NeuroImmune pharmacology and therapeutics最新文献

Objective: To quantify neuropsychiatric symptoms reported by individuals with Post-Acute Sequelae of COVID-19 (PASC) using the NIH Toolbox^® for Assessment of Neurological and Behavioral Function (NIHTB) and Patient-Reported Outcomes Measurement Information System (PROMIS).

Methods: 30 PASC (20 women, 21-63 years) and 27 control (16 women, 25-68 years) participants completed three NIHTB batteries and selected PROMIS tests. Group differences on fully corrected T-scores were evaluated using analysis of covariance and Cohen's d effect sizes. A linear regression model predicted the effects from time since diagnosis.

Results: PASC had poorer emotional health and motor function than controls, including poorer locomotion, endurance and dexterity, but normal cognitive function, ~7 months post-infection, compared to controls. PASC participants had a steeper age-related decline on 2-Minute Walk than controls. T-scores on four cognitive and three motor tests improved with longer time since diagnosis.

Conclusion: NIHTB and PROMIS captured the poorer emotional health and motor function in PASC, including the novel findings of deficits locomotion and dexterity. The normal cognitive performance suggests subclinical effects that may be compensated by neural and cognitive reserves, and manifested subjectively by the negative psychological effects and fatigue. The persistent emotional and psychiatric symptoms necessitate mental health treatment be prioritized.

The 27th Scientific Conference of the Society on Neuroimmune Pharmacology (SNIP) in New Delhi, India, on March 15-18, 2023 is a historic summit of experts from around the world. The four day conference provides insights into the latest and most advanced science in the intersecting areas of neuroscience, immunology, pharmacology, and its translational aspects, in particular, HIV and drug abuse. Abstracts are ordered in three major groups: (1) Symposium speakers (S1-S64), (2) Investigator Posters (I1-I18), and (3) Trainee Poster (T1-T28).

Background: We recently reveal that anti-CD4 autoantibodies contribute to blunted CD4+ T cell reconstitution in HIV+ individuals on antiretroviral therapy (ART). Cocaine use is common among HIV+ individuals and is associated with accelerated disease progression. However, the mechanisms underlying cocaine-induced immune perturbations remain obscure.

Methods: We evaluated plasma levels of anti-CD4 IgG and markers of microbial translocation, as well as B-cell gene expression profiles and activation in HIV+ chronic cocaine users and non-users on suppressive ART, as well as uninfected controls. Plasma purified anti-CD4 IgGs were assessed for antibody-dependent cytotoxicity (ADCC).

Results: HIV+ cocaine users had increased plasma levels of anti-CD4 IgGs, lipopolysaccharide (LPS), and soluble CD14 (sCD14) versus non-users. An inverse correlation was observed in cocaine users, but not non-drug users. Anti-CD4 IgGs from HIV+ cocaine users mediated CD4+ T cell death through ADCC in vitro. B cells from HIV+ cocaine users exhibited activation signaling pathways and activation (cycling and TLR4 expression) related to microbial translocation versus non-users.

Conclusions: This study improves our understanding of cocaine associated B cell perturbations and immune failure and the new appreciation for autoreactive B cells as novel therapeutic targets.

Objectives: We aimed to compare brain white matter integrity in participants with post-COVID-19 conditions (PCC) and healthy controls.

Methods: We compared cognitive performance (NIH Toolbox^®), psychiatric symptoms and diffusion tensor imaging (DTI) metrics between 23 PCC participants and 24 controls. Fractional anisotropy (FA), axial (AD), radial (RD), and mean (MD) diffusivities were measured in 9 white matter tracts and 6 subcortical regions using MRICloud.

Results: Compared to controls, PCC had similar cognitive performance, but greater psychiatric symptoms and perceived stress, as well as higher FA and lower diffusivities in multiple white matter tracts (ANCOVA-p-values≤0.001-0.048). Amongst women, PCC had higher left amygdala-MD than controls (sex-by-PCC p=0.006). Regardless of COVID-19 history, higher sagittal strata-FA predicted greater fatigue (r=0.48-0.52, p<0.001) in all participants, and higher left amygdala-MD predicted greater fatigue (r=0.61, p<0.001) and anxiety (r=0.69, p<0.001) in women, and higher perceived stress (r=0.45, p=0.002) for all participants.

Conclusions: Microstructural abnormalities are evident in PCC participants averaged six months after COVID-19. The restricted diffusivity (with reduced MD) and higher FA suggest enhanced myelination or increased magnetic susceptibility from iron deposition, as seen in stress conditions. The higher amygdala-MD in female PCC suggests persistent neuroinflammation, which might contribute to their fatigue, anxiety, and perceived stress.

Objectives: Spatial-temporal biodistribution of antiretroviral drugs (ARVs) can now be achieved using MRI by utilizing chemical exchange saturation transfer (CEST) contrasts. However, the presence of biomolecules in tissue limits the specificity of current CEST methods. To overcome this limitation, a Lorentzian line-shape fitting algorithm was developed that simultaneously fits CEST peaks of ARV protons on its Z-spectrum.

Case presentation: This algorithm was tested on the common first line ARV, lamivudine (3TC), that has two peaks resulting from amino (-NH₂) and hydroxyl (-OH) protons in 3TC. The developed dual-peak Lorentzian function fitted these two peaks simultaneously, and used the ratio of -NH₂ and -OH CEST contrasts as a constraint parameter to measure 3TC presence in brains of drug-treated mice. 3TC biodistribution calculated using the new algorithm was compared against actual drug levels measured using UPLC-MS/MS. In comparison to the method that employs the -NH₂ CEST peak only, the dual-peak Lorentzian fitting algorithm showed stronger correlation with brain tissue 3TC levels, signifying estimation of actual drug levels.

Conclusions: We concluded that 3TC levels can be extracted from confounding CEST effects of tissue biomolecules resulting in improved specificity for drug mapping. This algorithm can be expanded to measure a variety of ARVs using CEST MRI.

Human immunodeficiency virus type 1 (HIV-1) is a chronic disease that afflicts over 38 million people worldwide without a known cure. The advent of effective antiretroviral therapies (ART) has significantly decreased the morbidity and mortality associated with HIV-1 infection in people living with HIV-1 (PWH), thanks to durable virologic suppression. Despite this, people with HIV-1 experience chronic inflammation associated with co-morbidities. While no single known mechanism accounts for chronic inflammation, there is significant evidence to support the role of the NLRP3 inflammasome as a key driver. Numerous studies have demonstrated therapeutic impact of cannabinoids, including exerting modulatory effects on the NLRP3 inflammasome. Given the high rates of cannabinoid use in PWH, it is of great interest to understand the intersecting biology of the role of cannabinoids in HIV-1-associated inflammasome signaling. Here we describe the literature of chronic inflammation in people with HIV, the therapeutic impact of cannabinoids in PWH, endocannabinoids in inflammation, and HIV-1-associated inflammation. We describe a key interaction between cannabinoids, the NLRP3 inflammasome, and HIV-1 viral infection, which supports further investigation of the critical role of cannabinoids in HIV-1 infection and inflammasome signaling.