A5064769935- HIV Research and Treatment
- HIV/AIDS drug development and treatment
- HIV/AIDS Research and Interventions
- Herpesvirus Infections and Treatments
- Hepatitis C virus research
- Mosquito-borne diseases and control
- Reproductive System and Pregnancy
- Protein Degradation and Inhibitors
- interferon and immune responses
- Virology and Viral Diseases
- Cytomegalovirus and herpesvirus research
- Immune Cell Function and Interaction
- Biochemical and Molecular Research
- Hepatitis B Virus Studies
- RNA Interference and Gene Delivery
- Pneumocystis jirovecii pneumonia detection and treatment
- Immunotherapy and Immune Responses
- Photochromic and Fluorescence Chemistry
- Psoriasis: Treatment and Pathogenesis
- Viral Infections and Immunology Research
- Vector-borne infectious diseases
- Fibromyalgia and Chronic Fatigue Syndrome Research
- Virus-based gene therapy research
- Carbohydrate Chemistry and Synthesis
- Toxin Mechanisms and Immunotoxins
University of North Carolina at Chapel Hill
1997-2022
Triangle
2019-2021
G1 Therapeutics (United States)
2020
GlaxoSmithKline (United States)
2004-2018
Research Triangle Park Foundation
2004-2018
University of North Carolina Health Care
2017
Johns Hopkins University Center for AIDS Research
2003-2011
Hospital Universitario de Fuenlabrada
2006
AIDS United
2003
The Ohio State University
2000
Transmitted HIV-1 drug resistance can compromise initial antiretroviral therapy (ART); therefore, its detection is important for patient management. The absence of drug-associated selection pressure in treatment-naïve persons cause drug-resistant viruses to decline levels undetectable by conventional bulk sequencing (minority variants). We used sensitive and simple tests investigate evidence transmitted drug-naïve assess the clinical implications minority variants.We performed a...
ABSTRACT Vaccine vectors derived from Venezuelan equine encephalitis virus (VEE) that expressed simian immunodeficiency (SIV) immunogens were tested in rhesus macaques as part of the effort to design a safe and effective vaccine for human virus. Immunization with VEE replicon particles induced both humoral cellular immune responses. Four four vaccinated animals protected against disease at least 16 months following intravenous challenge pathogenic SIV swarm, while two controls required...
A molecularly cloned attenuated strain of Venezuelan equine encephalitis virus (VEE) has been genetically configured as a replication-competent vaccine vector for the expression heterologous viral proteins (N. L. Davis, K. W. Brown, and R. E. Johnston, J. Virol. 70:3781-3787, 1996). The matrix/capsid (MA/CA) coding domain human immunodeficiency type 1 (HIV-1) was into VEE to determine ability stimulate an anti-HIV immune response in mice. VEE-MA/CA replicated rapidly cytoplasm baby hamster...
Among CD4+ T cells, helper 17 (Th17) cells are particularly susceptible to HIV-1 infection and depleted from mucosal sites, which causes damage the gut barrier, resulting in a microbial translocation-induced systemic inflammation, hallmark of disease progression. Furthermore, proportion latently infected Th17 persist long term gastrointestinal lymphatic tract where low-level transcription is observed. This residual viremia contributes chronic immune activation. Thus, key players HIV...
Latency reversal strategies for HIV cure using inhibitor of apoptosis protein (IAP) antagonists (IAPi) induce unprecedented levels latent reservoir expression without immunotoxicity during suppressive antiretroviral therapy (ART). However, full targeting the may require combinatorial approaches. A Jurkat latency model screen IAPi combination partners demonstrated synergistic with bromodomain (BD) and extraterminal domain inhibitors (BETi). Mechanistic investigations CRISPR-CAS9 single-cell...
To compare alternative class-sparing antiretroviral regimens in treatment-naive subjects.Open-label, multicenter, randomized trial of up to 3 consecutive treatment over 96 weeks.Two hundred ninety-one subjects received abacavir (ABC) and lamivudine efavirenz (nonnucleoside reverse transcriptase inhibitors [NNRTIs]), ritonavir-boosted amprenavir (protease inhibitor [PI]), or stavudine (nucleoside [NRTI]) by random assignment. The primary end points were the percentages with plasma HIV-1 RNA...
Protease inhibitors represent some of the most potent agents available for therapeutic strategies designed to inhibit human immunodeficiency virus type 1 (HIV-1) replication. Under certain circumstances develops resistance inhibitor, thereby negating benefits this therapy. We have carried out selections high-level each three protease (indinavir, ritonavir, and saquinavir) in cell culture. Mutations accumulated over course increasing selective pressure. There was significant overlap identity...
Resistance-associated mutations in the HIV-1 protease modify viral fitness through changes catalytic activity and altered binding affinity for substrates inhibitors. In this report, we examine effects of 31 at 26 amino acid positions to determine their impact on infectivity inhibitor sensitivity. We found that primary resistance individually decrease generally increase sensitivity inhibitors, indicating reduced virion-associated reduces virion level per is then more easily titrated by a...
Abacavir (ABC) selects for four mutations (K65R, L74V, Y115F and M184V) in HIV-1 reverse transcriptase (RT), both vitro during monotherapy vivo. The aim of this analysis was to compare the selection these other nucleoside inhibitor (NRTI)-associated by ABC-containing therapies presence absence concurrent lamivudine (3TC) and/or zidovudine (ZDV) assess effect on phenotypic susceptibility NRTIs.This study a retrospective patterns NRTI-associated selected following virological failure six...
The CCR100136 (EPIC) study evaluated the antiviral activity of novel CCR5 entry inhibitor aplaviroc in combination with lopinavir-ritonavir drug-naïve human immunodeficiency virus type 1-infected subjects. Although trial was stopped prematurely due to idiosyncratic hepatotoxicity, 11 subjects met protocol-defined virologic failure criteria. Clonal analyses viral envelope tropism, susceptibility, and env sequencing were performed on plasma at day 1 time failure. Molecular evolutionary also...
HIV-1 utilizes CD4 and either chemokine (C-C motif) receptor 5 (CCR5) or (C-X-C 4 (CXCR4) to gain entry into host cells. Small molecule CCR5 antagonists are currently being developed for the treatment of infection. Because may also use CXCR4 entry, inhibitors is controversial patients harboring CCR5-using CXCR4-using (dual/mixed-tropic) viruses. The goal present study was determine proportion CCR5-tropic CXCR4-tropic viruses in dual/mixed-tropic virus isolates from drug-naïve phenotypic...
A macrocycle provides diverse functionality and stereochemical complexity in a conformationally preorganized ring structure, it occupies unique chemical space drug discovery. However, the synthetic challenge to access this structural class is high hinders exploration of macrocycles. In study, efficient routes macrocyclized betulin derivatives have been established. The containing compounds showed equal potency compared bevirimat multiple HIV-1 antiviral assays. synthesis biological...
Abstract The leading strategy towards eradication of human immunodeficiency virus (HIV) infection is the depletion viral reservoirs through reversal latency, followed by clearance persistently infected cells. To date, a latency reversing agent (LRA) that reactivates majority quiescent provirus population, without significant off-target effects, has not been identified. We show here molecules mimicking active N-terminal tetrapeptide second mitochondrial-derived activator caspases (SMACm)...
In 2009, a retrospective study reported the detection of xenotropic murine leukemia virus-related virus (XMRV) in clinical isolates derived from individuals with chronic fatigue syndrome or myalgic encephalomyelitis (CFS). While many efforts to confirm this observation failed, one report detected polytropic (pMLV), instead XMRV. both studies, Polymerase Chain Reaction (PCR)-based methods were employed which could provide basis for development practical diagnostic tool. To these we...
Previous use of the HIV-1 protease inhibitor saquinavir resulted in infrequent appearance mutations gene associated with resistance. We have examined ability to select for resistance mutations. In multiple selections cell culture saquinavir, similar patterns were reproducibly observed and number increased increasing selective pressure. a small subjects who showed an antiviral response when was added their therapeutic regimen, detected viral genomic RNA vivo after 30 40 weeks therapy. These...
The CCR102881 (ASCENT) study evaluated the antiviral activity of novel CCR5 entry inhibitor aplaviroc plus a fixed-dose combination lamivudine-zidovudine (Combivir) in drug-naïve human immunodeficiency virus type 1-infected subjects with only CCR5-tropic detected plasma. Although trial was stopped prematurely due to idiosyncratic hepatotoxicity, eight met protocol-defined virologic failure criteria. Clonal analyses viral envelope tropism, susceptibility, and env sequencing were performed on...
HIV-associated encephalopathy (HIV-AE) is a severe neurologic condition that affects HIV-infected children. The potential benefit of antiretroviral (ARV) agents with good cerebrospinal fluid (CSF) penetration remains to be defined. Abacavir (ABC) achieves CSF concentrations and studies high-dose ABC showed in adults HIV dementia. present study evaluated the safety virologic, immunologic neuropsychological responses an ARV regimen including children HIV-AE.Children between 3 months 18 years...
Thymidine-sparing triple-nucleoside regimens have exhibited poor virologic response despite apparent phenotypic susceptibility to 2 of 3 regimen components at early time points. Phenotypic resistance masking by wild-type virus may explain this discrepancy. Consistent with notion were (1) the presence low-level nucleoside reverse-transcriptase inhibitor-resistant human immunodeficiency in subjects receiving failing first-line consisting tenofovir (TDF), abacavir (ABC), and lamivudine (3TC);...