Article
Immunology
Rajesh T. Gandhi, Ronald J. Bosch, Hanna Mar, Gregory M. Laird, Elias K. Halvas, Laura Hovind, Ann C. Collier, Sharon A. Riddler, Albine Martin, Kristen Ritter, Deborah K. McMahon, Joseph J. Eron, Joshua C. Cyktor, John W. Mellors
Summary: In people with HIV and viral suppression by antiretroviral therapy, the levels of intact proviral DNA initially decrease rapidly, but then slow down and may even increase over time. Different patterns of intact proviral DNA decay were observed, with some individuals experiencing a slower decline or even an increase in levels. The levels of defective proviral DNA remained stable. Mechanisms such as the persistence of cells with silent proviruses and the expansion of cells with intact proviruses may contribute to the slowing or reversal of the decay of intact proviral DNA.
JOURNAL OF INFECTIOUS DISEASES
(2023)
Article
Multidisciplinary Sciences
Caroline Dufour, Corentin Richard, Marion Pardons, Marta Massanella, Antoine Ackaoui, Ben Murrell, Bertrand Routy, Rejean Thomas, Jean-Pierre Routy, Remi Fromentin, Nicolas Chomont
Summary: The phenotypic diversity of HIV-infected cells persisting during antiretroviral therapies (ART) was investigated. CD4+ T cells expressing integrin VLA-4 were found to be enriched in replication-competent HIV. Clonally expanded cells with identical proviruses displayed diverse phenotypes, indicating the role of cellular proliferation in the phenotypic diversification of the HIV reservoir. Genetically intact and inducible viral genomes were associated with higher levels of VLA-4 expression in CD4+ T cells. Replication-competent HIV was highly enriched in memory CD4+ T cells expressing high levels of VLA-4.
NATURE COMMUNICATIONS
(2023)
Article
Immunology
Amy S. Huang, Victor Ramos, Thiago Y. Oliveira, Christian Gaebler, Mila Jankovic, Michel C. Nussenzweig, Lillian B. Cohn
Summary: Latent intact HIV-1 proviruses persist in long-lived CD4(+) T cells and can undergo clonal expansion. Expanded clones of CD4(+) T cells in the latent reservoir seem to preferentially integrate within ZNF genes, which may contribute to maintaining HIV-1 latency.
JOURNAL OF EXPERIMENTAL MEDICINE
(2021)
Article
Multidisciplinary Sciences
Christian Gaebler, Lilian Nogueira, Elina Stoffel, Thiago Y. Oliveira, Gaelle Breton, Katrina G. Millard, Martina Turroja, Allison Butler, Victor Ramos, Michael S. Seaman, Jacqueline D. Reeves, Christos J. Petroupoulos, Irina Shimeliovich, Anna Gazumyan, Caroline S. Jiang, Nikolaus Jilg, Johannes F. Scheid, Rajesh Gandhi, Bruce D. Walker, Michael C. Sneller, Anthony Fauci, Tae-Wook Chun, Marina Caskey, Michel C. Nussenzweig
Summary: Immunotherapy with anti-HIV-1 antibodies has the potential to suppress infection and increase the rate of clearance of infected cells. A clinical study showed that 76% of HIV-infected individuals who received a combination of antibodies maintained virologic suppression for at least 20 weeks without antiretroviral therapy. The administration of antibodies affected the HIV-1 reservoir, but further research is needed to define the precise effect of antibody immunotherapy.
Article
Immunology
Rajesh T. Gandhi, Joshua C. Cyktor, Ronald J. Bosch, Hanna Mar, Gregory M. Laird, Albine Martin, Ann C. Collier, Sharon A. Riddler, Bernard J. Macatangay, Charles R. Rinaldo, Joseph J. Eron, Janet D. Siliciano, Deborah K. McMahon, John W. Mellors
Summary: Intact, replication-competent proviruses are selectively lost over time during suppressive ART, while defective provirus levels remain stable. The proportion of intact proviruses within the total HIV-1 DNA reservoir decreases over time on ART. Levels of intact proviruses on ART are correlated with total HIV-1 DNA and residual plasma viremia, but not with markers of inflammation or immune activation.
JOURNAL OF INFECTIOUS DISEASES
(2021)
Article
Medicine, Research & Experimental
Yik Lim Kok, Valentina Vongrad, Sandra E. Chaudron, Mohaned Shilaih, Christine Leemann, Kathrin Neumann, Katharina Kusejko, Francesca Di Giallonardo, Herbert Kuster, Dominique L. Braun, Roger D. Kouyos, Huldrych F. Gunthard, Karin J. Metzner
Summary: Characteristics of HIV-1 integration sites are established as early as during primary infection and are found in both resting and activated CD4(+) T cells. HIV-1 integration sites preferentially occur in specific genes and highly expressed genes, regardless of the activation state of CD4(+) T cells. The preference for cancer-related genes is more prominent at later stages of HIV-1 infection.
Article
Multidisciplinary Sciences
Daniel B. Reeves, Charline Bacchus-Souffan, Mark Fitch, Mohamed Abdel-Mohsen, Rebecca Hoh, Haelee Ahn, Mars Stone, Frederick Hecht, Jeffrey Martin, Steven G. Deeks, Marc K. Hellerstein, Joseph M. McCune, Joshua T. Schiffer, Peter W. Hunt
Summary: The persistence of HIV in people on suppressive antiretroviral therapy is linked to physiological mechanisms of CD4+ T cells. This study investigates the longitudinal kinetics of HIV DNA and cell turnover rates in different CD4 cell subsets. The results indicate that HIV clears faster in more proliferative/differentiated CD4 cell subsets and therapies targeting proliferation and differentiation may reduce HIV DNA levels.
NATURE COMMUNICATIONS
(2023)
Article
Multidisciplinary Sciences
Leila B. Giron, Clovis S. Palmer, Qin Liu, Xiangfan Yin, Emmanouil Papasavvas, Radwa Sharaf, Behzad Etemad, Mohammad Damra, Aaron R. Goldman, Hsin-Yao Tang, Rowena Johnston, Karam Mounzer, Jay R. Kostman, Pablo Tebas, Alan Landay, Luis J. Montaner, Jeffrey M. Jacobson, Jonathan Z. Li, Mohamed Abdel-Mohsen
Summary: The study identified non-invasive plasma biomarkers that predict both the duration and probability of HIV remission after treatment interruption. These biomarkers were validated in two independent cohorts and were found to be associated with HIV latency reactivation and inflammatory pathways.
NATURE COMMUNICATIONS
(2021)
Article
Clinical Neurology
Catherine R. Cochrane, Thomas A. Angelovich, Sarah J. Byrnes, Emily Waring, Aleks C. Guanizo, Gemma S. Trollope, Jingling Zhou, Judith Vue, Lachlan Senior, Emma Wanicek, Janna Jamal Eddine, Matthew J. Gartner, Trisha A. Jenkins, Paul R. Gorry, Bruce J. Brew, Sharon R. Lewin, Jacob D. Estes, Michael Roche, Melissa J. Churchill
Summary: This study provides the first quantitative assessment of intact and defective HIV reservoirs in the brains of people with HIV. Despite antiretroviral therapy, HIV persists in the CNS, with similar levels of viral reservoirs in the brain and lymphoid tissue. Importantly, CNS resident CD68+ myeloid cells in virally suppressed individuals were found to harbor HIV DNA, indicating the presence of a CNS resident HIV reservoir.
ANNALS OF NEUROLOGY
(2022)
Article
Microbiology
Stuart R. Jefferys, Samuel D. Burgos, Jackson J. Peterson, Sara R. Selitsky, Anne-Marie Turner, Lindsey I. James, Yi-Hsuan Tsai, Alisha R. Coffey, David M. Margolis, Joel Parker, Edward P. Browne
Summary: HIV latency in CD4 T cells is a major barrier to curing HIV infection, characterized by elevated activity of specific transcription factors like Forkhead TFs and Kruppel-like factors, as well as the involvement of the protein CTCF in establishing latency. Targeting these factors may lead to new strategies to eliminate the HIV reservoir.
Article
Multidisciplinary Sciences
Jennifer A. White, Francesco R. Simonetti, Subul Beg, Natalie F. McMyn, Weiwei Dai, Niklas Bachmann, Jun Lai, William C. Ford, Christina Bunch, Joyce L. Jones, Ruy. M. Ribeiro, Alan S. Perelson, Janet D. Siliciano, Robert F. Siliciano
Summary: This study analyzed the viral decay process in HIV-infected individuals receiving ART and distinguished intact and defective proviruses using IPDA. The findings showed that CD4(+) T cells with intact proviruses decayed slower initially and then accelerated after a few months. 2LTR circles could not be used as a simple marker for ongoing viral replication. The rate of decay varied among individuals with different defect positions in the genome. Understanding these decay processes is crucial for accurate assessment of the viral reservoir and provides insights into the characteristics of surviving cells.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Review
Biochemistry & Molecular Biology
Steven G. Deeks, Nancie Archin, Paula Cannon, Simon Collins, R. Brad Jones, Marein A. W. P. de Jong, Olivier Lambotte, Rosanne Lamplough, Thumbi Ndung'u, Jeremy Sugarman, Caroline T. Tiemessen, Linos Vandekerckhove, Sharon R. Lewin
Summary: Despite the success of antiretroviral therapy (ART) for people living with HIV, lifelong treatment is required and there is no cure. Various methods including immune activators, neutralizing antibodies, therapeutic vaccines, and gene editing tools have shown promise in curing HIV in nonhuman primate models, with optimism for human clinical trials. Future HIV cure strategies may focus on in vivo delivery of gene-editing tools to target the virus, boost immunity, or protect cells from infection.
Article
Microbiology
Laura P. Kincer, Sarah Beth Joseph, Maria M. Gilleece, Blake M. Hauser, Sabrina Sizemore, Shuntai Zhou, Clara Di Germanio, Henrik Zetterberg, Dietmar Fuchs, Steven G. Deeks, Serena Spudich, Magnus Gisslen, Richard W. Price, Ronald Swanstrom
Summary: HIV-1 can persist in a latent reservoir in individuals receiving antiretroviral therapy, and rebound virus can be detected in the cerebrospinal fluid during treatment interruption. In this study, we found that high viral loads and clonally amplified viral lineages in the cerebrospinal fluid were correlated with the influx of white blood cells. Additionally, we did not observe rebound macrophage-tropic virus in the cerebrospinal fluid, indicating that the CNS may not be a source of this virus. We propose a model in which R5 T cell-tropic virus is released from infected T cells in the CNS during treatment interruption.
NATURE MICROBIOLOGY
(2023)
Article
Cell Biology
Xiaodong Lian, Ce Gao, Xiaoming Sun, Chenyang Jiang, Kevin B. Einkauf, Kyra W. Seiger, Joshua M. Chevalier, Yuko Yuki, Maureen Martin, Rebecca Hoh, Michael J. Peluso, Mary Carrington, Ezequiel Ruiz-Mateos, Steven G. Deeks, Eric S. Rosenberg, Bruce D. Walker, Mathias Lichterfeld, Xu G. Yu
Summary: The study found that defective proviruses in elite controllers are more commonly located in permissive genic euchromatin positions, while intact proviruses are frequently found in heterochromatin regions, indicating differential immune selection pressure on intact and defective proviruses in ECs. The intact and defective proviruses from ECs also showed reduced frequencies of escape mutations in key immune response regions, possibly due to the small and poorly inducible reservoir in ECs. Additionally, a subset of ECs harbored nef deletions in intact proviruses, which may increase viral vulnerability to host immunity in these individuals.
SCIENCE TRANSLATIONAL MEDICINE
(2021)
Review
Virology
Joel Henrique Ellwanger, Bruna Kulmann-Leal, Marina Ziliotto, Jose Artur Bogo Chies
Summary: Genome integrity is crucial for cell functioning, and chromosome instability from factors like replication stress, pollution, and viral infections can lead to age-related diseases. Limited information exists on how viral infections affect micronucleus formation and other chromosomal aberrations. HIV infection can directly cause chromosome instability through interactions with host DNA and indirectly through chronic inflammation or ART use. This article reviews studies on genomic instability in HIV infection, discussing its connections with immunosenescence and age-related diseases. Monitoring HIV-infected individuals should consider the increased risk of chromosome instability, and interventions like reducing genotoxin exposure and antioxidant-rich diets should be considered. Therapies targeting chronic inflammation in HIV infection are needed.
Article
Medicine, General & Internal
Gabriela Turk, Kyra Seiger, Xiaodong Lian, Weiwei Sun, Elizabeth M. Parsons, Ce Gao, Yelizaveta Rassadkina, Maria Laura Polo, Alejandro Czernikier, Yanina Ghiglione, Alejandra Vellicce, Joseph Varriale, Jun Lai, Yuko Yuki, Maureen Martin, Ajantha Rhodes, Sharon R. Lewin, Bruce D. Walker, Mary Carrington, Robert Siliciano, Janet Siliciano, Mathias Lichterfeld, Natalia Laufer, Xu G. Yu
Summary: The study evaluated persistent HIV-1 reservoir cells in an elite controller, revealing the absence of genome-intact and replication-competent HIV-1, suggesting a potential natural sterilizing cure of HIV-1 infection.
ANNALS OF INTERNAL MEDICINE
(2022)
Article
Biochemistry & Molecular Biology
Kevin B. Einkauf, Matthew R. Osborn, Ce Gao, Weiwei Sun, Xiaoming Sun, Xiaodong Lian, Elizabeth M. Parsons, Gregory T. Gladkov, Kyra W. Seiger, Jane E. Blackmer, Chenyang Jiang, Steven A. Yukl, Eric S. Rosenberg, Xu G. Yu, Mathias Lichterfeld
Summary: By studying the evolution of transcriptionally active and silent proviral genomes and epigenomes in individuals receiving antiretroviral therapy, we have found that transcriptionally active HIV-1 proviruses are dynamically evolving under host factors' selection pressure.
Article
Biology
Noah J. Silverstein, Yetao Wang, Zachary Manickas-Hill, Claudia Carbone, Ann Dauphin, Brittany P. Boribong, Maggie Loiselle, Jameson Davis, Maureen M. Leonard, Leticia Kuri-Cervantes, Nuala J. Meyer, Michael R. Betts, Jonathan Z. Li, Bruce D. Walker, Xu G. Yu, Lael M. Yonker, Jeremy Luban
Summary: This study suggests that the abundance of specific lymphoid cell types is associated with the severity and recovery of COVID-19. Innate lymphoid cells (ILCs) decrease in number with age and in males, and their decreased abundance is seen in COVID-19 patients and children with MIS-C. However, the numbers of ILCs gradually recover in children with MIS-C. These results indicate that the abundance of lymphoid cell subsets plays a significant role in COVID-19 severity and recovery, potentially contributing to disease tolerance and tissue homeostasis.
Article
Multidisciplinary Sciences
Radwa Sharaf, Garrett M. Frampton, Lee A. Albacker
Summary: Telomerase-mediated lengthening is a mechanism by which cancer cells avoid cell senescence caused by shortened telomeres. The study found rare occurrences of tumor samples where TERC template mutations were reflected in telomeric repeats.
Article
Microbiology
Xiaodong Lian, Kyra W. Seiger, Elizabeth M. Parsons, Ce Gao, Weiwei Sun, Gregory T. Gladkov, Isabelle C. Roseto, Kevin B. Einkauf, Matthew R. Osborn, Joshua M. Chevalier, Chenyang Jiang, Jane Blackmer, Mary Carrington, Eric S. Rosenberg, Michael M. Lederman, Deborah K. McMahon, Ronald J. Bosch, Jeffrey M. Jacobson, Rajesh T. Gandhi, Michael J. Peluso, Tae-Wook Chun, Steven G. Deeks, Xu G. Yu, Mathias Lichterfeld
Summary: Long-term antiretroviral therapy (ART) in HIV-1 infected individuals leads to significant changes in the viral reservoir profile, with intact proviruses preferentially integrated in heterochromatin locations. These intact proviruses are more likely to persist and avoid elimination compared to proviruses in permissive chromosomal locations. This altered viral reservoir structure may contribute to deep latency and reduced rebound viremia upon treatment interruptions.
CELL HOST & MICROBE
(2023)
Article
Infectious Diseases
Catherine K. Koofhethile, Stefano Rinaldi, Yelizaveta Rassadkina, Vinh B. Dinh, Ce Gao, Suresh Pallikkuth, Pilar Garcia-Broncano, Lesley R. de Armas, Rajendra Pahwa, Nicola Cotugno, Paula Vaz, Maria Grazia Lain, Paolo Palma, Xu G. Yu, Roger Shapiro, Savita Pahwa, Mathias Lichterfeld
Summary: This study longitudinally analyzed the proviral landscape in infants with HIV-1 infection and found that early initiation of antiretroviral therapy led to a rapid decline in intact proviruses. The results also suggest that the vulnerability of intact proviruses to antiviral immunity may contribute to their disproportionate under-representation.
INTERNATIONAL JOURNAL OF INFECTIOUS DISEASES
(2023)
Article
Multidisciplinary Sciences
Behzad Etemad, Xiaoming Sun, Yijia Li, Meghan Melberg, Daniela Moisi, Rachel Gottlieb, Hayat Ahmed, Evgenia Aga, Ronald J. Bosch, Edward P. Acosta, Yuko Yuki, Maureen P. Martin, Mary Carrington, Rajesh T. Gandhi, Jeffrey M. Jacobson, Paul Volberding, Elizabeth Connick, Ronald Mitsuyasu, Ian Frank, Michael Saag, Joseph J. Eron, Daniel Skiest, David M. Margolis, Diane Havlir, Robert T. Schooley, Michael M. Lederman, Xu G. Yu, Jonathan Z. Li
Summary: This study evaluated the mechanisms of HIV post-treatment control and found that post-treatment controllers (PTCs) had stable HIV reservoirs and better immunological profiles. These findings have implications for future studies aiming at achieving an HIV functional cure.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2023)
Article
Cell Biology
Elmira Esmaeilzadeh, Behzad Etemad, Christy L. Lavine, Lauren Garneau, Yijia Li, James Regan, Colline Wong, Radwa Sharaf, Elizabeth Connick, Paul Volberding, Manish Sagar, Michael S. Seaman, Jonathan Z. Li
Summary: Early initiation of antiretroviral therapy (ART) can alter viral rebound kinetics after analytic treatment interruption (ATI) and may promote HIV-1 remission. Autologous neutralizing antibodies (aNAbs) play a key role in the immune response to HIV-1. In this study, we investigated the role of aNAbs in shaping post-ATI HIV-1 rebound variants. Our findings suggest that aNAbs matured during suppressive ART and exerted selective pressure on rebounding viruses. Certain pre-ATI features, such as HIV-1 sequence similarity to consensus subtype B, restricted proviral diversity, and a strong aNAbs response, were associated with post-treatment control.
SCIENCE TRANSLATIONAL MEDICINE
(2023)
Article
Oncology
James F. Haberberger, Worthy Pegram, Nicholas Britt, Kelsie Schiavone, Eric Severson, Radwa Sharaf, Lee A. Albacker, Erik Williams, Mirna Lechpammer, Amanda Hemmerich, Douglas Lin, Richard S. P. Huang, Matthew Hiemenz, Julia Elvin, Ryon Graf, Glenn Lesser, David Kram, Roy Strowd, Wenya Linda Bi, Lori A. Ramkissoon, Michael B. Cohen, Prasanth Reddy, James Creeden, Jeffrey S. Ross, Brian M. Alexander, Shakti H. Ramkissoon
Summary: This study conducted comprehensive genomic profiling (CGP) on 661 young adult glioblastomas, using the 2016 WHO classification, and identified variants with pathogenic function, common copy number variants (CNVs), and novel fusion events. The study also explored tumor mutational burden (TMB), mutational signatures, anatomic location, and tumor recurrence. Through unsupervised machine learning, 10 genomic classes were identified and related to current guidelines and literature for therapeutic and prognostic descriptions.
Article
Genetics & Heredity
Radwa Sharaf, Dexter X. Jin, John Grady, Christine Napier, Ericka Ebot, Garrett M. Frampton, Lee A. Albacker, David M. Thomas, Meagan Montesion
Summary: In this study, researchers found that tumor cells in sarcomas have a mechanism for limitless replication, which requires the activation of a telomere maintenance mechanism. They also observed that alterations in RAD51B and GID4 genes were more associated with high telomeric content in sarcoma samples compared to alterations in ATRX and DAXX genes. These findings provide research opportunities for understanding the critical pathway in tumorigenesis.
NPJ GENOMIC MEDICINE
(2023)
Meeting Abstract
Oncology
Beatrice J. Sun, Nova Xu, Tiffany M. Yue, Kevin B. Einkauf, Byrne Lee
ANNALS OF SURGICAL ONCOLOGY
(2023)
Meeting Abstract
Oncology
Beatrice J. Sun, Carlos I. Ayala, Kevin B. Einkauf, Nova Xu, Tiffany M. Yue, Byrne Lee
ANNALS OF SURGICAL ONCOLOGY
(2023)
Article
Immunology
Joshua M. Francis, Del Leistritz-Edwards, Augustine Dunn, Christina Tarr, Jesse Lehman, Conor Dempsey, Andrew Hamel, Violeta Rayon, Gang Liu, Yuntong Wang, Marcos Wille, Melissa Durkin, Kane Hadley, Aswathy Sheena, Benjamin Roscoe, Mark Ng, Graham Rockwell, Margaret Manto, Elizabeth Gienger, Joshua Nickerson, Amir Moarefi, Michael Noble, Thomas Malia, Philip D. Bardwell, William Gordon, Joanna Swain, Mojca Skoberne, Karsten Sauer, Tim Harris, Ananda W. Goldrath, Alex K. Shalek, Anthony J. Coyle, Christophe Benoist, Daniel C. Pregibon
Summary: HLA genotype conditions the CD8(+) T cell response to SARS-CoV-2, influencing epitope specificity, TCR sequence diversity, and utilization of immune memory T cells. Single-cell transcriptomics revealed functional diversity of SARS-CoV-2-reactive T cells associated with disease stage and epitope specificity.
SCIENCE IMMUNOLOGY
(2022)