scholarly journals Co-receptor signaling in the pathogenesis of neuroHIV

Retrovirology ◽  
2021 ◽  
Vol 18 (1) ◽  
Author(s):  
E. A. Nickoloff-Bybel ◽  
L. Festa ◽  
O. Meucci ◽  
P. J. Gaskill
Keyword(s):  
Hiv Infection ◽  
Signaling Pathways ◽  
Receptor Activation ◽  
Model Systems ◽  
Signaling Cascades ◽  
Target Cells ◽  
People Living With Hiv ◽  
Receptor Signaling ◽  
Comprehensive Overview ◽  
The Impact

AbstractThe HIV co-receptors, CCR5 and CXCR4, are necessary for HIV entry into target cells, interacting with the HIV envelope protein, gp120, to initiate several signaling cascades thought to be important to the entry process. Co-receptor signaling may also promote the development of neuroHIV by contributing to both persistent neuroinflammation and indirect neurotoxicity. But despite the critical importance of CXCR4 and CCR5 signaling to HIV pathogenesis, there is only one therapeutic (the CCR5 inhibitor Maraviroc) that targets these receptors. Moreover, our understanding of co-receptor signaling in the specific context of neuroHIV is relatively poor. Research into co-receptor signaling has largely stalled in the past decade, possibly owing to the complexity of the signaling cascades and functions mediated by these receptors. Examining the many signaling pathways triggered by co-receptor activation has been challenging due to the lack of specific molecular tools targeting many of the proteins involved in these pathways and the wide array of model systems used across these experiments. Studies examining the impact of co-receptor signaling on HIV neuropathogenesis often show activation of multiple overlapping pathways by similar stimuli, leading to contradictory data on the effects of co-receptor activation. To address this, we will broadly review HIV infection and neuropathogenesis, examine different co-receptor mediated signaling pathways and functions, then discuss the HIV mediated signaling and the differences between activation induced by HIV and cognate ligands. We will assess the specific effects of co-receptor activation on neuropathogenesis, focusing on neuroinflammation. We will also explore how the use of substances of abuse, which are highly prevalent in people living with HIV, can exacerbate the neuropathogenic effects of co-receptor signaling. Finally, we will discuss the current state of therapeutics targeting co-receptors, highlighting challenges the field has faced and areas in which research into co-receptor signaling would yield the most therapeutic benefit in the context of HIV infection. This discussion will provide a comprehensive overview of what is known and what remains to be explored in regard to co-receptor signaling and HIV infection, and will emphasize the potential value of HIV co-receptors as a target for future therapeutic development.

scholarly journals Neurotrophins as Key Regulators of Cell Metabolism: Implications for Cholesterol Homeostasis

2021 ◽  
Vol 22 (11) ◽  
pp. 5692
Author(s):  
Mayra Colardo ◽  
Noemi Martella ◽  
Daniele Pensabene ◽  
Silvia Siteni ◽  
Sabrina Di Bartolomeo ◽  
...  
Keyword(s):  
Growth Factors ◽  
Cholesterol Metabolism ◽  
System Development ◽  
Cell Metabolism ◽  
Redox Balance ◽  
Nervous System Development ◽  
Cholesterol Homeostasis ◽  
Signaling Cascades ◽  
Target Cells ◽  
The Impact

Neurotrophins constitute a family of growth factors initially characterized as predominant mediators of nervous system development, neuronal survival, regeneration and plasticity. Their biological activity is promoted by the binding of two different types of receptors, leading to the generation of multiple and variegated signaling cascades in the target cells. Increasing evidence indicates that neurotrophins are also emerging as crucial regulators of metabolic processes in both neuronal and non-neuronal cells. In this context, it has been reported that neurotrophins affect redox balance, autophagy, glucose homeostasis and energy expenditure. Additionally, the trophic support provided by these secreted factors may involve the regulation of cholesterol metabolism. In this review, we examine the neurotrophins’ signaling pathways and their effects on metabolism by critically discussing the most up-to-date information. In particular, we gather experimental evidence demonstrating the impact of these growth factors on cholesterol metabolism.

scholarly journals Emergency Room “Opt-Out” HIV Testing Pre- and During COVID-19 Pandemic in a Large Community Health System

2021 ◽  
Vol 20 ◽  
pp. 232595822110412
Author(s):  
Paula Eckardt ◽  
Jianli Niu ◽  
Sheila Montalvo
Keyword(s):  
Hiv Infection ◽  
Hiv Testing ◽  
Healthcare System ◽  
South Florida ◽  
Hiv Care ◽  
People Living With Hiv ◽  
Testing Program ◽  
Large Community ◽  
Opt Out ◽  
The Impact

Background: South Florida has the highest HIV rates across the country. Emergency Rooms (ERs) are optimal clinical sites for the identification of people living with HIV. We aimed to evaluate the feasibility and yield of opt-out HIV testing among ER patients in a large community healthcare system in South Florida, and determine the impact of the COVID-19 pandemic on HIV testing. Methods: This was a retrospective study conducted in the Memorial Healthcare System, Hollywood, Florida. HIV test was offered on an “opt-out” basis to patients aged 16 years or older presenting to the ER of the Memorial Regional Hospital between July 2018 and August 2020. Number of ER visits, HIV testing offered, acceptance of HIV testing, tested positive for HIV infection and linkage to care were reviewed and analyzed. Results: A total of 105,264 (53.7%) patients of 196,110 ER visits were eligible for HIV testing and 39,261 (37.3%) completed HIV testing. Of those tested, 206 (0.5%) patients tested positive, with 54 (26.2%) new infected patients and 152 (73.8%) known infected patients who had not disclosed their status. 45 (60%) of 75 patients with known HIV infections who were not engaged in HIV care were successfully relinked into care after testing, and engagement in care increased from 50.7% pre-testing to 80.3% post-testing (p = 0.001). 45 (83.3%) of 54 newly diagnosed patients were successfully linked into care. During the COVID-19 pandemic, there was a significant reduction in both the ER visits and HIV tests as compared with the pre-pandemic period (p = 0.007 and p < 0.001, respectively). Conclusion: An “Opt-out” HIV testing program was successfully implemented in a community hospital ERs. The use of this strategy successfully identified patients with undiagnosed HIV infection and improved their engagement in HIV care. Given the impact of COVID-19 pandemic on the testing program, new strategies should develop to reduce service disruption and maintain the progress of “Opt-out” HIV testing.

Multiple nuclear receptor signaling pathways mediate the actions of synthetic progestins in target cells

2012 ◽  
Vol 357 (1-2) ◽  
pp. 60-70 ◽  
Author(s):  
Nicole L. Moore ◽  
Theresa E. Hickey ◽  
Lisa M. Butler ◽  
Wayne D. Tilley
Keyword(s):  
Signaling Pathways ◽  
Nuclear Receptor ◽  
Target Cells ◽  
Receptor Signaling

scholarly journals Impact of HIV Infection on COVID-19 Outcomes Among Hospitalized Adults in the U.S.

2021 ◽  
Author(s):  
Matthew S. Durstenfeld ◽  
Kaiwen Sun ◽  
Yifei Ma ◽  
Fatima Rodriguez ◽  
Eric A. Secemsky ◽  
...  
Keyword(s):  
Hospital Mortality ◽  
Hiv Infection ◽  
Risk Ratio ◽  
Severity Of Illness ◽  
Risk Difference ◽  
Adverse Outcomes ◽  
People Living With Hiv ◽  
Cardiac Events ◽  
Living With Hiv ◽  
The Impact

AbstractBackgroundWhether HIV infection is associated with differences in clinical outcomes among people hospitalized with COVID-19 is uncertain.ObjectiveTo evaluate the impact of HIV infection on COVID-19 outcomes among hospitalized patients.MethodsUsing the American Heart Association’s COVID-19 Cardiovascular Disease registry, we used hierarchical mixed effects models to assess the association of HIV with in-hospital mortality accounting for patient demographics and comorbidities and clustering by hospital. Secondary outcomes included major adverse cardiac events (MACE), severity of illness, and length of stay (LOS).ResultsThe registry included 21,528 hospitalization records of people with confirmed COVID-19 from 107 hospitals in 2020, including 220 people living with HIV (PLWH). PLWH were younger (56.0+/-13.0 versus 61.3+/-17.9 years old) and more likely to be male (72.3% vs 52.7%), Non-Hispanic Black (51.4% vs 25.4%), on Medicaid (44.5% vs 24.5), and active tobacco users (12.7% versus 6.5%).Of the study population, 36 PLWH (16.4%) had in-hospital mortality compared with 3,290 (15.4%) without HIV (Risk ratio 1.06, 95%CI 0.79-1.43; risk difference 0.9%, 95%CI −4.2 to 6.1%; p=0.71). After adjustment for age, sex, race, and insurance, HIV was not associated with in-hospital mortality (aOR 1.13; 95%CI 0.77-1.6; p 0.54) even after adding body mass index and comorbidities (aOR 1.15; 95%CI 0.78-1.70; p=0.48). HIV was not associated with MACE (aOR 0.99, 95%CI 0.69-1.44, p=0.91), severity of illness (aOR 0.96, 95%CI 0.62-1.50, p=0.86), or LOS (aOR 1.03; 95% CI 0.76-1.66, p=0.21).ConclusionHIV was not associated with adverse outcomes of COVID-19 including in-hospital mortality, MACE, or severity of illness.Condensed AbstractWe studied 21,528 patients hospitalized with COVID-19 at 107 hospitals in AHA’s COVID-19 registry to examine the association between HIV and COVID-19 outcomes. More patients with HIV were younger, male, non-Hispanic Black, on Medicaid and current smokers. HIV was not associated with worse COVID-19 in-hospital mortality (Risk ratio 1.06, 95%CI 0.79-1.43; p=0.71) even after adjustment (aOR 1.15; 95%CI 0.78-1.70; p=0.48). HIV was also not associated with MACE (aOR 0.99, 95%CI 0.69-1.44, p=0.91) or severity of illness (aOR 0.96, 95%CI 0.62-1.50, p=0.86. Our findings do not support that HIV is a major risk factor for adverse COVID-19 outcomes.

scholarly journals Genetic architecture of cardiometabolic risks in people living with HIV

BMC Medicine ◽  
2020 ◽  
Vol 18 (1) ◽  
Author(s):  
Haoxiang Chang ◽  
Anshuman Sewda ◽  
Carla Marquez-Luna ◽  
Sierra R. White ◽  
Bridget M. Whitney ◽  
...  
Keyword(s):  
Hiv Infection ◽  
Immune Cell ◽  
Risky Behaviors ◽  
Research Network ◽  
Risk Scores ◽  
People Living With Hiv ◽  
Lipid Levels ◽  
Genetic Loci ◽  
Increased Risk ◽  
The Impact

Abstract Background Advances in antiretroviral therapies have greatly improved the survival of people living with human immunodeficiency virus (HIV) infection (PLWH); yet, PLWH have a higher risk of cardiovascular disease than those without HIV. While numerous genetic loci have been linked to cardiometabolic risk in the general population, genetic predictors of the excessive risk in PLWH are largely unknown. Methods We screened for common and HIV-specific genetic variants associated with variation in lipid levels in 6284 PLWH (3095 European Americans [EA] and 3189 African Americans [AA]), from the Centers for AIDS Research Network of Integrated Clinical Systems cohort. Genetic hits found exclusively in the PLWH cohort were tested for association with other traits. We then assessed the predictive value of a series of polygenic risk scores (PRS) recapitulating the genetic burden for lipid levels, type 2 diabetes (T2D), and myocardial infarction (MI) in EA and AA PLWH. Results We confirmed the impact of previously reported lipid-related susceptibility loci in PLWH. Furthermore, we identified PLWH-specific variants in genes involved in immune cell regulation and previously linked to HIV control, body composition, smoking, and alcohol consumption. Moreover, PLWH at the top of European-based PRS for T2D distribution demonstrated a > 2-fold increased risk of T2D compared to the remaining 95% in EA PLWH but to a much lesser degree in AA. Importantly, while PRS for MI was not predictive of MI risk in AA PLWH, multiethnic PRS significantly improved risk stratification for T2D and MI. Conclusions Our findings suggest that genetic loci involved in the regulation of the immune system and predisposition to risky behaviors contribute to dyslipidemia in the presence of HIV infection. Moreover, we demonstrate the utility of the European-based and multiethnic PRS for stratification of PLWH at a high risk of cardiometabolic diseases who may benefit from preventive therapies.

scholarly journals The Impact of Migration on HIV Infection Situation (Analytical Review)

2019 ◽  
Vol 74 (2) ◽  
pp. 88-97
Author(s):  
Anastasia V. Pokrovskaya ◽  
Valeriy V. Yumaguzin ◽  
Dmitry E. Kireev ◽  
Maria V. Vinnik ◽  
Vadim V. Pokrovskiy
Keyword(s):  
Hiv Infection ◽  
Hiv Positive ◽  
People Living With Hiv ◽  
Negative Effects ◽  
State Budget ◽  
Global Epidemic ◽  
Legal Norms ◽  
The World ◽  
Living With Hiv ◽  
The Impact

Today, the unstable political and economic situation in the world has led to an intensified migration and changes in their directions. The legal norms regarding the status of migrants, including people living with HIV, are also changing. Over the past 10 years laws restricting the entry and residence of HIV-infected foreign citizens have been repealed in many countries, but in Russia the deportation and prohibition of long-term stay of HIV positive international migrants are still in effect. This review presents the main aspects of the impact of migration on the spread of HIV in the world and Russia, as well as the possible positive and negative effects of decriminalization of migrants living with HIV in terms of epidemic situation, socio-demographic and economic processes. The argument for retaining the deportation is due to the potential risk of the spread of the disease by foreigners and the unresolved organization of medical care and treatment of HIV infection for foreign migrants, which are provided for Russian citizens from the state budget. On the other hand, the deportation law touches upon ethical aspects, violating freedom of movement, the right to privacy and freedom from discrimination. Despite the presence or absence of restrictive measures against HIV-positive migrants, HIV has spread throughout all countries and led to a global epidemic. Prevention of HIV infection among general population of the country, regardless of their migration status, is a priority on the way to stop the spread of infection. 

scholarly journals GABABR Modulation of Electrical Synapses and Plasticity in the Thalamic Reticular Nucleus

2021 ◽  
Vol 22 (22) ◽  
pp. 12138
Author(s):  
Huaixing Wang ◽  
Julie S. Haas
Keyword(s):  
Signaling Pathways ◽  
Neuronal Activity ◽  
Gabab Receptor ◽  
Receptor Activation ◽  
Gabab Receptors ◽  
Electrical Synapse ◽  
Thalamic Reticular Nucleus ◽  
Reticular Nucleus ◽  
Electrical Synapses ◽  
The Impact

Two distinct types of neuronal activity result in long-term depression (LTD) of electrical synapses, with overlapping biochemical intracellular signaling pathways that link activity to synaptic strength, in electrically coupled neurons of the thalamic reticular nucleus (TRN). Because components of both signaling pathways can also be modulated by GABAB receptor activity, here we examined the impact of GABAB receptor activation on the two established inductors of LTD in electrical synapses. Recording from patched pairs of coupled rat neurons in vitro, we show that GABAB receptor inactivation itself induces a modest depression of electrical synapses and occludes LTD induction by either paired bursting or metabotropic glutamate receptor (mGluR) activation. GABAB activation also occludes LTD from either paired bursting or mGluR activation. Together, these results indicate that afferent sources of GABA, such as those from the forebrain or substantia nigra to the reticular nucleus, gate the induction of LTD from either neuronal activity or afferent glutamatergic receptor activation. These results add to a growing body of evidence that the regulation of thalamocortical transmission and sensory attention by TRN is modulated and controlled by other brain regions. Significance: We show that electrical synapse plasticity is gated by GABAB receptors in the thalamic reticular nucleus. This effect is a novel way for afferent GABAergic input from the basal ganglia to modulate thalamocortical relay and is a possible mediator of intra-TRN inhibitory effects.

scholarly journals Dishevelled coordinates phosphoinositide kinases PI4KIIIα and PIP5KIγ for efficient PtdInsP2 synthesis

2022 ◽  
Author(s):  
Lizbeth de la Cruz ◽  
Raul Riquelme ◽  
Oscar Vivas ◽  
Andres Barria ◽  
Jill B. Jensen
Keyword(s):  
Plasma Membrane ◽  
Synergistic Effect ◽  
Receptor Activation ◽  
Scaffolding Protein ◽  
Signaling Cascades ◽  
Receptor Signaling ◽  
Cellular Processes ◽  
Lipid Kinases

Phosphatidylinositol(4,5)-bisphosphate (PtdInsP2) is an important modulator of many cellular processes and its abundance in the plasma membrane is closely regulated. We examined the hypothesis that the scaffolding protein Dishevelled can bind the lipid kinases PI4K and PIP5K, facilitating synthesis of PtdInsP2 directly from PtdIns. This report used several assays for PtdInsP2 to examine the cooperative function of phosphoinositide kinases and Dishevelled in the context of two receptor signaling cascades. Simultaneous overexpression of PI4KIIIα and PIP5KIγ had a synergistic effect on PtdInsP2 synthesis that was recapitulated by overexpression of Dishevelled. Increasing the activity of Dishevelled by overexpression increased resting plasma membrane PtdInsP2. Knockdown of Dishevelled reduced resting plasma membrane PtdInsP2 and slowed PtdInsP2 resynthesis following receptor activation. We confirm that Dishevelled promotes coupling of PI4KIIIα and PIP5KIγ and show that this interaction is essential for efficient resynthesis of PtdInsP2 following receptor activation.

scholarly journals Exploring major signaling cascades in melanomagenesis: a rationale route for targetted skin cancer therapy

2018 ◽  
Vol 38 (5) ◽  
Author(s):  
Paola M. Dantonio ◽  
Marianne O. Klein ◽  
Maria Renata V.B. Freire ◽  
Camila N. Araujo ◽  
Ana Carolina Chiacetti ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Transforming Growth Factor ◽  
Survival Rates ◽  
Transforming Growth Factor Β ◽  
Janus Kinase ◽  
Mitogen Activated Protein Kinase ◽  
Signaling Cascades ◽  
Mitogen Activated Protein ◽  
Metastatic Sites ◽  
The Impact

Although most melanoma cases may be treated by surgical intervention upon early diagnosis, a significant portion of patients can still be refractory, presenting low survival rates within 5 years after the discovery of the illness. As a hallmark, melanomas are highly prone to evolve into metastatic sites. Moreover, melanoma tumors are highly resistant to most available drug therapies and their incidence have increased over the years, therefore leading to public health concerns about the development of novel therapies. Therefore, researches are getting deeper in unveiling the mechanisms by which melanoma initiation can be triggered and sustained. In this context, important progress has been achieved regarding the roles and the impact of cellular signaling pathways in melanoma. This knowledge has provided tools for the development of therapies based on the intervention of signal(s) promoted by these cascades. In this review, we summarize the importance of major signaling pathways (mitogen-activated protein kinase (MAPK), phosphoinositide 3-kinase (PI3K)-Akt, Wnt, nuclear factor κ-light-chain-enhancer of activated B cell (NF-κB), Janus kinase (JAK)-signal transducer and activator of transcription (STAT), transforming growth factor β (TGF-β) and Notch) in skin homeostasis and melanoma progression. Available and developing melanoma therapies interfering with these signaling cascades are further discussed.

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