Human immunodeficiency virus 1
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1097829 | ENA |
REPOSITORIES: ENA
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Project description:For many therapeutic drugs, including antiretroviral drugs used to treat people living with HIV-1 (PLWH), we have little data on the potential effects on the developing human brain due to limited access to tissue and historical constraints on the inclusion of pregnant populations in clinical trials. Human induced pluripotent stem cells (iPSCs) offer a new avenue to gain insight on how drugs may impact human cell types representative of the developing central nervous system. To prevent vertical transmission of HIV and promote the health of pregnant PLWH, antiretroviral therapy must be initiated and/or maintained throughout pregnancy. However, many antiretroviral drugs are approved for widespread use following clinical testing only in non-pregnant populations and there may be limited information on potential teratogenicity until pregnancy outcomes are evaluated. The integrase strand transfer inhibitor dolutegravir (DTG) is a frontline antiretroviral drug that is effective in viral suppression of HIV but was previously reported to be associated with a slight increase in the risk for neural tube defects in one study, although this has not been replicated in other cohorts. To directly investigate the potential impact of DTG on human cortical neurogenesis, we measured the effects of daily drug exposure on the early stages of corticogenesis in a human iPSC-based forebrain organoid model. We observed deficits in organoid structure and impaired neurogenesis in DTG-treated organoids compared to vehicle-treated control organoids after 20 or 40 days in culture. Our highest dose of DTG (10µM) resulted in significantly smaller organoids with a reduced density of neural rosette structures compared to vehicle-treated controls. Mechanistically, RNA-sequencing and immunohistological analysis suggests dysregulated amino acid transport and activation of the integrated stress response in the DTG-treated organoids, and functionally, a small molecule integrated stress response inhibitor (ISRIB) could partially rescue increased expression of proteins related to cell cycle regulation. Together, these results illustrate the potential for human iPSC-based strategies to reveal biological processes during neurogenesis that may be affected by therapeutic drugs and provide complementary data in relevant human cell types to augment preclinical investigations of drug safety during pregnancy.
2024-09-18 | GSE275931 | GEO
Project description:The brain and spinal cord are formed during neurulation, a developmental process that occurs during the first month of pregnancy and can be modified by low serum levels of folic acid (FA), environmental factors, or genetic predispositions. In 2018, data from a surveillance study in Botswana, a country with one of the highest incidences of human immunodeficiency virus (HIV) and lacking mandatory food folate fortification programs, revealed an increased risk of neural tube defects (NTDs) among newborns whose mothers were taking Dolutegravir (DTG) during the first trimester of pregnancy. Subsequently, the World Health Organization and the U.S. Food and Drug Administration issued recommendations and guidelines emphasizing the potential risks associated with the use of DTG-based antiretroviral therapies during pregnancy. To elucidate the potential mechanisms underlying the DTG-induced NTDs, we sought to employ a rapid experimental system to test specific hypotheses. Brain organoids are three-dimensional cellular structures that can be used to study early neural development, and to assess the potential neurotoxicity of drugs and other compounds. To understand the development of brain organoids in the presence of DTG, we analyzed gene expression from RNA sequencing together with biomechanical information from Optical Coherence Tomography, Optical Coherence Elastography and Brillouin microscopy. Our sequencing data indicates that DTG induces the expression of folate receptor (FOLR1) and modulates the expression of genes required for neurogenesis. The Brillouin frequency shift observed at the surface of DTG-exposed brain organoids indicates an increase in superficial tissue stiffness, while reverberant Optical Coherence Elastography measurements indicate decreased organoid volumes and an internal stiffness decrease.
2024-04-10 | GSE263394 | GEO
Project description:The antiretroviral drugs, dolutegravir, maraviroc and ritonavir-boosted atazanavir, affect inflammation and insulin sensitivity in human coronary endothelial cells through different pathways.
2020-02-05 | GSE137247 | GEO
Project description:This study aimed at investigating the monocytic transcriptome distinction between patients with sustained virus suppression (BDL) and patients with virological failure during highly active antiretroviral therapy (HAART). This study provides the first transcriptomic distinctions in monocytes between viremic patients and BDLs on HAART. Our results reflected the outcome balanced between subversion of monocyte transcriptome by HIV and compensatory effect adapted by host cells.
2013-12-30 | GSE52900 | GEO
Project description:This study aimed at investigating the monocytic transcriptome distinction between patients with sustained virus suppression (BDL) and patients with virological failure during highly active antiretroviral therapy (HAART). This study provides the first transcriptomic distinctions in monocytes between viremic patients and BDLs on HAART. Our results reflected the outcome balanced between subversion of monocyte transcriptome by HIV and compensatory effect adapted by host cells. Total RNA obtained from primary monocytes from five HIV+ patients on HAART who sustainably controlled HIV below detection level (BDL), five HIV+ patients on HAART who consecutively experienced viremia and four healthy HIV sero-negative controls were compared against each other.
2013-12-30 | E-GEOD-52900 | biostudies-arrayexpress
Project description:Population Effectiveness of Dolutegravir Implementation in Sub-Saharan Africa (DISCO)
| PRJNA1100753 | ENA
Project description:Prevalence and Evolution of Low Frequency HIV Drug Resistance Mutations Detected by Ultra Deep Sequencing in Patients Experiencing First Line Antiretroviral Therapy Failure
| PRJNA230547 | ENA
Project description:Yin Yang 2 (YY2) is a member of the Yin Yang family of transcription factors. Although the bioactivity of YY2 has been previously studied, its role in cardiovascular diseases is not known. We observed the increased expression of YY2 in failing human hearts compared with control hearts, raising the question of whether YY2 is involved in the pathogenesis of cardiomyopathy. To investigate the potential contribution of YY2 to the development of cardiomyopathy, we crossed two transgenic (Tg) mouse lines, pCAG-YY2-Tg+ and -MHC-Cre, to generate two independent double transgenic (dTg) mouse lines in which the conditional cardiomyocyte-specific expression of YY2 driven by the -MHC promoter was mediated by Cre recombinase, starting at embryonic day 9.0. In dTg mice, we observed partial embryonic lethality and hearts with defective cardiomyocyte proliferation. Surviving dTg mice from both lines developed cardiomyopathy and heart failure that occurred with aging, showing different degrees of severity that were associated with the level of transgene expression. The development of cardiomyopathy was accompanied by increased levels of cardiac disease markers, apoptosis, and cardiac fibrosis. Our studies further revealed that the Cre-mediated cardiomyocyte-specific increase in YY2 expression led to increased levels of Beclin 1 and LC3II, indicating that YY2 is involved in mediating autophagic activity in mouse hearts in vivo. Also, compared with control hearts, dTG mouse hearts showed increased JNK activity. Because autophagy and JNK activity are important for maintaining cardiac homeostasis, the dysregulation of these signaling pathways may contribute to YY2-induced cardiomyopathy and heart failure in vivo.
2020-02-25 | GSE145808 | GEO
Project description:Effective antiretroviral therapy (ART) has significantly reduced mortality of people living with HIV (PLWH). Increased survival and aging of PLWH is associated with increased incidence of at-risk alcohol use and of metabolic comorbidities; and in women, menopause may be an additional factor contributing to metabolic dysregulation, particularly in adipose tissue. We examined the differential effects of chronic binge alcohol (CBA) administration and ovariectomy (OVX) on the omental adipose tissue (OmAT) proteome of simian immunodeficiency virus (SIV) infected macaques. Quantitative discovery-based proteomics identified 1429 differentially expressed proteins. Ingenuity Pathway Analysis calculated z-scores, or activation predictions for a disease or functional pathway. Results revealed functional pathways associated with protein changes centered around the “OmAT metaboproteome profile”. CBA did not affect functional pathways of metabolic disease; but dysregulated proteins involved in AMPK signaling and lipid metabolism. Based on IPA’s calculated z-score, OVX-mediated proteome changes promote pathways associated with glucose and lipid associated metabolic disease. Additionally, OVX was predicted to promote apoptosis, necrosis and reactive oxygen species (ROS) pathways, while CBA was predicted to inhibit these OVX-associated changes. These results provide evidence for the role of ovarian hormone loss in mediating OmAT metaboproteome dysregulation in HIV/SIV and suggest that CBA modifies OVX-associated changes. In the context of OVX, CBA administraton produced larger metabolic and cellular effects; which we speculate may reflect a protective role of estrogen against CBA-mediated adipose tissue injury in female SIV-infected macaques.
2022-08-12 | PXD023076 | Pride
Project description:To further understand expression patterns of musashi1 overexpression (DTG) in mouse skin,we have employed microarray expression profiling as a discovery platform to identify different genes expression with DTG mouse and Control mouse. Comparision with Control mouse,upgene is 3772 in DTG mouse, downgene is 5529. mTOR pathway, RAS pathway, PI3K-AKT pathway,IL6-JAK-Stat3 pathway and so on are activated, WNT Pathway is inhibited.
2020-11-12 | GSE117284 | GEO