A5043040808- HIV Research and Treatment
- HIV/AIDS drug development and treatment
- HIV/AIDS Research and Interventions
- Immune Cell Function and Interaction
- T-cell and B-cell Immunology
- Immunotherapy and Immune Responses
- Hematopoietic Stem Cell Transplantation
- Multiple Myeloma Research and Treatments
- Erythrocyte Function and Pathophysiology
- CAR-T cell therapy research
- Acute Myeloid Leukemia Research
- Hemoglobinopathies and Related Disorders
- Cytomegalovirus and herpesvirus research
- Virus-based gene therapy research
- SARS-CoV-2 and COVID-19 Research
- Blood groups and transfusion
- SARS-CoV-2 detection and testing
- Herpesvirus Infections and Treatments
- Viral Infectious Diseases and Gene Expression in Insects
- Biosensors and Analytical Detection
- Advances in Oncology and Radiotherapy
- Radiation Dose and Imaging
- HIV-related health complications and treatments
- Clinical Laboratory Practices and Quality Control
- Cancer Treatment and Pharmacology
University of Pennsylvania
2014-2023
Hospital of the University of Pennsylvania
1997-2023
Columbia University
2013
Hutchison/MRC Research Centre
2001
Medical Research Council
2001
Rockefeller University
1993-1998
University of British Columbia
1996
Aaron Diamond AIDS Research Center
1996
Fairfield Hospital
1994
HIV-1 reservoirs preclude virus eradication in patients receiving highly active antiretroviral therapy (HAART). The best characterized reservoir is a small, difficult-to-quantify pool of resting memory CD4(+) T cells carrying latent but replication-competent viral genomes. Because strategies targeting this are now being tested clinical trials, well-validated high-throughput assays that quantify urgently needed. Here we compare eleven different approaches for quantitating persistent 30 on...
A procedure has been developed to isolate dendritic cells a high degree of purity from fresh blood. Prior enrichment methods have relied upon an initial 1-2-d culture period. Purified isolates lack the characteristic morphology, phenotype, and immunostimulatory function cells. The purified appearance medium sized lymphocytes express substantial levels CD4, but T cell molecules CD3, CD8, receptor. When placed in culture, mature manner resembling previously described, cytokine-dependent...
Significance The presence of “defective” HIV-1 proviruses in HIV-infected patients has been well documented. current consensus view the is that these are dead-end products do not give rise to progeny virus and thus collectively represent a “graveyard” viruses. We describe defective capable transcribing novel unspliced HIV-RNA species on combination antiretroviral therapy. propose persistently present therapy-treated conventional sense, but rather incomplete forms encoding translationally...
Post-acute sequelae of COVID-19 (PASC, "Long COVID") pose a significant global health challenge. The pathophysiology is unknown, and no effective treatments have been found to date. Several hypotheses formulated explain the etiology PASC, including viral persistence, chronic inflammation, hypercoagulability, autonomic dysfunction. Here, we propose mechanism that links all four in single pathway provides actionable insights for therapeutic interventions. We find PASC are associated with...
After initiating antiretroviral therapy (ART), a rapid decline in HIV viral load is followed by long period of undetectable viremia. Viral outgrowth assay suggests the reservoir continues to slowly. Here, we use full-length sequencing longitudinally study proviral landscape four subjects on ART investigate selective pressures influencing dynamics treatment-resistant reservoir. We find intact and defective proviruses that contain genetic elements favoring efficient protein expression decrease...
HIV-1 actively replicates in dendritic cell (DC)-T cocultures, but it has been difficult to demonstrate substantial infection of purified mature DCs. We now find that begins reverse transcription much more efficiently DCs than T cells, even though cells have higher levels CD4 and gp120 binding. isolated from skin or blood precursors behave similarly. Several M-tropic strains the T-tropic strain IIIB enter efficiently, as assessed by progressive formation early products after a 90-min virus...
Quantitative methods to measure human immunodeficiency virus type 1 (HIV-1) integration promise be important tools in dissecting the mechanisms whereby latent reservoirs of provirus are established, most notably resting T cells patients receiving antiretroviral therapy. Here we describe a fluorescence-monitored, nested PCR assay that is able quantify relatively rare events occur within these cells. Following DNA extraction, nonkinetic preamplification step performed with primers bind genomic...
ABSTRACT Resting CD4 + T cells are the best-defined reservoir of latent human immunodeficiency virus type 1 (HIV-1) infection, but how is formed unclear. Understanding latently infected forms critical because it a major barrier to curing HIV infection. The system described here may provide an in vitro model HIV-1 infection resting cells. We demonstrated that integrates into genomes vitro-inoculated have not received activating stimuli and entered cell cycle stage G 1b . A percentage contain...
Elite suppressors (ES) are a rare population of HIV-infected individuals that capable naturally controlling the infection without use highly active anti-retroviral therapy (HAART). Patients on HAART often achieve viral control to similar (undetectable) levels. Accurate and sensitive methods measure burden needed elucidate important differences between these two patient populations in order better understand their mechanisms control. Viral quantification ES patients has been limited...
HIV infection can be treated effectively with antiretroviral agents, but the persistence of a latent reservoir integrated proviruses prevents eradication from infected individuals. The chromosomal environment has been proposed to influence latency, determinants transcriptional repression have not fully clarified, and it is unclear whether same molecular mechanisms drive latency in different cell culture models. Here we compare data five vitro models based on primary human T cells or line....
ABSTRACT DC-SIGN is a C-type lectin expressed on dendritic cells and restricted macrophage populations in vivo that binds gp120 acts trans to enable efficient infection of T by human immunodeficiency virus type 1 (HIV-1). We report here DC-SIGN, when cis with CD4 coreceptors, allowed more both HIV simian (SIV) strains, although the extent varied from 2- 40-fold, depending strain. Expression target did not alleviate requirement for or coreceptor viral entry. Stable expression multiple...
Resting CD4(+) T cells restrict human immunodeficiency virus (HIV) infection at or before reverse transcription, resulting in slower kinetics of transcription. In a previous study, we showed that, despite this restriction HIV integration occurs resting cells, albeit with kinetics. that the were mixture memory and naïve cells. Here asked whether more quiescent cell subset could be directly infected by and, if so, level was comparable to We found integrates without prior activation The...
The study of HIV-infected "controllers" who are able to maintain low levels plasma HIV RNA in the absence antiretroviral therapy (ART) may provide insights for cure and vaccine strategies. Despite maintaining very viremia, controllers have elevated immune activation accelerated atherosclerosis. However, degree which low-level replication contributes these phenomena is not known. Sixteen asymptomatic were prospectively treated with ART 24 weeks. Controllers had a statistically significant...
Despite the efficacy of antiretroviral therapy (ART), HIV persists in a latent form and remains hurdle to eradication. CD4+ T lymphocytes harbor majority reservoir, but role individual subsets unclear. cells were sorted into central, transitional, effector memory, naive cells. We measured DNA performed proviral sequencing more than 1900 proviruses 2 subjects at 9 years after ART initiation estimate contribution each subset reservoir. Although our study was limited subjects, we obtained...
While the dendritic cells (DCs) of mouse and man have been extensively studied, until recently those non-human primates remained poorly characterized. We present a method for generating large numbers DCs from precursors in rhesus macaque blood, based on techniques developed human blood. For 7 days, T cell-depleted population mononuclear was cultured 1% plasma with GM-CSF IL-4, both to initiate DC differentiation inhibit macrophage development. On day 7, 50% culture medium replaced...
Resting CD4+ T cells infected with HIV persist in the presence of suppressive anti-viral therapy (ART) and are barriers to a cure. One potential curative approach, therapeutic vaccination, is fueled by recognition ability subset elite controllers (EC) control virus without due robust anti-HIV immune responses. Controllers have low levels integrated DNA replication competent virus, suggesting small reservoir. As our recent data indicates some reservoir can produce proteins (termed GPR for...