A5044654137- HIV Research and Treatment
- HIV/AIDS Research and Interventions
- HIV/AIDS drug development and treatment
- Immune Cell Function and Interaction
- Cytomegalovirus and herpesvirus research
- HIV-related health complications and treatments
- Immunotherapy and Immune Responses
- Immune Response and Inflammation
- T-cell and B-cell Immunology
- Reproductive tract infections research
- RNA Interference and Gene Delivery
- Hepatitis C virus research
- Reproductive System and Pregnancy
- Chronic Lymphocytic Leukemia Research
- Immunodeficiency and Autoimmune Disorders
- Herpesvirus Infections and Treatments
- Virus-based gene therapy research
- Infant Nutrition and Health
- Infection Control and Ventilation
- Adolescent Sexual and Reproductive Health
- Cytokine Signaling Pathways and Interactions
- COVID-19 and healthcare impacts
- COVID-19 epidemiological studies
- Antimicrobial Resistance in Staphylococcus
- Blood disorders and treatments
University of Nebraska at Omaha
2019-2025
Aarhus University Hospital
2015-2021
Aarhus University
2015-2021
University of North Carolina at Chapel Hill
2011-2017
Office of Infectious Diseases
2011-2017
Indiana University School of Medicine
2013-2016
EarthTech International (United States)
2015
Johns Hopkins University Center for AIDS Research
2011-2013
The University of Texas Southwestern Medical Center
2005-2010
University of North Dakota
2002-2004
Pharmacologically-induced activation of replication competent proviruses from latency in the presence antiretroviral treatment (ART) has been proposed as a step towards curing HIV-1 infection. However, until now, approaches to reverse humans have yielded mixed results. Here, we report proof-of-concept phase Ib/IIa trial where 6 aviremic infected adults received intravenous 5 mg/m2 romidepsin (Celgene) once weekly for 3 weeks while maintaining ART. Lymphocyte histone H3 acetylation, cellular...
Background Worldwide, vaginal transmission now accounts for more than half of newly acquired HIV-1 infections. Despite the urgency to develop and implement novel approaches capable preventing HIV transmission, this process has been hindered by lack adequate small animal models preclinical efficacy safety testing. Given importance route we investigated susceptibility humanized mice intravaginal infection. Methods Findings We show that female reproductive tract bone marrow–liver–thymus (BLT)...
Abstract Background Aerosol transmission of COVID-19 is the subject ongoing policy debate. Characterizing aerosol produced by people with critical to understanding role aerosols in transmission. Objective We investigated presence virus size-fractioned from six patients admitted into mixed acuity wards April 2020. Methods Size-fractionated samples and size distributions were collected positive patients. analyzed for viral RNA, cultured Vero E6 cells. Serial RT-PCR cells indicated where...
Intrarectal infection between men who have sex with represents a predominant form of human immunodeficiency virus (HIV) transmission in developed countries. Currently there are no adequate small animal models that recapitulate intrarectal HIV transmission. Here we demonstrate lymphocytes generated situ from hematopoietic stem cells reconstitute the gastrointestinal tract humanized mice CD4+ T rendering them susceptible to after single inoculation results systemic depletion gut-associated...
Here we demonstrate that a combination of tenofovir, emtricitabine, and raltegravir effectively suppresses peripheral systemic HIV replication in humanized BLT mice. We also antiretroviral therapy (ART)-treated mice harbor latently infected resting human CD4+ T cells can be induced ex vivo to produce HIV. observed the levels present are within range those circulating patients undergoing suppressive ART. These results potential as an attractive model for testing efficacy novel eradication strategies.
Successful antiretroviral pre-exposure prophylaxis (PrEP) for mucosal and intravenous HIV-1 transmission could reduce new infections among targeted high-risk populations including discordant couples, injection drug users, women men who have sex with men. Targeted PrEP be particularly effective at slowing the spread of if a single combination were found to broadly protective across multiple routes transmission. Therefore, we designed our in vivo preclinical study systematically investigate...
Recent iPrEx clinical trial results provided evidence that systemic preexposure prophylaxis (PrEP) with emtricitabine (FTC) and tenofovir disoproxil fumarate (TDF) can partially prevent rectal HIV transmission in humans. Similarly, we have previously demonstrated administration of the same FTC-TDF combination efficiently prevented humanized bone marrow/liver/thymus (BLT) mice. The CAPRISA 004 recently topical application could vaginal HIV-1 To further validate usefulness BLT mouse model for...
Treatment with latency reversing agents (LRAs) enhances human immunodeficiency virus type 1 (HIV-1) transcription in vivo but leads to only modest reductions the size of reservoir, possibly due insufficient immune-mediated elimination infected cells. We hypothesized that a single drug molecule—a novel Toll-like receptor 9 (TLR9) agonist, MGN1703—could function as an enhancer innate immunity and LRA vivo. conducted single-arm, open-label study which 15 virologically suppressed HIV-1–infected...
Antiretroviral therapy (ART) can reduce HIV levels in plasma to undetectable levels, but rather little is known about the effects of ART outside peripheral blood regarding persistent virus production tissue reservoirs. Understanding dynamics ART-induced reductions viral RNA (vRNA) throughout body important for development strategies eradicate infectious from patients. Essential a successful eradication component capable killing persisting infected cells during ART. Therefore, we determined...
ABSTRACT Toll-like receptor (TLR) agonists are potent enhancers of innate antiviral immunity and may also reverse HIV-1 latency. Therefore, TLR have a potential role in the context “shock-and-kill” approach to eradicate HIV-1. Our extensive preclinical evaluation suggests that novel TLR9 agonist, MGN1703, indeed perform both functions an eradication trial. Peripheral blood mononuclear cells (PBMCs) from aviremic HIV-1-infected donors on antiretroviral therapy (ART) were incubated with...
Abstract Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission causing disease 2019 (COVID-19) may occur through multiple routes. We collected aerosol samples around six patients admitted into mixed acuity wards in April of 2020 to identify the risk airborne SARS-CoV-2. Measurements were made characterize size distribution particles, and size-fractionated, assess presence infectious virus particles sizes >4.1 µm, 1-4 <1 µm patient environment. Samples analyzed by...
This was an exploratory, single-arm clinical trial that tested the immune enhancement effects of 24-weeks Toll-like receptor 9 (TLR9) agonist (MGN1703; Lefitolimod; 60 mg × 2 weekly) therapy.We enrolled HIV-1-infected individuals on suppressive combination antiretroviral therapy. Safety assessed throughout study. The primary outcome reduction in total CD4 T-cell viral DNA levels. Secondary outcomes included safety, detailed immunological and virological analyses, time to rebound (viral load...
Abstract In simian-human immunodeficiency virus (SHIV)-infected non-human primates, broadly neutralizing antibodies (bNAbs) against the appear to stimulate T cell immunity. To determine whether this phenomenon also occurs in humans we measured HIV-1-specific cellular immunity longitudinally individuals with HIV-1 starting antiviral therapy (ART) or without adjunctive bNAb 3BNC117 treatment. Using activation-induced marker (AIM) assay and interferon-γ release, observe that frequencies of Pol-...
Abstract Inducing antiretroviral therapy (ART)-free virological control is a critical step toward human immunodeficiency virus type 1 (HIV-1) cure. In this phase 2a, placebo-controlled, double-blinded trial, 43 people (85% males) with HIV-1 on ART were randomized to (1) placebo/placebo, (2) lefitolimod (TLR9 agonist)/placebo, (3) placebo/broadly neutralizing anti-HIV-1 antibodies (bNAbs) or (4) lefitolimod/bNAb. interruption (ATI) started at week 3. Lefitolimod was administered once weekly...
Currently, over 15% of new HIV infections occur in children. Breastfeeding is a major contributor to infants. This represents paradox the field because vitro, breast milk has been shown have strong inhibitory effect on infectivity. However, this never demonstrated vivo. Here, we address important using first humanized mouse model oral transmission. We established that reconstitution cavity and upper gastrointestinal (GI) tract bone marrow/liver/thymus (BLT) mice with human leukocytes,...
Abstract The ‘shock and kill’ approach to cure human immunodeficiency virus (HIV) includes transcriptional induction of latent HIV-1 proviruses using latency-reversing agents (LRAs) with targeted immunotherapy purge infected cells. administration LRAs (panobinostat or vorinostat) HIV-1-infected individuals on antiretroviral therapy induces a significant increase in cell-associated unspliced (CA-US) RNA from CD4 + T However, it is important discern whether the increases CA-US are due limited...
HIV-1 persists as a latent infection in CD4 + T cells that can be found lymphoid tissues infected individuals during ART. However, the importance of this tissue reservoir and its contribution to viral rebound upon ART interruption are not clear. In study, we sought compare from blood lymph node five HIV-1-infected individuals. Further, analyzed viruses rebound. We observed frequencies intact proviruses were same node. Moreover, expanded clones bearing identical These sequences did appear...
We previously reported that inhibition of endosomal/lysosomal function can dramatically enhance human immunodeficiency virus type 1 (HIV-1) infectivity, suggesting under these conditions productive HIV-1 infection occur via the endocytic pathway. Here we further examined this effect with bafilomycin A1 (BFLA-1) and show enhancement infectivity extends to all isolates tested regardless coreceptor usage. However, isolate-specific differences were observed in magnitude effect. This was...
Rectal microbicides are being developed to prevent new HIV infections in both men and women. We focused our vivo preclinical efficacy study on rectally-applied tenofovir. BLT humanized mice (n = 43) were rectally inoculated with either the primary isolate HIV-1JRCSF or MSM-derived transmitted/founder (T/F) virus HIV-1THRO within 30 minutes following treatment topical 1% tenofovir vehicle. Under experimental conditions, absence of drug we observed 50% 60% rectal transmission by HIV-1THRO,...