Pre-pandemic Metabolic Correlates of COVID-19 Severity and Long COVID Incidence in People Living with HIV.

Host metabolic dysregulation, especially in tryptophan metabolism, is intricately linked to COVID-19 severity and its post-acute sequelae (Long COVID). People living with HIV (PLWH) experience similar metabolic dysregulation and face an increased risk of developing Long COVID. However, whether pre-existing HIV-associated metabolic dysregulations contribute in predisposing PLWH to severe COVID-19 outcomes remains underexplored. Analyzing pre-pandemic samples from PLWH with documented post-infection outcomes, we found specific metabolic alterations, including increased tryptophan catabolism, predicting an elevated risk of severe COVID-19 and the incidence of Long COVID. These alterations warrant further investigation for their potential prognostic and mechanistic significance in determining COVID-19 complications.

Circulating immune and plasma biomarkers of time to HIV rebound in HIV controllers treated with vesatolimod.

Background: Antiretroviral therapy (ART) for HIV-1 treatment has improved lifespan but requires lifelong adherence for people living with HIV (PLWH), highlighting the need for a cure. Evaluation of potential cure strategies requires analytic treatment interruption (ATI) with close monitoring of viral rebound. Predictive biomarkers for HIV-1 rebound and/or duration of control during ATI will facilitate these HIV cure trials while minimizing risks. Available evidence suggests that host immune, glycomic, lipid, and metabolic markers of inflammation may be associated with HIV-1 persistence in PLWH who are treated during chronic HIV-1 infection. Methods: We conducted post-hoc analysis of HIV controllers who could maintain low levels of plasma HIV-1 without ART in a phase 1b vesatolimod trial. Baseline and pre-ATI levels of immune, glycomic, lipidomic, and metabolomic markers were tested for association with ATI outcomes (time of HIV-1 rebound to 200 copies/mL and 1,000 copies/mL, duration of HIV-1 RNA ≤400 copies/mL and change in intact proviral HIV-1 DNA during ATI) using Spearman's correlation and Cox proportional hazards model. Results: Higher levels of CD69+CD8+ T-cells were consistently associated with shorter time to HIV-1 rebound at baseline and pre-ATI. With few exceptions, baseline fucosylated, non-galactosylated, non-sialylated, bisecting IgG N-glycans were associated with shorter time to HIV rebound and duration of control as with previous studies. Baseline plasma MPA and HPA binding glycans and non-galactosylated/non-sialylated glycans were associated with longer time to HIV rebound, while baseline multiply-galactosylated glycans and sialylated glycans, GNA-binding glycans, NPA-binding glycans, WGA-binding glycans, and bisecting GlcNAc glycans were associated with shorter time to HIV rebound and duration of control. Fourteen bioactive lipids had significant baseline associations with longer time to rebound and duration of control, and larger intact proviral HIV-1 DNA changes; additionally, three baseline bioactive lipids were associated with shorter time to first rebound and duration of control. Conclusion: Consistent with studies in HIV non-controllers, proinflammatory glycans, lipids, and metabolites were generally associated with shorter duration of HIV-1 control. Notable differences were observed between HIV controllers vs. non-controllers in some specific markers. For the first time, exploratory biomarkers of ATI viral outcomes in HIV-controllers were investigated but require further validation.

HIV rebound in HIV controllers is associated with a specific fecal microbiome profile.

HIV infection is associated with gut dysbiosis, and microbiome variability may affect HIV control when antiretroviral therapy (ART) is stopped. The TLR7 agonist, vesatolimod, was previously associated with a modest delay in viral rebound following analytical treatment interruption in HIV controllers (HCs). Using a retrospective analysis of fecal samples from HCs treated with vesatolimod or placebo (NCT03060447), people with chronic HIV (CH; NCT02858401) or without HIV (PWOH), we examined fecal microbiome profile in HCs before/after treatment, and in CH and PWOH. Microbiome diversity and abundance were compared between groups to investigate the association between specific phyla/species, immune biomarkers, and viral outcomes during treatment interruption. Although there were no significant differences in gut microbiome diversity between people with and without HIV, HCs, and CH shared common features that distinguished them from PWOH. there was a trend toward greater microbiome diversity among HCs. Treatment with vesatolimod reduced dysbiosis in HCs. Firmicutes positively correlated with T-cell activation, while Bacteroidetes and Euryarchaeota inversely correlated with TLR7-mediated immune activation. Specific types of fecal microbiome abundance (e.g. Alistipes putredinis) positively correlated with HIV rebound. In conclusion, variability in the composition of the fecal microbiome is associated with markers of immune activation following vesatolimod treatment and ART interruption.

Clinical performance and wear resistance of milled resin composite material versus direct nanohybrid bulk-fill resin composite in the restoration of endodontically treated posterior teeth over 1 year: Randomized clinical trial.

Context: The restorative complexities associated with endodontically treated teeth surpass those encountered with vital ones. The field of adhesive dentistry experienced a significant advancement that led to a shift in treatment approach toward bonded restorations. Aim: The aim of the study was to assess the clinical performance of using indirect Milled composite or direct bulk-fill resin composite restorations for endo-treated teeth, as well as to measure the amount of wear on the occlusal tables of both restorations using a digital scanner. Subjects and Methods: Participants were divided into two groups, where R1 represents the endodontically treated teeth restored with Milled composite, R2 represents the endodontically treated teeth restored with direct bulk-fill composite where 13 patients in each group were treated with a total number of 26 restorations in all patients. Where each restoration was assessed immediately at baseline (T0), 6 months (T6), and 12 months (T12) using the modified United States Public Health Service criteria. Moreover, wear was measured immediately at (T0) and (T12) intraorally and extraorally using intraoral scanners and three-dimensional surface-based superimposition software. Statistical Analysis Used: Chi-squared test, Mann-Whitney U-test, Friedman's test, Nemenyi post hoc test, Shapiro-Wilk test, paired t-tests, intraclass correlation coefficient. Results: At all intervals, the majority of the cases in both groups had an alpha score. Some cases exhibited bravo scores in both groups at T6 and T12 regarding the color match, marginal adaptation, marginal discoloration, and marginal integrity without statistically significant difference (P > 0.05). Direct nanohybrid bulk-fill resin composite showed a greater amount of wear without a statistically significant difference (P > 0.05). Extraoral measurement was significantly higher than intraoral measurement (P < 0.001). There was no significant reliability/agreement between both methods. Conclusions: Both milled composite and direct bulk-fill resin composite restorations in endodontically treated teeth demonstrated appropriate clinical performance and minimal wear over an 1-year follow-up period.

Sea cucumber physiological response to abiotic stress: Emergent contaminants and climate change.

The ocean is facing a multitude of abiotic stresses due to factors such as climate change and pollution. Understanding how organisms in the ocean respond to these global changes is vital to better predicting consequences. Sea cucumbers are popular echinoderms with multiple ecological, nutritional, and pharmaceutical benefits. Here, we reviewed the effects of environmental change on an ecologically important echinoderm of the ocean, aiming to understand their response better, which could facilitate healthy culture programs under environmental changes and draw attention to knowledge gaps. After screening articles from the databases, 142 studies were included on the influence of emergent contaminants and climate variation on the early developmental stages and adults of sea cucumbers. We outlined the potential mechanism underlying the physiological response of sea cucumbers to emerging contaminants and climate change. It can be concluded that the physiological response of sea cucumbers to emergent contaminants differs from their response to climate change. Sea cucumbers could accumulate pollutants in their organs but are aestivated when exposed to extreme climate change. Research showed that the physiological response of sea cucumbers to pollutants indicates that these pollutants impair critical physiological processes, particularly during the more susceptible early phases of development compared to adults, and the accumulation of these pollutants in adults is often observed. For climate change, sea cucumbers showed gradual adaptation to the slight variation. However, sea cucumbers undergo aestivation under extreme conditions. Based on this review, critical suggestions for future research are presented, and we call for more efforts focusing on the co-occurrence of different stressors to extend the knowledge regarding the effects of environmental changes on these economically and ecologically important species.

Targeting branched N-glycans and fucosylation sensitizes ovarian tumors to immune checkpoint blockade.

Aberrant glycosylation is a crucial strategy employed by cancer cells to evade cellular immunity. However, it's unclear whether homologous recombination (HR) status-dependent glycosylation can be therapeutically explored. Here, we show that the inhibition of branched N-glycans sensitizes HR-proficient, but not HR-deficient, epithelial ovarian cancers (EOCs) to immune checkpoint blockade (ICB). In contrast to fucosylation whose inhibition sensitizes EOCs to anti-PD-L1 immunotherapy regardless of HR-status, we observe an enrichment of branched N-glycans on HR-proficient compared to HR-deficient EOCs. Mechanistically, BRCA1/2 transcriptionally promotes the expression of MGAT5, the enzyme responsible for catalyzing branched N-glycans. The branched N-glycans on HR-proficient tumors augment their resistance to anti-PD-L1 by enhancing its binding with PD-1 on CD8+ T cells. In orthotopic, syngeneic EOC models in female mice, inhibiting branched N-glycans using 2-Deoxy-D-glucose sensitizes HR-proficient, but not HR-deficient EOCs, to anti-PD-L1. These findings indicate branched N-glycans as promising therapeutic targets whose inhibition sensitizes HR-proficient EOCs to ICB by overcoming immune evasion.

Immunoglobulin G N-glycan markers of accelerated biological aging during chronic HIV infection.

People living with HIV (PLWH) experience increased vulnerability to premature aging and inflammation-associated comorbidities, even when HIV replication is suppressed by antiretroviral therapy (ART). However, the factors associated with this vulnerability remain uncertain. In the general population, alterations in the N-glycans on IgGs trigger inflammation and precede the onset of aging-associated diseases. Here, we investigate the IgG N-glycans in cross-sectional and longitudinal samples from 1214 women and men, living with and without HIV. PLWH exhibit an accelerated accumulation of pro-aging-associated glycan alterations and heightened expression of senescence-associated glycan-degrading enzymes compared to controls. These alterations correlate with elevated markers of inflammation and the severity of comorbidities, potentially preceding the development of such comorbidities. Mechanistically, HIV-specific antibodies glycoengineered with these alterations exhibit a reduced ability to elicit anti-HIV Fc-mediated immune activities. These findings hold potential for the development of biomarkers and tools to identify and prevent premature aging and comorbidities in PLWH.

Validation of the Arabic Version of Feeding Handicap Index for Children with Developmental Disabilities (A-FHI-C).

Children with developmental disabilities have different feeding and swallowing problems. The purposes of the present study were to develop an Arabic version of the FHI-C and to evaluate its validity, consistency, and reliability in Arabic children with developmental disabilities for assessing how feeding and swallowing problems impair the physical, functional, and emotional aspects of children's lives. A prospective study including 113 children [62 children with autism spectrum disorder (ASD), 24 with cerebral palsy (CP), 27 with intellectual disability (ID)], in the age range of 2 to 10 years, selected randomly from the swallowing clinic, phoniatrics unit, Otorhinolaryngology department, University hospital between September 2023 and December 2023 complaining of feeding and swallowing problems. Validity was established by comparing patients` scores to typically developed controls (31 children). For test-retest reliability, forty parents filled out the A-FHI-C again two weeks after their initial visit. Cronbach's alpha for A-FHI-C was 0.986, indicating good internal consistency. Intraclass correlation showed 0.850 with a 95% confidence interval from 0.779 to 0.898. All three clinical groups had significantly higher total FHI-C and FHI-C domain scores than the control group, indicating good validation. A-FHI-C was found to have significantly high test-retest reliability. The current study indicates that in children with ASD, CP, ID, feeding problems are more prevalent than children who are typically developed. The scores obtained can be used by phoniatricans to evaluate feeding problems and monitor the progress of the therapy plan in children with developmental disorders.

Systems analysis of innate and adaptive immunity in Long COVID.

Since the onset of the COVID-19 pandemic, significant progress has been made in developing effective preventive and therapeutic strategies against severe acute SARS-CoV-2 infection. However, the management of Long COVID (LC), an infection-associated chronic condition that has been estimated to affect 5-20% of individuals following SARS-CoV-2 infection, remains challenging due to our limited understanding of its mechanisms. Although LC is a heterogeneous disease that is likely to have several subtypes, immune system disturbances appear common across many cases. The extent to which these immune perturbations contribute to LC symptoms, however, is not entirely clear. Recent advancements in multi-omics technologies, capable of detailed, cell-level analysis, have provided valuable insights into the immune perturbations associated with LC. Although these studies are largely descriptive in nature, they are the crucial first step towards a deeper understanding of the condition and the immune system's role in its development, progression, and resolution. In this review, we summarize the current understanding of immune perturbations in LC, covering both innate and adaptive immune responses, and the cytokines and analytes involved. We explore whether these findings support or challenge the primary hypotheses about LC's underlying mechanisms. We also discuss the crosstalk between various immune system components and how it can be disrupted in LC. Finally, we emphasize the need for more tissue- and subtype-focused analyses of LC, and for enhanced collaborative efforts to analyze common specimens from large cohorts, including those undergoing therapeutic interventions. These collective efforts are vital to unravel the fundaments of this new disease, and could also shed light on the prevention and treatment of the larger family of chronic illnesses linked to other microbial infections.

Synthesis of Cross-Linked and Sterilized Water-Soluble Electrospun Nanofiber Biomatrix of Streptomycin-Imbedded PVA/CHN/ß-CD for Wound Healing.

The diagnosis and prognosis of chronic wounds are demanding and require objective assessment. Because of their potential medicinal applications, the syntheses of biopolymeric chitosan (CHN) structure and PVA-based mixed electrospun nanofibers with biomimetic features were thoroughly investigated. This study created different formulas, including a guest molecule and capping agent, using supporting PVA as a vehicle. CHN was used as a biomodifier, and beta-cyclodextrin (ß-CD) as a smoother and more efficiently entraps streptomycin (STP) compared with the silver sheet wound dressing. The relevant analyses showed that the size distribution increased with the incorporation of PVA, CHN, and ß-CD to 120.3, 161.9, and 192.02 nm. The webs boosted particle size and released content stability to 96.4% without compromising the nanofiber structure. Examining the synergistic effects of the PVA/CHN/STP/ß-CD nanoformulation against pathogenic strains of S. aureus, P. aeruginosa, and Aspergillus niger, clean zones were 47 ± 3.4, 45 ± 3.0, and 49 ± 3.7 mm were produced. PVA/CHN/STP/ß-CD formula exhibited a 98.9 ± 0.6% cell viability and wound closure of 100% at 72 h. The results reveal that the PVA/CHN/STP/ß-CD formula is promising for medical applications, especially in wound healing, compared with the silver sheet.

Distinct intestinal microbial signatures linked to accelerated systemic and intestinal biological aging.

BACKGROUND: People living with HIV (PLWH), even when viral replication is controlled through antiretroviral therapy (ART), experience persistent inflammation. This inflammation is partly attributed to intestinal microbial dysbiosis and translocation, which may lead to non-AIDS-related aging-associated comorbidities. The extent to which living with HIV - influenced by the infection itself, ART usage, sexual orientation, or other associated factors - affects the biological age of the intestines is unclear. Furthermore, the role of microbial dysbiosis and translocation in the biological aging of PLWH remains to be elucidated. To investigate these uncertainties, we used a systems biology approach, analyzing colon and ileal biopsies, blood samples, and stool specimens from PLWH on ART and people living without HIV (PLWoH) as controls. RESULTS: PLWH exhibit accelerated biological aging in the colon, ileum, and blood, as measured by various epigenetic aging clocks, compared to PLWoH. Investigating the relationship between microbial translocation and biological aging, PLWH had decreased levels of tight junction proteins in the intestines, along with increased microbial translocation. This intestinal permeability correlated with faster biological aging and increased inflammation. When investigating the relationship between microbial dysbiosis and biological aging, the intestines of PLWH had higher abundance of specific pro-inflammatory bacteria, such as Catenibacterium and Prevotella. These bacteria correlated with accelerated biological aging. Conversely, the intestines of PLWH had lower abundance of bacteria known for producing the anti-inflammatory short-chain fatty acids, such as Subdoligranulum and Erysipelotrichaceae, and these bacteria were associated with slower biological aging. Correlation networks revealed significant links between specific microbial genera in the colon and ileum (but not in feces), increased aging, a rise in pro-inflammatory microbe-related metabolites (e.g., those in the tryptophan metabolism pathway), and a decrease in anti-inflammatory metabolites like hippuric acid. CONCLUSIONS: We identified specific microbial compositions and microbiota-related metabolic pathways that are intertwined with intestinal and systemic biological aging. This microbial signature of biological aging is likely reflecting various factors including the HIV infection itself, ART usage, sexual orientation, and other aspects associated with living with HIV. A deeper understanding of the mechanisms underlying these connections could offer potential strategies to mitigate accelerated aging and its associated health complications. Video Abstract.

Predictors of HIV rebound differ by timing of antiretroviral therapy initiation.

BACKGROUNDIdentifying factors that predict the timing of HIV rebound after treatment interruption will be crucial for designing and evaluating interventions for HIV remission.METHODSWe performed a broad evaluation of viral and immune factors that predict viral rebound (AIDS Clinical Trials Group A5345). Participants initiated antiretroviral therapy (ART) during chronic (N = 33) or early (N = 12) HIV infection with ≥ 2 years of suppressive ART and restarted ART if they had 2 viral loads ≥ 1,000 copies/mL after treatment interruption.RESULTSCompared with chronic-treated participants, early-treated individuals had smaller and fewer transcriptionally active HIV reservoirs. A higher percentage of HIV Gag-specific CD8+ T cell cytotoxic response was associated with lower intact proviral DNA. Predictors of HIV rebound timing differed between early- versus chronic-treated participants, as the strongest reservoir predictor of time to HIV rebound was level of residual viremia in early-treated participants and intact DNA level in chronic-treated individuals. We also identified distinct sets of pre-treatment interruption viral, immune, and inflammatory markers that differentiated participants who had rapid versus slow rebound.CONCLUSIONThe results provide an in-depth overview of the complex interplay of viral, immunologic, and inflammatory predictors of viral rebound and demonstrate that the timing of ART initiation modifies the features of rapid and slow viral rebound.TRIAL REGISTRATIONClinicalTrials.gov NCT03001128FUNDINGNIH National Institute of Allergy and Infectious Diseases, Merck.

Influence of copper(I) nicotinate complex on the Notch1 signaling pathway in triple negative breast cancer cell lines.

Triple negative breast cancer (TNBC) is a subtype of breast cancer which is characterized by its aggressiveness, poor and short overall survival. In this concept, there is a growing demand for metal-based compounds in TNBC therapy as copper complex that have a less toxic effect on normal cells and could stimulate apoptotic cell death. Additionally, Notch1 signaling pathway has received great attention as one of the most important potential targets for developing a novel therapeutic strategy. The present study is an attempt to assess the promising chemotherapeutic activities of copper(I) nicotinate (CNC) through its impact on the expression of downstream genes of Notch1 signaling pathway and the cell fate of TNBC. The co-treatment of TNBC cells with doxorubicin (Doxo) and CNC was also investigated. To approach the objective of the present study, TNBC cell lines; HCC1806 and MDAMB231, were utilized. MTT assay was used to determine the IC50 values of CNC and Doxo. After treatment, microtubule-associated protein light chain3 (LC3) were determined by flow cytometry. Additionally, qRT-PCR technique was used to detect the changes in genes levels that are involved Notch1 signaling pathway. Moreover, autophagosomes were monitored and imaged by Transmission electron microscopy. Treatment of TNBC cells with CNC modulated Notch1 signaling pathway in different manners with respect to the type of cells and the applied dose of CNC. The observed effects of CNC may reflect the possible anti-cancer activities of CNC in both types of TNBC. However, cell type and CNC dose should be considered.

Low phosphorus increases hepatic lipid deposition, oxidative stress and inflammatory response via Acetyl-CoA carboxylase-dependent manner in zebrafish liver cells.

Acetyl-CoA carboxylase (ACC) plays a regulatory role in both fatty acid synthesis and oxidation, controlling the process of lipid deposition in the liver. Given that existing studies have shown a close relationship between low phosphorus (P) and hepatic lipid deposition, this study was conducted to investigate whether ACC plays a crucial role in this relationship. Zebrafish liver cell line (ZFL) was incubated under low P medium (LP, P concentration: 0.77 mg/L) or adequate P medium (AP, P concentration: 35 mg/L) for 240 h. The results showed that, compared with AP-treated cells, LP-treated cells displayed elevated lipid accumulation, and reduced fatty acid ß-oxidation, ATP content, and mitochondrial mass. Furthermore, transcriptomics analysis revealed that LP-treated cells significantly increased lipid synthesis (Acetyl-CoA carboxylases (acc), Stearyl coenzyme A dehydrogenase (scd)) but decreased fatty acid ß-oxidation (Carnitine palmitoyltransferase I (cptI)) and (AMP-activated protein kinase (ampk)) mRNA levels compared to AP-treated cells. The phosphorylation of AMPK and ACC, and the protein expression of CPTI were significantly decreased in LP-treated cells compared with those in AP-treated cells. After 240 h of LP treatment, PF-05175157 (an ACC inhibitor) was supplemented in the LP treatment for an additional 12 h. PF-05175157-treated cells showed higher phosphorylation of ACC, higher protein expression of CPTI, and lower protein expression of FASN, lower TG content, enhanced fatty acid ß-oxidation, increased ATP content, and mitochondrial mass compared with LP-treated cells. PF-05175157 also relieved the LP-induced oxidative stress and inflammatory response. Overall, these findings suggest that ACC is a promising target for treating LP-induced elevation of lipid deposition in ZFL, and can alleviate oxidative stress and inflammatory response.

Accident due to Incorrect Selection of Diode Laser Technique in the Treatment of Oral Venous Malformation.

Venous malformation (VM) originates from a congenital venous network disorder, configuring about 40% of the vascular anomalies that occur in the head and neck region. The usage of diode lasers in the treatment of VM is associated with various advantages, such as short operating time and few postoperative complications. Nevertheless, for larger and deeper VM treatment, it may require more than one session for the complete resolution of the lesion. Laser surgery for oral VM may induce heat accumulation due to excessive irradiation causing adverse events postoperatively, including pain and ulcer formation with scarring. In this clinical case, it was recommended to use the leopard technique (LT) to reduce the lesion size, evaluate the remaining unhealed lesion, and apply different laser techniques to obtain the complete resolution of the lesion.

Distinct Intestinal Microbial Signatures Linked to Accelerated Biological Aging in People with HIV.

Background: People with HIV (PWH), even with controlled viral replication through antiretroviral therapy (ART), experience persistent inflammation. This is partly due to intestinal microbial dysbiosis and translocation. Such ongoing inflammation may lead to the development of non-AIDS-related aging-associated comorbidities. However, there remains uncertainty regarding whether HIV affects the biological age of the intestines and whether microbial dysbiosis and translocation influence the biological aging process in PWH on ART. To fill this knowledge gap, we utilized a systems biology approach, analyzing colon and ileal biopsies, blood samples, and stool specimens from PWH on ART and their matched HIV-negative counterparts. Results: Despite having similar chronological ages, PWH on ART exhibit accelerated biological aging in the colon, ileum, and blood, as measured by various epigenetic aging clocks, compared to HIV-negative controls. Investigating the relationship between microbial translocation and biological aging, PWH on ART had decreased levels of tight junction proteins in the colon and ileum, along with increased microbial translocation. This increased intestinal permeability correlated with faster intestinal and systemic biological aging, as well as increased systemic inflammation. When investigating the relationship between microbial dysbiosis and biological aging, the intestines of PWH on ART had higher abundance of specific pro-inflammatory bacterial genera, such as Catenibacterium and Prevotella. These bacteria significantly correlated with accelerated local and systemic biological aging. Conversely, the intestines of PWH on ART had lower abundance of bacterial genera known for producing short-chain fatty acids and exhibiting anti-inflammatory properties, such as Subdoligranulum and Erysipelotrichaceae, and these bacteria taxa were associated with slower biological aging. Correlation networks revealed significant links between specific microbial genera in the colon and ileum (but not in feces), increased aging, a rise in pro-inflammatory microbial-related metabolites (e.g., those in the tryptophan metabolism pathway), and a decrease in anti-inflammatory metabolites like hippuric acid and oleic acid. Conclusions: We identified a specific microbial composition and microbiome-related metabolic pathways that are intertwined with both intestinal and systemic biological aging in PWH on ART. A deeper understanding of the mechanisms underlying these connections could potentially offer strategies to counteract premature aging and its associated health complications in PWH.

Siglec-7 glyco-immune binding mAbs or NK cell engager biologics induce potent antitumor immunity against ovarian cancers.

Ovarian cancer (OC) is a lethal gynecologic malignancy, with modest responses to CPI. Engagement of additional immune arms, such as NK cells, may be of value. We focused on Siglec-7 as a surface antigen for engaging this population. Human antibodies against Siglec-7 were developed and characterized. Coculture of OC cells with PBMCs/NKs and Siglec-7 binding antibodies showed NK-mediated killing of OC lines. Anti-Siglec-7 mAb (DB7.2) enhanced survival in OC-challenged mice. In addition, the combination of DB7.2 and anti-PD-1 demonstrated further improved OC killing in vitro. To use Siglec-7 engagement as an OC-specific strategy, we engineered an NK cell engager (NKCE) to simultaneously engage NK cells through Siglec-7, and OC targets through FSHR. The NKCE demonstrated robust in vitro killing of FSHR+ OC, controlled tumors, and improved survival in OC-challenged mice. These studies support additional investigation of the Siglec-7 targeting approaches as important tools for OC and other recalcitrant cancers.

Estimating the contribution of CD4 T cell subset proliferation and differentiation to HIV persistence.

Persistence of HIV in people living with HIV (PWH) on suppressive antiretroviral therapy (ART) has been linked to physiological mechanisms of CD4+ T cells. Here, in the same 37 male PWH on ART we measure longitudinal kinetics of HIV DNA and cell turnover rates in five CD4 cell subsets: naïve (TN), stem-cell- (TSCM), central- (TCM), transitional- (TTM), and effector-memory (TEM). HIV decreases in TTM and TEM but not in less-differentiated subsets. Cell turnover is ~10 times faster than HIV clearance in memory subsets, implying that cellular proliferation consistently creates HIV DNA. The optimal mathematical model for these integrated data sets posits HIV DNA also passages between CD4 cell subsets via cellular differentiation. Estimates are heterogeneous, but in an average participant's year ~10 (in TN and TSCM) and ~104 (in TCM, TTM, TEM) proviruses are generated by proliferation while ~103 proviruses passage via cell differentiation (per million CD4). In simulations, therapies blocking proliferation and/or enhancing differentiation could reduce HIV DNA by 1-2 logs over 3 years. In summary, HIV exploits cellular proliferation and differentiation to persist during ART but clears faster in more proliferative/differentiated CD4 cell subsets and the same physiological mechanisms sustaining HIV might be temporarily modified to reduce it.

Serotonin reduction in post-acute sequelae of viral infection.

Post-acute sequelae of COVID-19 (PASC, "Long COVID") pose a significant global health challenge. The pathophysiology is unknown, and no effective treatments have been found to date. Several hypotheses have been formulated to explain the etiology of PASC, including viral persistence, chronic inflammation, hypercoagulability, and autonomic dysfunction. Here, we propose a mechanism that links all four hypotheses in a single pathway and provides actionable insights for therapeutic interventions. We find that PASC are associated with serotonin reduction. Viral infection and type I interferon-driven inflammation reduce serotonin through three mechanisms: diminished intestinal absorption of the serotonin precursor tryptophan; platelet hyperactivation and thrombocytopenia, which impacts serotonin storage; and enhanced MAO-mediated serotonin turnover. Peripheral serotonin reduction, in turn, impedes the activity of the vagus nerve and thereby impairs hippocampal responses and memory. These findings provide a possible explanation for neurocognitive symptoms associated with viral persistence in Long COVID, which may extend to other post-viral syndromes.