Biological And Clinical Markers Of Neuronal Injury In Primary And Chronic Hiv-1 Infection

The use of antiretroviral therapy (ART) has shifted the neurological manifestations of HIV-1 infection toward mild but debilitating HIV-associated neurocognitive disorder (HAND). Through two studies, we sought to characterize neuronal injury during primary and chronic HIV infection and to describe its relationship with HAND. The aim of the first study was to quantify cerebrospinal fluid (CSF) and neuroimaging biomarkers of neuronal injury in primary HIV infection (PHI). We compared CSF levels of neurofilament light chain (NFL), tau, and amyloid proteins in 92 subjects with PHI and 25 controls and examined relationships with disease progression and neuroinflammation, neuropsychological testing, and proton-magnetic resonance spectroscopy (MRS). We hypothesized that PHI is characterized by increased CSF NFL that correlates with neuronal inflammation, and that tau and amyloid levels are normal in PHI. NFL was elevated in PHI (p=0.0004) and correlated with CSF neopterin (r=0.38, p=0.0005), IP-10 (r=0.39, p=0.002), WBCs (r=0.32, p=0.004), and CSF:plasma albumin ratio (r=0.60, p\u3c0.0001). NFL correlated with decreased N-acteylaspartate and glutamate in the anterior cingulate, frontal white matter, and parietal gray matter (r\u3e0.30, p\u3c0.05). Beta-amyloid was elevated in PHI (p=0.0005) and correlated with time infected (r=0.34, p=0.003). Neither marker correlated with neuropsychological abnormalities. T-tau and amyloid precursor proteins did not differ between groups. The aim of the second study was to characterize HIV-infected patients with neuro-symptomatic CSF `escape,\u27 defined as detectable CSF HIV RNA in the setting of treatment-suppressed plasma levels or CSF RNA \u3e1 log higher than plasma RNA. We conducted a retrospective case series of virologically controlled HIV-infected patients on ART with progressive neurological abnormalities who were determined to have CSF `escape\u27 at 4 urban medical centers in the United States and Europe. We recorded levels of CSF HIV RNA and inflammatory markers, clinical signs and symptoms, and magnetic resonance imaging (MRI) findings. We hypothesized that individuals with this condition would have inflammation in CSF and MRI studies, that CSF virus would be resistant to the ART regimen, and that symptoms would improve when ART was changed based upon central nervous system (CNS) drug penetration and resistance genotyping. 10 patients presented with sensory, motor, and cognitive abnormalities. Median CSF HIV RNA was 3900 copies/mL; median plasma HIV RNA was 62 copies/mL. Median CD4+ T cell count was 482 cells/mm3. All patients had been controlled \u3c500 copies/mL for median 27.5 months and 5/10 had been suppressed \u3c50 copies/mL for median 19.5 months. Patients were on a stable ART regimen for median 21 months. All had CSF pleocytosis or elevated CSF protein; 7/8 had MRI abnormalities; and 6/7 harbored CSF resistance mutations. Following optimization of ART, 8/9 patients improved clinically. Although these processes occur at distinct time points in the disease, both neuronal injury during PHI and the development of symptomatic CSF `escape\u27 in chronic, well-treated infection are associated with, and possibly caused by, mechanisms involving immune activation and inflammation within the CNS. The inflammatory milieu induced by the activity of HIV in invading cells and triggering an immune response has important implications throughout the time course of infection, and may be particularly important for understanding the pathophysiology of HAND

Rapid onset of hypercalcemia from high-grade lymphoma in the setting of HIV-related immune reconstitution inflammatory syndrome.

Hypercalcemia in HIV patients has been previously reported, but 1,25-(OH)2 vitamin D-mediated hypercalcemia, due to increased activity of extrarenal 1-alpha hydroxylase, is rarely described with HIV-related infections or malignancies. We describe a case of 1,25-(OH)2 vitamin D-mediated hypercalcemia in a patient presenting with progressive cognitive decline and weakness. Initial evaluation revealed a new diagnosis of HIV, for which he was started on antiretroviral therapy (ART). He was also noted to have mild asymptomatic hypocalcemia, likely from his acute illness and malnutrition, which was not further investigated at the time. While the patient's mental status initially improved with ART, he became progressively delirious and was found to be hypercalcemic approximately 4 weeks after the initiation of ART. Possible etiologies for hypercalcemia were vigorously evaluated, including granulomatous disease, infection, and malignancy, in the setting of suspected immune reconstitution inflammatory syndrome (IRIS), due to recent initiation of ART. Infectious workup was unrevealing, but computed tomography (CT) of the chest, abdomen, and pelvis revealed new extensive diffuse lymphadenopathy and hepatomegaly, not present on admission studies. Cytology and flow cytometry of a liver biopsy specimen revealed CD10 positive high-grade B-cell lymphoma. Chemotherapy was not pursued due to poor performance status. Over the next week, spontaneous tumor lysis developed, and the patient expired. Postmortem, his 1,25-(OH)2 vitamin D level returned as markedly elevated. Immunohistochemical staining of his liver biopsy tissue showed strong expression of CYP27B1. 1,25-(OH)2 vitamin D-mediated hypercalcemia is uncommon in a patient with newly diagnosed HIV and, in this case, was likely due to IRIS unmasking an underlying high-grade lymphoma and restoration of immune function (including T-cells and cytokine production). This case emphasizes the importance of including aggressive lymphomas, capable of progressing over days to weeks, in the evaluation of hypercalcemia in HIV patients at risk for developing IRIS and the rapid dynamic changes in mineral homeostasis that can occur with such an aggressive tumor in an immunocompromised host

Infectious Mimicry Complicates Diagnosis in Hemophagocytic Syndrome Caused by Anaplastic Large-Cell Lymphoma

Hemophagocytic syndrome (HPS) arises secondary to genetic, rheumatologic, neoplastic, and infectious causes. We discuss a patient whose presentation was consistent with systemic infection but was discovered to have HPS of unknown etiology. The presenting symptoms, as well as unremarkable malignancy and rheumatologic workups, led to the pursuit of an infectious cause, but the patient was ultimately discovered to have an occult anaplastic large-cell lymphoma (ALCL). This case demonstrates the diagnostic challenges that result from infectious mimicry in the context of HPS—first, in distinguishing noninfectious HPS from the systemic inflammation that can result from a widespread infectious process, second, in the identification of the precipitating cause of HPS. While evidence of these challenges has been suggested by the limited literature on HPS and ALCL, our case illustrates the diagnostic dilemma that arises when tissue biopsy does not quickly reveal an etiology. It is important that all physicians be aware that HPS can mimic infection and be prepared to redirect the workup when an infectious etiology for HPS cannot be identified

Bidirectional Exchanges of Medical Students Between Institutional Partners in Global Health Clinical Education Programs: Putting Ethical Principles into Practice

BackgroundOne-third of US medical students participate in global health (GH) education, and approximately one-quarter of US medical schools have structured programs that offer special recognition in GH. GH clinical electives (GHCEs) are opportunities for students to experience a medical system and culture different from their own. GHCEs are administered through institutional affiliation agreements, often between an institution in a high-income country (HIC) and one in a low- or middle-income country (LMIC). Although these agreements suggest the exchange of students in both directions, GHCEs are traditionally characterized by students from HICs traveling to LMICs.ObjectivesThe goal of this study was to investigate the availability of opportunities for students from LMICs participating in GHCEs at partner institutions in HICs and to describe the costs of these opportunities for students from LMICs.MethodsWe conducted a web-based search of 30 US institutions previously identified as having structured programs in GH. We determined which of these schools have programs that accept medical students from international schools for GHCEs, as well as the administrative requirements, types of fees, and other costs to the international student based on information available on the web. Descriptive statistics were employed for the quantitative analysis of costs.FindingsWe found that, although the majority of US institutions with structured GH programs sending students to sites abroad accept international students at their sites in the United States, nearly one-fifth of programs do not offer such opportunities for bidirectional exchange. We also characterized the substantial costs of such experiences, because this can represent a significant barrier for students from LMICs.ConclusionsAccess to GHCEs in US partner institutions should be an important underlying ethical principle in the establishment of institutional partnerships. The opportunities available to and experiences of students from LMIC partner institutions are important areas for future GH education research

Comparative Analysis of Tandem Repeats from Hundreds of Species Reveals Unique Insights into Centromere Evolution

Centromeres are essential for chromosome segregation, yet their DNA sequences evolve rapidly. In most animals and plants that have been studied, centromeres contain megabase-scale arrays of tandem repeats. Despite their importance, very little is known about the degree to which centromere tandem repeats share common properties between different species across different phyla. We used bioinformatic methods to identify high-copy tandem repeats from 282 species using publicly available genomic sequence and our own data. The assumption that the most abundant tandem repeat is the centromere DNA was true for most species whose centromeres have been previously characterized, suggesting this is a general property of genomes. Our methods are compatible with all current sequencing technologies. Long Pacific Biosciences sequence reads allowed us to find tandem repeat monomers up to 1,419 bp. High-copy centromere tandem repeats were found in almost all animal and plant genomes, but repeat monomers were highly variable in sequence composition and in length. Furthermore, phylogenetic analysis of sequence homology showed little evidence of sequence conservation beyond ~50 million years of divergence. We find that despite an overall lack of sequence conservation, centromere tandem repeats from diverse species showed similar modes of evolution, including the appearance of higher order repeat structures in which several polymorphic monomers make up a larger repeating unit. While centromere position in most eukaryotes is epigenetically determined, our results indicate that tandem repeats are highly prevalent at centromeres of both animals and plants. This suggests a functional role for such repeats, perhaps in promoting concerted evolution of centromere DNA across chromosomes

VirusMINT: a viral protein interaction database

Understanding the consequences on host physiology induced by viral infection requires complete understanding of the perturbations caused by virus proteins on the cellular protein interaction network. The VirusMINT database (http://mint.bio.uniroma2.it/virusmint/) aims at collecting all protein interactions between viral and human proteins reported in the literature. VirusMINT currently stores over 5000 interactions involving more than 490 unique viral proteins from more than 110 different viral strains. The whole data set can be easily queried through the search pages and the results can be displayed with a graphical viewer. The curation effort has focused on manuscripts reporting interactions between human proteins and proteins encoded by some of the most medically relevant viruses: papilloma viruses, human immunodeficiency virus 1, Epstein–Barr virus, hepatitis B virus, hepatitis C virus, herpes viruses and Simian virus 40

Characterizing Symptoms and Identifying Biomarkers of Long COVID in People With and Without HIV: Protocol for a Remotely Conducted Prospective Observational Cohort Study

Background: Living with HIV is a risk factor for severe acute COVID-19, but it is unknown whether it is a risk factor for long COVID./ Objective: This study aims to characterize symptoms, sequelae, and cognition formally and prospectively 12 months following SARS-CoV-2 infection in people living with HIV compared with people without HIV. People with no history of SARS-CoV-2 infection, both with and without HIV, are enrolled as controls. The study also aims to identify blood-based biomarkers or patterns of immune dysregulation associated with long COVID./ Methods: This prospective observational cohort study enrolled participants into 1 of the following 4 study arms: people living with HIV who had SARS-CoV-2 infection for the first time <4 weeks before enrollment (HIV+COVID+ arm), people without HIV who had SARS-CoV-2 infection for the first time within 4 weeks of enrollment (HIV−COVID+ arm), people living with HIV who believed they never had SARS-CoV-2 infection (HIV+COVID− arm), and people without HIV who believed they never had SARS-CoV-2 infection (HIV−COVID− arm). At enrollment, participants in the COVID+ arms recalled their symptoms, mental health status, and quality of life in the month before having SARS-CoV-2 infection via a comprehensive survey administered by telephone or on the web. All participants completed the same comprehensive survey 1, 2, 4, 6, and 12 months after post–acute COVID-19 symptom onset or diagnosis, if asymptomatic, (COVID+ arms) or after enrollment (COVID− arms) on the web or by telephone. In total, 11 cognitive assessments were administered by telephone at 1 and 4 months after symptom onset (COVID+ arms) or after enrollment (COVID− arms). A mobile phlebotomist met the participants at a location of their choice for height and weight measurements, orthostatic vital signs, and a blood draw. Participants in the COVID+ arms donated blood 1 and 4 months after COVID-19, and participants in the COVID− arms donated blood once or none. Blood was then shipped overnight to the receiving study laboratory, processed, and stored./ Results: This project was funded in early 2021, and recruitment began in June 2021. Data analyses will be completed by summer 2023. As of February 2023, a total of 387 participants were enrolled in this study, with 345 participants having completed enrollment or baseline surveys together with at least one other completed study event. The 345 participants includes 76 (22%) HIV+COVID+, 121 (35.1%) HIV−COVID+, 78 (22.6%) HIV+COVID−, and 70 (20.3%) HIV−COVID− participants./ Conclusions: This study will provide longitudinal data to characterize COVID-19 recovery over 12 months in people living with and without HIV. Additionally, this study will determine whether biomarkers or patterns of immune dsyregulation associate with decreased cognitive function or symptoms of long COVID

Pharmacodynamic changes in tumor and immune cells drive iberdomide's clinical mechanisms of activity in relapsed and refractory multiple myeloma

Iberdomide is a next-generation cereblon (CRBN)-modulating agent in the clinical development in multiple myeloma (MM). The analysis of biomarker samples from relapsed/refractory patients enrolled in CC-220-MM-001 (ClinicalTrials.gov: NCT02773030), a phase 1/2 study, shows that iberdomide treatment induces significant target substrate degradation in tumors, including in immunomodulatory agent (IMiD)-refractory patients or those with low CRBN levels. Additionally, some patients with CRBN genetic dysregulation who responded to iberdomide have a similar median progression-free survival (PFS) (10.9 months) and duration of response (DOR) (9.5 months) to those without CRBN dysregulation (11.2 month PFS, 9.4 month DOR). Iberdomide treatment promotes a cyclical pattern of immune stimulation without causing exhaustion, inducing a functional shift in T cells toward an activated/effector memory phenotype, including in triple-class refractory patients and those receiving IMiDs as a last line of therapy. This analysis demonstrates that iberdomide's clinical mechanisms of action are driven by both its cell-autonomous effects overcoming CRBN dysregulation in MM cells, and potent immune stimulation that augments anti-tumor immunity