treatment of SIVcpz-induced immunodeficiency in a captive western chimpanzee
- Author
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Barbian, Hannah J., primary, Jackson-Jewett, Raven, additional, Brown, Corrine S., additional, Bibollet-Ruche, Frederic, additional, Learn, Gerald H., additional, Decker, Timothy, additional, Kreider, Edward F., additional, Li, Yingying, additional, Denny, Thomas N., additional, Sharp, Paul M., additional, Shaw, George M., additional, Lifson, Jeffrey, additional, Acosta, Edward P., additional, Saag, Michael S., additional, Bar, Katharine J., additional, and Hahn, Beatrice H., additional
- Published
- 2017
- Full Text
- View/download PDF
14. Effect of HIV Antibody VRC01 on Viral Rebound after Treatment Interruption
- Author
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Bar, Katharine J., primary, Sneller, Michael C., additional, Harrison, Linda J., additional, Justement, J. Shawn, additional, Overton, Edgar T., additional, Petrone, Mary E., additional, Salantes, D. Brenda, additional, Seamon, Catherine A., additional, Scheinfeld, Benjamin, additional, Kwan, Richard W., additional, Learn, Gerald H., additional, Proschan, Michael A., additional, Kreider, Edward F., additional, Blazkova, Jana, additional, Bardsley, Mark, additional, Refsland, Eric W., additional, Messer, Michael, additional, Clarridge, Katherine E., additional, Tustin, Nancy B., additional, Madden, Patrick J., additional, Oden, KaSaundra, additional, O’Dell, Sijy J., additional, Jarocki, Bernadette, additional, Shiakolas, Andrea R., additional, Tressler, Randall L., additional, Doria-Rose, Nicole A., additional, Bailer, Robert T., additional, Ledgerwood, Julie E., additional, Capparelli, Edmund V., additional, Lynch, Rebecca M., additional, Graham, Barney S., additional, Moir, Susan, additional, Koup, Richard A., additional, Mascola, John R., additional, Hoxie, James A., additional, Fauci, Anthony S., additional, Tebas, Pablo, additional, and Chun, Tae-Wook, additional
- Published
- 2016
- Full Text
- View/download PDF
15. Within-host evolution of HIV-1: Novel pathways of virus escape from cellular and humoral immunity
- Author
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Kreider, Edward F and Kreider, Edward F
- Abstract
Longitudinal HIV-1 single genome sequencing (SGS), which permits unambiguous genetic characterization of circulating viral strains without introduction of PCR error, can be used to identify sites in the viral genome that are under selective pressure. Following transmission, the earliest sites under positive selection often fall in cytotoxic T lymphocyte (CTL) epitopes. During escape from CTL immune pressure, viral sequences typically exhibit nonsynonymous mutations within the span of the cognate T cell epitope. I applied SGS to study sequence evolution in the HIV-1 5’ leader sequence, which is thought to be translationally silent. I observed mutational patterns consistent with CTL escape and demonstrated that the HIV-1 5’ leader expresses T cell antigens from non-canonical one-off AUG codons (e.g. CUG). While these non-canonical start codons can be mutated during CTL escape, a reverse transcriptase overextension error periodically restores a one-off AUG within the 5’ leader. As infection ensues, sites under selection within the gene encoding the viral envelope glycoprotein (Env) often fall within autologous neutralizing antibody epitopes. In a subset of individuals, the strain-specific neutralizing antibody response develops into a broadly cross-reactive neutralizing antibody (bnAb) response. To understand what factors influence bnAb ontogeny, I used SGS to study Env evolution both during natural infection and immunotherapy. I found viral diversification in bnAb contact residues and divergence of the virus population into multiple persistent lineages to precede bnAb development. Taken together, these data demonstrate that longitudinal HIV-1 SGS can be used to discover novel aspects of virus biology and host-pathogen interactions.
- Published
- 2016
16. A Naturally Occurring rev1-vpu Fusion Gene Does Not Confer a Fitness Advantage to HIV-1
- Author
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Langer, Simon M., primary, Hopfensperger, Kristina, additional, Iyer, Shilpa S., additional, Kreider, Edward F., additional, Learn, Gerald H., additional, Lee, Lan-Hui, additional, Hahn, Beatrice H., additional, and Sauter, Daniel, additional
- Published
- 2015
- Full Text
- View/download PDF
17. Early Engagement in HIV Research: Evaluation of the Penn CFAR Scholars Program Aimed at Increasing Diversity of the HIV/AIDS Workforce.
- Author
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Kreider EF, Ortega-Burgos Y, Dumeng-Rodriguez J, Gesualdi J, O'Brien C, Bracy D, Johnson J, Bowman J, Metzger D, Dine CJ, Favor K, Jordan-Sciutto KL, and Momplaisir F
- Subjects
- Humans, Workforce, Educational Status, Schools, Acquired Immunodeficiency Syndrome, HIV Infections prevention & control
- Abstract
Background: Demographic diversity is not represented in the HIV/AIDS workforce. Engagement of underrepresented trainees as early as high school may address this disparity., Methods: We established the Penn Center for AIDS Research (CFAR) Scholars Program, a mentored research experience for underrepresented minority (URM) trainees spanning educational stages from high school to medical school. The program provides participants with tailored educational programming, professional skill building, and mentored research experiences. We conducted qualitative interviews with scholar, mentor, and leadership groups to evaluate the program's impact., Results: Eleven participants were selected to partake in 1 of 5 existing mentored research programs as CFAR scholars. Scholars attended an 8-week HIV Seminar Series that covered concepts in the basic, clinical, behavioral, and community-based HIV/AIDS research. Program evaluation revealed that scholars' knowledge of HIV pathophysiology and community impact increased because of these seminars. In addition, they developed tangible skills in literature review, bench techniques, qualitative assessment, data analysis, and professional network building. Scholars reported improved academic self-efficacy and achieved greater career goal clarity. Areas for improvement included clarification of mentor-mentee roles, expectations for longitudinal mentorship, and long-term engagement between scholars. Financial stressors, lack of social capital, and structural racism were identified as barriers to success for URM trainees., Conclusion: The Penn CFAR Scholars Program is a novel mentored research program that successfully engaged URM trainees from early educational stages. Barriers and facilitators to sustained efforts of diversifying the HIV/AIDS workforce were identified and will inform future program planning., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)
- Published
- 2023
- Full Text
- View/download PDF
18. Longitudinal Antigenic Sequences and Sites from Intra-Host Evolution (LASSIE) Identifies Immune-Selected HIV Variants.
- Author
-
Hraber P, Korber B, Wagh K, Giorgi EE, Bhattacharya T, Gnanakaran S, Lapedes AS, Learn GH, Kreider EF, Li Y, Shaw GM, Hahn BH, Montefiori DC, Alam SM, Bonsignori M, Moody MA, Liao HX, Gao F, and Haynes BF
- Subjects
- Antigens, Viral genetics, Genetic Variation, HIV classification, HIV genetics, HIV isolation & purification, Humans, Longitudinal Studies, Antigens, Viral immunology, HIV immunology, HIV Infections immunology, HIV Infections virology, Immune Evasion, Selection, Genetic, Virology methods
- Abstract
Within-host genetic sequencing from samples collected over time provides a dynamic view of how viruses evade host immunity. Immune-driven mutations might stimulate neutralization breadth by selecting antibodies adapted to cycles of immune escape that generate within-subject epitope diversity. Comprehensive identification of immune-escape mutations is experimentally and computationally challenging. With current technology, many more viral sequences can readily be obtained than can be tested for binding and neutralization, making down-selection necessary. Typically, this is done manually, by picking variants that represent different time-points and branches on a phylogenetic tree. Such strategies are likely to miss many relevant mutations and combinations of mutations, and to be redundant for other mutations. Longitudinal Antigenic Sequences and Sites from Intrahost Evolution (LASSIE) uses transmitted founder loss to identify virus "hot-spots" under putative immune selection and chooses sequences that represent recurrent mutations in selected sites. LASSIE favors earliest sequences in which mutations arise. With well-characterized longitudinal Env sequences, we confirmed selected sites were concentrated in antibody contacts and selected sequences represented diverse antigenic phenotypes. Practical applications include rapidly identifying immune targets under selective pressure within a subject, selecting minimal sets of reagents for immunological assays that characterize evolving antibody responses, and for immunogens in polyvalent "cocktail" vaccines.
- Published
- 2015
- Full Text
- View/download PDF
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