Neurosarcoidosis of the trigeminal nerve: clinical accompaniments, radiographic findings, and association with neuralgia.

BACKGROUND: Cranial neuropathy is a principal disease manifestation of neurosarcoidosis, but many forms remain poorly described, including trigeminal nerve disease despite its frequency in reported cohorts (5-12%). Herein, we characterize the clinical course of patients with neurosarcoidosis involving the trigeminal nerve. METHODS: A single-center retrospective cohort analysis of patients with biopsy-proven sarcoidosis involving the trigeminal nerve was conducted between 1/1/2000-3/7/2023. RESULTS: The trigeminal nerve was affected in 14/245 (5.7%) patients, being clinically symptomatic in 5/245 (2.0%) and asymptomatic with radiographic involvement in 9/245 (3.7%). 14/14 (100.0%) patients had systemic sarcoidosis. In the symptomatic group, trigeminal neuropathy was an inaugural feature in 4/5 (80.0%), unilateral in 5/5 (100.0%) with the V1 subdivision most affected (4/5, 80.0%), and associated with neuralgia in 2/5 (40.0%). On MRI, the cisternal nerve roots (9/14, 64.3%), Meckel's cave (7/14, 50.0%), and cavernous sinus (5/14, 35.7%) were most commonly affected, and 14/14 (100.0%) patients had extra-trigeminal neuroinflammation on cranial MRI. CSF was abnormal in at least one dimension in 11/12 (91.7%) tested. All three treated patients with symptomatic trigeminal neuropathy responded to immunomodulatory treatment, and symptomatic treatments for trigeminal neuralgia were helpful in two patients. After a median follow-up period of 63 months, the median modified Rankin scale score was 1 for both subgroups. CONCLUSION: Neurosarcoidosis may involve any portion of the trigeminal apparatus, and when affected, it frequently demonstrates a mismatch in radiographic involvement from its clinical manifestations of facial numbness and pain, and typically occurs in association with other clinical or radiographic manifestations of neurosarcoidosis.

Novel method to quantify phenotypic markers of HIV-associated neurocognitive disorder in a murine SCID model.

Despite combined antiretroviral therapy (cART), HIV infection in the CNS persists with reported increases in activation of macrophages (MΦ), microglia, and surrounding astrocytes/neurons, conferring HIV-induced inflammation. Chronic inflammation results in HIV-associated neurocognitive disorders (HAND) with reported occurrence of up to half of individuals with HIV infection. The existing HAND mouse model used by laboratories including ours, and the effect of novel agents on its pathology present with labor-intensive and time-consuming limitations since brain sections and immunohistochemistry assays have to be performed and analyzed. A novel flow cytometry-based system to objectively quantify phenotypic effects of HIV using a SCID mouse HAND model was developed which demonstrated that the HIV-infected mice had significant increases in astrogliosis, loss of neuronal dendritic marker, activation of murine microglia, and human macrophage explants compared to uninfected control mice. HIV p24 could also be quantified in the brains of the infected mice. Correlation of these impairments with HIV-induced brain inflammation and previous behavioral abnormalities studies in mice suggests that this model can be used as a fast and relevant throughput methodology to quantify preclinical testing of novel treatments for HAND.

Baricitinib reverses HIV-associated neurocognitive disorders in a SCID mouse model and reservoir seeding in vitro.

BACKGROUND: Since HIV-associated neurocognitive disorders (HANDs) occur in up to half of HIV-positive individuals, even with combined antiretroviral therapy (cART), adjunctive therapies are needed. Chronic CNS inflammation contributes to HAND and HIV encephalitis (HIVE). Baricitinib is a JAK 1/2 inhibitor approved in the USA, EU, and Japan for rheumatoid arthritis, demonstrating potent inhibition of IL-6, D-dimer, CRP, TNF-α, IFN-α/ß, and other pro-inflammatory cytokines. METHODS: Our modified murine HAND model was used to evaluate the ability of baricitinib to cross the blood-brain barrier (BBB) and modulate monocyte/macrophage-driven HAND. Severity of HAND was measured by assessing cognitive performance of low- and high-dose baricitinib treated versus untreated HAND mice. The severity of brain neuroinflammation was evaluated in these mouse groups after flow cytometric analyses. We also assessed the ability of baricitinib to block events in myeloid and lymphoid cells in vitro that may undergird the persistence of HIV in the central nervous system (CNS) in primary human macrophages (Mϕ) and lymphocytes including HIV replication, HIV-induced activation, reservoir expansion, and reservoir maintenance. RESULTS: In vivo, both doses of 10 and 50 mg/kg qd baricitinib crossed the BBB and reversed behavioral abnormalities conferred by HIV infection. Moreover, baricitinib significantly reduced HIV-induced neuroinflammation marked by glial activation: activated microglia (MHCII+/CD45+) and astrogliosis (GFAP). Baricitinib also significantly reduced the percentage of p24+ human macrophages in mouse brains (p < 0.05 versus HAND mice; t test). In vitro, baricitinib significantly reduced markers of persistence, reservoir size, and reseeding in Mϕ. CONCLUSION: These results show that blocking the JAK/STAT pathway reverses cognitive deficits and curtails inflammatory markers in HAND in mice. Our group recently reported safety and tolerability of ruxolitinib in HIV-infected individuals (Marconi et al., Safety, tolerability and immunologic activity of ruxolitinib added to suppressive ART, 2019), underscoring potential safety and utility of JAK inhibitors for additional human trials. The data reported herein coupled with our recent human trial with JAK inhibitors provide compelling preclinical data and impetus for considering a trial of baricitinib in HAND individuals treated with cART to reverse cognitive deficits and key events driving viral persistence.

Aging, comorbidities, and the importance of finding biomarkers for HIV-associated neurocognitive disorders.

HIV-associated neurocognitive disorders (HAND) continue to affect a large proportion of persons living with HIV despite effective viral suppression with combined antiretroviral therapy (cART). Importantly, milder versions of HAND have become more prevalent. The pathogenesis of HAND in the era of cART appears to be multifactorial with contributions from central nervous system (CNS) damage that occur prior to starting cART, chronic immune activation, cART neurotoxicity, and various age-related comorbidities (i.e., cardiovascular and cerebrovascular disease, diabetes, hyperlipidemia). Individuals with HIV may experience premature aging, which could also contribute to cognitive impairment. Likewise, degenerative disorders aside from HAND increase with age and there is evidence of shared pathology between HAND and other neurodegenerative diseases, such as Alzheimer's disease, which can occur with or without co-existing HAND. Given the aforementioned complex interactions associated with HIV, cognitive impairment, and aging, it is important to consider an age-appropriate differential diagnosis for HAND as the HIV-positive population continues to grow older. These factors make the accuracy and reliability of the diagnosis of mild forms of HAND in an aging population of HIV-infected individuals challenging. The complexity of current diagnosis of mild HAND also highlights the need to develop reliable biomarkers. Ultimately, the identification of a set of specific biomarkers will be required to achieve early and accurate diagnosis, which will be necessary assuming specific treatments for HAND are developed.

Measurement of Human Immunodeficiency Virus p24 Antigen in Human Cerebrospinal Fluid With Digital Enzyme-Linked Immunosorbent Assay and Association With Decreased Neuropsychological Performance.

New tools are needed to understand human immunodeficiency virus central nervous system involvement. Testing 15 cerebrospinal fluid (CSF) samples for p24 antigen, using a high-sensitivity assay, we found a strong correlation trend between CSF p24 concentration and worse neuropsychological performance.

A mouse model of HIV-associated neurocognitive disorders: a brain-behavior approach to discover disease mechanisms and novel treatments.

HIV-associated neurocognitive disorders (HAND) remain highly prevalent despite combined antiretroviral therapy (cART). Although the most common forms of HAND are mild and identified through neuropsychological testing, there is evidence that with aging these mild forms become more prevalent and may advance to the most severe form of HAND, HIV-associated dementia. Therefore, novel therapies must be developed that can be used adjunctively with cART to prevent deterioration or restore normal cognitive function. In order to develop innovative treatments, animal models are used for preclinical testing. Ideally, a HAND animal model should portray similar mild cognitive deficits that are found in humans. A mouse model of HAND is discussed, which demonstrates mild behavioral deficits and has been used to investigate cART and novel treatments for HAND. This model also shows correlations between abnormal mouse behavior due to HIV in the brain and pathological parameters such as gliosis and neuronal abnormalities. A recent advancement utilizes the object recognition test to monitor mouse behavior before and after treatment. It is postulated that this model is well suited for preclinical testing of novel therapies and provides correlations of mild cognitive impairment with pathological markers that can give further insight into the pathophysiology of HAND.

Peroxisome proliferator-activated receptor-γ agonists attenuate biofilm formation by Pseudomonas aeruginosa.

Pseudomonas aeruginosa is a significant contributor to recalcitrant multidrug-resistant infections, especially in immunocompromised and hospitalized patients. The pathogenic profile of P. aeruginosa is related to its ability to secrete a variety of virulence factors and to promote biofilm formation. Quorum sensing (QS) is a mechanism wherein P. aeruginosa secretes small diffusible molecules, specifically acyl homo serine lactones, such as N-(3-oxo-dodecanoyl)-l-homoserine lactone (3O-C12-HSL), that promote biofilm formation and virulence via interbacterial communication. Strategies that strengthen the host's ability to inhibit bacterial virulence would enhance host defenses and improve the treatment of resistant infections. We have recently shown that peroxisome proliferator-activated receptor γ (PPARγ) agonists are potent immunostimulators that play a pivotal role in host response to virulent P. aeruginosa Here, we show that QS genes in P. aeruginosa (strain PAO1) and 3O-C12-HSL attenuate PPARγ expression in bronchial epithelial cells. PAO1 and 3O-C12-HSL induce barrier derangements in bronchial epithelial cells by lowering the expression of junctional proteins, such as zonula occludens-1, occludin, and claudin-4. Expression of these proteins was restored in cells that were treated with pioglitazone, a PPARγ agonist, before infection with PAO1 and 3O-C12-HSL. Barrier function and bacterial permeation studies that have been performed in primary human epithelial cells showed that PPARγ agonists are able to restore barrier integrity and function that are disrupted by PAO1 and 3O-C12-HSL. Mechanistically, we show that these effects are dependent on the induction of paraoxonase-2, a QS hydrolyzing enzyme, that mitigates the effects of QS molecules. Importantly, our data show that pioglitazone, a PPARγ agonist, significantly inhibits biofilm formation on epithelial cells by a mechanism that is mediated via paraoxonase-2. These findings elucidate a novel role for PPARγ in host defense against P. aeruginosa Strategies that activate PPARγ can provide a therapeutic complement for treatment of resistant P. aeruginosa infections.-Bedi, B., Maurice, N. M., Ciavatta, V. T., Lynn, K. S., Yuan, Z., Molina, S. A., Joo, M., Tyor, W. R., Goldberg, J. B., Koval, M., Hart, C. M., Sadikot, R. T. Peroxisome proliferator-activated receptor-γ agonists attenuate biofilm formation by Pseudomonas aeruginosa.

Cerebrospinal fluid interferon alpha levels correlate with neurocognitive impairment in ambulatory HIV-Infected individuals.

HIV-associated neurocognitive disorders (HANDs) continue to be common and are associated with increased morbidity and mortality. However, the underlying mechanisms in the combination antiretroviral therapy (cART) era are not fully understood. Interferon alpha (IFNα) is an antiviral cytokine found to be elevated in the cerebrospinal fluid (CSF) of individuals with advanced HIV-associated dementia in the pre-cART era. In this cross-sectional study, we investigated the association between IFNα and neurocognitive performance in ambulatory HIV-infected individuals with milder impairment. An eight-test neuropsychological battery representing six cognitive domains was administered. Individual scores were adjusted for demographic characteristics, and a composite neuropsychological score (NPT-8) was calculated. IFNα and CSF neurofilament light chain (NFL) levels were measured using enzyme-linked immunosorbent assay (ELISA). There were 15 chronically infected participants with a history of significant immunocompromise (median nadir CD4+ of 49 cells/µl). Most participants were neurocognitively impaired (mean global deficit score of 0.86). CSF IFNα negatively correlated with three individual tests (Trailmaking A, Trailmaking B, and Stroop Color-Word) as well as the composite NPT-8 score (r = -0.67, p = 0.006). These negative correlations persisted in multivariable analyses adjusting for chronic hepatitis B and C. Additionally, CSF IFNα correlated strongly with CSF NFL, a marker of neuronal damage (rho = 0.748, p = 0.0013). These results extend findings from individuals with severe HIV-associated dementia in the pre-cART era and suggest that IFNα may continue to play a role in HAND pathogenesis during the cART era. Further investigation into the role of IFNα is indicated.

In vitro and Ex vivo Neurotoxic Effects of Efavirenz are Greater than Those of Other Common Antiretrovirals.

Although antiretroviral (ARV) therapy has reduced the incidence of severe dementia associated with HIV infection, there has been a rise in milder neurocognitive complaints. Data from HIV patients taking ARVs have shown measurable neurocognitive improvements during drug cessation, suggesting a neurotoxic role of the therapy itself. Mechanisms underlying potential ARV neurotoxicity have not been thoroughly investigated, however pathologic oxidative stress and mitochondrial dysfunction have been suspected. Using DIV 16 primary rat cortical neuron culture, we tested eight ARVs from the three most commonly prescribed ARV classes: nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs/NtRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), and protease inhibitors (PIs) for effects on neuron viability and morphology after 24 h of drug exposure. Of the tested NRTIs, only stavudine at nearly 100 times the target plasma concentration affected neuron viability with no appreciable change in morphology. Dideoxyinosine induced dendritic simplification at 100 times target plasma concentrations, but did not adversely affect viability. The sole NtRTI, tenofovir, induced dendritic simplification at approximately 3-4 times target plasma concentration, but did not affect viability. Of the tested PIs, only amprenavir decreased neuron viability at nearly 100 times the target plasma concentration. The non-nucleoside reverse transcriptase inhibitor, efavirenz, consistently reduced viability (at 50 µM) and induced dendritic simplification (at 20 µM) nearest the target plasma concentration. Probing mitochondrial energetics of DIV16 cortical neurons after exposure to 20 µM efavirenz showed rapid diminution of mitochondrial-dependent oxygen consumption. Further, 20 µM efavirenz decreased excitability in ex vivo slice culture whereas 2 µM had no effect.

The Janus kinase inhibitor ruxolitinib reduces HIV replication in human macrophages and ameliorates HIV encephalitis in a murine model.

A hallmark of persistent HIV-1 infection in the central nervous system is increased activation of mononuclear phagocytes and surrounding astrogliosis, conferring persistent HIV-induced inflammation. This inflammation is believed to result in neuronal dysfunction and the clinical manifestations of HIV-associated neurocognitive disorders (HAND). The Jak/STAT pathway is activated in macrophages/myeloid cells upon HIV-1 infection, modulating many pro-inflammatory pathways that result in HAND, thereby representing an attractive cellular target. Thus, the impact of ruxolitinib, a Janus Kinase (Jak) 1/2 inhibitor that is FDA approved for myelofibrosis and polycythemia vera, was assessed for its potential to inhibit HIV-1 replication in macrophages and HIV-induced activation in monocytes/macrophages in culture. In addition, a murine model of HIV encephalitis (HIVE) was used to assess the impact of ruxolitinib on histopathological features of HIVE, brain viral load, as well as its ability to penetrate the blood-brain-barrier (BBB). Ruxolitinib was found to inhibit HIV-1 replication in macrophages, HIV-induced activation of monocytes (CD14/CD16) and macrophages (HLA-DR, CCR5, and CD163) without apparent toxicity. In vivo, systemically administered ruxolitinib was detected in the brain during HIVE in SCID mice and markedly inhibited astrogliosis. Together, these data indicate that ruxolitinib reduces HIV-induced activation and infiltration of monocytes/macrophages in vitro, reduces the replication of HIV in vitro, penetrates the BBB when systemically administered in mice and reduces astrogliosis in the brains of mice with HIVE. These data suggest that ruxolitinib will be useful as a novel therapeutic to treat humans with HAND.

Preliminary study of a novel cognitive assessment device for the evaluation of HIV-associated neurocognitive impairment.

Given the high prevalence of HIV-associated neurocognitive disorders (HAND), we examined the performance of a novel computerized cognitive assessment device (NCAD) for the evaluation of neurocognitive impairment in the setting of HIV. In addition to a standard 8-test neuropsychological battery, each participant underwent testing with the NCAD, which requires approximately 20 min and has been shown to accurately measure neurocognition in elderly individuals. The NCAD yields seven subtest scores in addition to an overall predictive score that is calculated based on subtest results. Thirty-nine HIV-infected participants were included in this study; the majority of which (71.8 %) had undetectable plasma HIV RNA levels and a history of significant immunocompromise (median nadir CD4+ count 34 cells/µl). The mean composite neuropsychological score (NPT-8) was 46.07, and mean global deficit score (GDS) was 0.59. NCAD total subtest accuracy correlated significantly with NPT-8 (Pearson correlation r = 0.59, p < 0.0001) as well as GDS (Spearman's rho = -0.36, p = 0.02). NCAD predictive score also correlated significantly with NPT-8 (Spearman's rho = -0.5601, p = 0.0016) and GDS (Spearman's rho = 0.45, p = 0.0144). When using the most recent nosology of HAND criteria for neurocognitive impairment, the area under the curve (AUC) for NCAD total subtest accuracy was 0.7562 (p = 0.012), while the AUC for the HIV dementia scale was 0.508 (p = 0.930). While not as comprehensive as a full neuropsychological battery, the NCAD shows promise as a rapid screening tool for HIV-infected individuals, and additional research of this device is indicated.

Concentration-Dependent Dual Role of Thrombin in Protection of Cultured Rat Cortical Neurons.

Thrombin's role in the nervous system is not well understood. Under conditions of blood-brain barrier compromise (e.g., neurosurgery or stroke), thrombin can result in neuroapoptosis and the formation of glial scars. Despite this, preconditioning with thrombin has been found to be neuroprotective in models of cerebral ischemia and intracerebral hemorrhage. We investigated the effects of physiologically relevant concentrations of thrombin on cortical neurons using two culture-based assays. We examined thrombin's effect on neurites by quantitative analysis of fluorescently labeled neurons. To characterize thrombin's effects on neuron survival, we spectrophotometrically measured changes in enzymatic activity. Using receptor agonists and thrombin inhibitors, we separately examined the role of thrombin and its receptor in neuroprotection. We found that low concentrations of thrombin (1 nM) enhances neurite growth and branching, neuron viability, and protects against excitotoxic damage. In contrast, higher concentrations of thrombin (100 nM) are potentially detrimental to neuronal health as evidenced by inhibition of neurite growth. Lower concentrations of thrombin resulted in equivalent neuroprotection as the antifibrinolytic, aprotinin, and the direct thrombin inhibitor, argatroban. Interestingly, exogenous application of the species-specific thrombin inhibitor, antithrombin III, was detrimental to neuronal health; suggesting that some endogenous thrombin is necessary for optimal neuron health in our culture system. Activation of the thrombin receptor, protease-activated receptor-1 (PAR-1), via micromolar concentrations of the thrombin receptor agonist peptide, TRAP, did not adversely affect neuronal viability. An optimal concentration of thrombin exists to enhance neuronal health. Neurotoxic effects of thrombin do not involve activation of PAR receptors and thus separate pharmacologic manipulation of thrombin's receptor in the setting of direct thrombin inhibitors could be a potential neuroprotective strategy.

Combined antiretroviral therapy reduces brain viral load and pathological features of HIV encephalitis in a mouse model.

The role of brain HIV load in the pathogenesis of HIV-associated neurocognitive disorders (HAND) is unclear. To try and determine if the amount of HIV drives the severity of pathology, a severe combined immunodeficient (SCID) mouse model of HIV encephalitis (HIVE) was utilized to determine the effectiveness of a systemically administered combined antiretroviral (cART) regimen. SCID mice were inoculated intracerebrally with HIV-infected or uninfected (control) human macrophages and treated subcutaneously with cART or saline for 10 days. Immunohistochemistry was then used to examine gliosis and neuronal damage. Drug levels were measured in brain and plasma using high-performance liquid chromatography. Peak plasma and brain levels of atazanavir, tenofovir, and emtricitabine were determined to be 1 h post-injection of cART therapy. cART significantly reduced neuropathological features of HIVE, including astrogliosis and the presence of mononuclear phagocytes, and ameliorated reduced MAP2 (neuronal integrity) staining. However, cART did not eradicate HIV from the brain. Using this animal model of HIVE, these data indicate effective penetration of cART reduces brain viral loads and HIV pathology, possibly by eliminating the production of HIV proteins, virus infected cells, or both. Importantly, these data suggest that viral load directly affects the extent of pathology seen in the brain, particularly neuronal damage, which implies that more effective suppression of HIV in the CNS could reduce currently highly prevalent forms of HAND. However, these data also strongly suggest that cART will not eliminate HIV from the brain and that adjunctive therapies must be developed.

The identification of intact HIV proviral DNA from human cerebrospinal fluid.

We evaluated the HIV-1 DNA reservoir in peripheral blood mononuclear cells (PBMC) and cerebrospinal fluid (CSF) in people with HIV (PWH) and associations to cognitive dysfunction. Using the intact proviral DNA assay (IPDA), an emerging technique to identify provirus that may be the source of viral rebound, we assessed HIV DNA in CSF and PBMC in PWH regardless of antiretroviral therapy (ART). CSF was used as a sampling surrogate for the central nervous system (CNS) as opposed to tissue. IDPA results (3' defective, 5' defective, and intact HIV DNA) were analyzed by compartment (Wilcoxon signed rank; matched and unmatched pairs). Cognitive performance, measured via a battery of nine neuropsychological (NP) tests, were analyzed for correlation to HIV DNA (Spearman's rho). 11 CSF and 8 PBMC samples from PWH were evaluated both unmatched and matched. Total CSF HIV DNA was detectable in all participants and was significantly higher than in matched PBMCs (p â€‹= â€‹0.0039). Intact CSF HIV DNA was detected in 7/11 participants and correlated closely with those in PBMCs but tended to be higher in CSF than in PBMC. CSF HIV DNA did not correlate with global NP performance, but higher values did correlate with worse executive function (p â€‹= â€‹0.0440). Intact HIV DNA is frequently present in the CSF of PWH regardless of ART. This further supports the presence of an HIV CNS reservoir and provides a method to study CNS reservoirs during HIV cure studies. Larger studies are needed to evaluate relationships with CNS clinical outcomes.

Honokiol hexafluoro confers reversal of neuropathological markers of HIV infection in a murine SCID model.

Cognitive impairment remains a persistent challenge in people living with HIV (PWLH) despite antiretroviral therapy (ART) due to ART's inability to eliminate brain HIV. HIV-induced cognitive dysfunction results from immune dysregulation, ongoing neuroinflammation, and the continuous virus presence, collectively contributing to cognitive deficits. Therefore, adjunctive therapies are needed to reduce cerebral HIV reservoirs, mitigate neuroinflammation, and impede cognitive dysfunction progression. Our study focused on Honokiol, known for its anti-inflammatory and neuroprotective properties, in an experimental mouse model simulating HIV-induced cognitive dysfunction. Using Honokiol Hexafluoro (HH), a synthetic analogue, we comprehensively evaluated its potential to ameliorate cognitive dysfunction and cerebral pathology in HIV-associated cognitive dysfunction. Our findings showed that HH treatment effectively reversed HIV-induced cognitive dysfunction, concurrently suppressing astrocyte activation, restoring neuronal dendritic arborization, and reducing microglial activation. Furthermore, HH remodeled the metabolic profile of HIV-infected human monocyte-derived macrophages, resulting in decreased activation and the promotion of a quiescent state in vitro.

Exploration of potential immune mechanisms in cervical dystonia.

BACKGROUND: Although there are many possible causes for cervical dystonia (CD), a specific etiology cannot be identified in most cases. Prior studies have suggested a relationship between autoimmune disease and some cases of CD, pointing to possible immunological mechanisms. OBJECTIVE: The goal was to explore the potential role of multiple different immunological mechanisms in CD. METHODS: First, a broad screening test compared neuronal antibodies in controls and CD. Second, unbiased blood plasma proteomics provided a broad screen for potential biologic differences between controls and CD. Third, a multiplex immunoassay compared 37 markers associated with immunological processes in controls and CD. Fourth, relative immune cell frequencies were investigated in blood samples of controls and CD. Finally, sequencing studies investigated the association of HLA DQB1 and DRB1 alleles in controls versus CD. RESULTS: Screens for anti-neuronal antibodies did not reveal any obvious abnormalities. Plasma proteomics pointed towards certain abnormalities of immune mechanisms, and the multiplex assay pointed more specifically towards abnormalities in T lymphocytes. Abnormal immune cell frequencies were identified for some CD cases, and these cases clustered together as a potential subgroup. Studies of HLA alleles indicated a possible association between CD and DRB1*15:03, which is reported to mediate the penetrance of autoimmune disorders. CONCLUSIONS: Altogether, the association of CD with multiple different blood-based immune measures point to abnormalities in cell-mediated immunity that may play a pathogenic role for a subgroup of individuals with CD.

Clade C HIV-1 isolates circulating in Southern Africa exhibit a greater frequency of dicysteine motif-containing Tat variants than those in Southeast Asia and cause increased neurovirulence.

BACKGROUND: HIV-1 Clade C (Subtype C; HIV-1C) is responsible for greater than 50% of infections worldwide. Unlike clade B HIV-1 (Subtype B; HIV-1B), which is known to cause HIV associated dementia (HAD) in approximately 15% to 30% of the infected individuals, HIV-1C has been linked with lower prevalence of HAD (0 to 6%) in India and Ethiopia. However, recent studies report a higher prevalence of HAD in South Africa, Zambia and Botswana, where HIV-1C infections predominate. Therefore, we examined whether Southern African HIV-1C is genetically distinct and investigated its neurovirulence. HIV-1 Tat protein is a viral determinant of neurocognitive dysfunction. Therefore, we focused our study on the variations seen in tat gene and its contribution to HIV associated neuropathogenesis. RESULTS: A phylogenetic analysis of tat sequences of Southern African (South Africa and Zambia) HIV isolates with those from the geographically distant Southeast Asian (India and Bangladesh) isolates revealed that Southern African tat sequences are distinct from Southeast Asian isolates. The proportion of HIV - 1C variants with an intact dicysteine motif in Tat protein (C30C31) was significantly higher in the Southern African countries compared to Southeast Asia and broadly paralleled the high incidence of HAD in these countries. Neuropathogenic potential of a Southern African HIV-1C isolate (from Zambia; HIV-1C 1084i), a HIV-1C isolate (HIV-1 IndieC1) from Southeast Asia and a HIV-1B isolate (HIV-1 ADA) from the US were tested using in vitro assays to measure neurovirulence and a SCID mouse HIV encephalitis model to measure cognitive deficits. In vitro assays revealed that the Southern African isolate, HIV-1C 1084i exhibited increased monocyte chemotaxis and greater neurotoxicity compared to Southeast Asian HIV-1C. In neurocognitive tests, SCID mice injected with MDM infected with Southern African HIV-1C 1084i showed greater cognitive dysfunction similar to HIV-1B but much higher than those exposed to Southeast Asian HIV - 1C. CONCLUSIONS: We report here, for the first time, that HIV-1C from Southern African countries is genetically distinct from Southeast Asian HIV-1C and that it exhibits a high frequency of variants with dicysteine motif in a key neurotoxic HIV protein, Tat. Our results indicate that Tat dicysteine motif determines neurovirulence. If confirmed in population studies, it may be possible to predict neurocognitive outcomes of individuals infected with HIV-1C by genotyping Tat.

Effect of HIV clade differences on the onset and severity of HIV-associated neurocognitive disorders.

The effects of evolutionary pressure on human immunodeficiency virus-1 (HIV) have resulted in a variety of clades and recombinants. The functional implications of HIV clades on disease onset and progression of HIV-associated neurocognitive disorders (HAND) have been suggested by clinical and basic science studies, which will be reviewed in detail. Some clinical studies suggest that patients infected with clade D show the greatest propensity for developing HIV-associated dementia (HAD) followed by clades B, C, and A, respectively. However, there are conflicting reports. This review summarizes clinical studies that have assessed behavioral abnormalities and HIV clade type in HAND patients, focusing on the clades stated above. The limitations include variations in testing used to define the cohorts, patient sample size, lack of HIV clade characterization, combination antiretroviral therapy (cART) availability, and other factors, which are highlighted and compared between clinical studies performed primarily in Africa and India. Basic science studies provide substantial evidence that HIV clade differences can result in varying degrees of neuropathology and are also reviewed in some detail. These studies indicate that there are a number of clade differences, most notably in Tat, that result in different degrees of neurovirulence or neuropathological effects in vitro and in a mouse model of HAND. In order to confirm the hypothesis that HIV clade differences are important determinants of HAND pathogenesis, larger, longitudinal studies that employ standard definitions of HAND and HIV clade testing must be performed. In a larger sense, HAND continues to be highly prevalent despite the advent of cART, and therefore, further studies into HAND pathogenesis are critical to develop better therapies.

Morphine exposure during HIV encephalitis in SCID mice.

HIV encephalitis (HIVE) is often complicated by opiate abuse. Based on human pathological, animal and in vitro studies, opiates are thought to exacerbate HIVE. To test this hypothesis we exposed 10 week old SCID mice with HIVE to morphine and examined histopathological parameters. Mice inoculated intracerebrally with either HIV-infected or uninfected (control mice) human macrophages were immediately implanted subcutaneously with pellets containing saline, morphine or morphine plus naltrexone. They were sacrificed after 10 days. Immunostaining for astrocytes (GFAP), mouse mononuclear phagocytes (CD45) and neuronal dendrites (MAP2) was analyzed by densitometry. HIVE mice exposed to either saline, morphine or morphine plus naltrexone also had brain sections counted for HIV+ human macrophages. Typical HIVE pathology was present, consistent with previously published studies. Surprisingly, there were no effects on astrogliosis, microgliosis and MAP2 decreases in the HIVE, morphine treated group. There was also no effect of morphine exposure on numbers of p24+ human macrophages. These results emphasize the complexities of modeling opiate effects in HIVE and the potential significance of opiate abuse on HIVE in humans.

Immune responses to SARS-CoV-2 vaccination in multiple sclerosis: a systematic review/meta-analysis.

INTRODUCTION: Responses to SARS-CoV-2 vaccination in patients with MS (pwMS) varies by disease-modifying therapies (DMTs). We perform a meta-analysis and systematic review of immune response to SARS-CoV-2 vaccines in pwMS. METHODS: Two independent reviewers searched PubMed, Google Scholar, and Embase from January 1, 2019-December 31, 2021, excluding prior SARS-CoV-2 infections. The meta-analysis of observational studies in epidemiology (MOOSE) guidelines were applied. The data were pooled using a fixed-effects model. RESULTS: Eight-hundred sixty-four healthy controls and 2203 pwMS from 31 studies were included. Antibodies were detected in 93% healthy controls (HCs), and 77% pwMS, with >93% responses in all DMTs (interferon-beta, glatiramer acetate, cladribine, natalizumab, dimethyl fumarate, alemtuzumab, and teriflunomide) except for 72% sphingosine-1-phosphate modulators (S1PM) and 44% anti-CD20 monoclonal antibodies (mAbs). T-cell responses were detected in most anti-CD20 and decreased in S1PM. Higher antibody response was observed in mRNA vaccines (99.7% HCs) versus non-mRNA vaccines (HCs: 72% inactivated virus; pwMS: 86% vector, 59% inactivated virus). A multivariate logistic regression model to predict vaccine response demonstrated that mRNA versus non-mRNA vaccines had a 3.4 odds ratio (OR) for developing immunity in anti-CD20 (p = 0.0052) and 7.9 OR in pwMS on S1PM or CD20 mAbs (p < 0.0001). Antibody testing timing did not affect antibody detection. CONCLUSION: Antibody responses are decreased in S1PM and anti-CD20; however, cellular responses were positive in most anti-CD20 with decreased T cell responses in S1PM. mRNA vaccines had increased seroconversion rates compared to non-RNA vaccines. Further investigation in how DMTs affect vaccine immunity are needed.