The V2 domain of HIV gp120 mimics an interaction between CD4 and integrin ⍺4ß7.

The CD4 receptor, by stabilizing TCR-MHC II interactions, plays a central role in adaptive immunity. It also serves as the HIV docking receptor. The HIV gp120 envelope protein binds directly to CD4. This interaction is a prerequisite for viral entry. gp120 also binds to ⍺4ß7, an integrin that is expressed on a subset of memory CD4+ T cells. HIV tropisms for CD4+ T cells and gut tissues are central features of HIV pathogenesis. We report that CD4 binds directly to ⍺4ß7 in a dynamic way, consistent with a cis regulatory interaction. The molecular details of this interaction are related to the way in which gp120 interacts with both receptors. Like MAdCAM-1 and VCAM-1, two recognized ligands of ⍺4ß7, the binding interface on CD4 includes 2 sites (1° and accessory), distributed across its two N-terminal IgSF domains (D1 and D2). The 1° site includes a sequence in the G ß-strand of CD4 D2, KIDIV, that binds directly to ⍺4ß7. This pentapeptide sequence occurs infrequently in eukaryotic proteins. However, a closely related and conserved sequence, KLDIV, appears in the V2 domain of gp120. KLDIV mediates gp120-⍺4ß7 binding. The accessory ⍺4ß7 binding site on CD4 includes Phe43. The Phe43 aromatic ring protrudes outward from one edge of a loop connecting the C'C" strands of CD4 D1. Phe43 is a principal contact for HIV gp120. It interacts with conserved residues in the recessed CD4 binding pocket. Substitution of Phe43 abrogates CD4 binding to both gp120 and ⍺4ß7. As such, the interactions of gp120 with both CD4 and ⍺4ß7 reflect elements of their interactions with each other. These findings indicate that gp120 specificities for CD4 and ⍺4ß7 are interrelated and suggest that selective pressures which produced a CD4 tropic virus that replicates in gut tissues are linked to a dynamic interaction between these two receptors.

Diagnostic merits of the Eosinophilic Esophagitis Diagnostic Panel from a single esophageal biopsy.

BACKGROUND: Eosinophilic esophagitis (EoE) is a histologically "patchy" disease with uneven eosinophil distribution along the esophagus, posing a dilemma for histologically analyzing endoscopic biopsy samples, especially when biopsy samples are limited to only the distal esophagus. OBJECTIVE: We investigated whether molecular mRNA profiling of a distal esophageal biopsy sample predicts eosinophilia in the proximal esophagus. METHODS: Esophageal biopsy samples (n = 507) from subjects with EoE were collected from multiple institutions, spanning adults and pediatric patients. Subjects were grouped on the basis of distinct distal (D) and proximal (P) eosinophil counts (D+P+, D+P-, D-P+, and D-P-, with + and - defined as ≥15 or <15 eosinophils/hpf, respectively). Molecular profiles were assessed by using the EoE Diagnostic Panel (EDP), a set of 96 esophageal transcripts used to derive the EDP score. RESULTS: The distal EDP score was correlated with proximal eosinophil levels (r = -0.73; P < .0001). EDP analysis of a histologically negative distal biopsy sample predicted the presence of proximal esophagitis with high sensitivity (85%). In a 2-year follow-up focusing on the cases with discordant histologic and EDP results, histologically negative patients (D-P-) had higher rates of EoE relapse when the EDP was positive than when the EDP was negative (odds ratio = 11; P = .003), indicating predictive medicine capacity. CONCLUSION: EDP analysis of a single distal esophageal biopsy sample predicts remote inflammation in patients with spatially heterogeneous eosinophilia and disease relapse in patients with histologic remission, providing diagnostic merit and predictive medicine capacity for molecular diagnosis of EoE.

Neutrophil Cathepsin G Regulates Dendritic Cell Production of IL-12 during Development of CD4 T Cell Responses to Antigens in the Skin.

Contact hypersensitivity (CHS) is a CD8 T cell-mediated response to hapten skin sensitization and challenge. Sensitization of wild-type (WT) mice induces hapten-reactive effector CD8 T cells producing IFN-γ and IL-17- and IL-4-producing CD4 T cells that cannot mediate CHS. Although CXCR2-dependent Ly6G+ (neutrophil) cell recruitment into hapten-challenged skin is required to direct effector CD8 T cell infiltration into the challenge site to elicit CHS, 2,4-dinitrofluorobenezene (DNFB) sensitization of CXCR2-/- mice and neutrophil-depleted WT mice induced both hapten-reactive CD4 and CD8 T cells producing IFN-γ and IL-17. CD4 T cell-mediated CHS responses were not generated during DNFB sensitization of neutrophil-depleted WT mice treated with anti-IL-12 mAb or neutrophil-depleted IL-12-/- mice. Neutrophil depletion during DNFB sensitization of WT mice markedly increased IL-12-producing hapten-primed dendritic cell numbers in the skin-draining lymph nodes. Sensitization of mice lacking the neutrophil serine protease cathepsin G (CG)-induced hapten-reactive CD4 and CD8 T cells producing IFN-γ and IL-17 with elevated and elongated CHS responses to DNFB challenge. Induction of CHS effector CD4 T cells producing IFN-γ in neutrophil-depleted WT mice was eliminated by s.c. injection of active, but not inactivated, CG during sensitization. Thus, hapten skin sensitization induces neutrophil release of CG that systemically inhibits hapten-presenting dendritic cell production of IL-12 and the development of hapten-reactive CD4 T cells to IFN-γ-producing CHS effector cells.

The Effectiveness of Facial Neuromuscular Retraining on Patients with Facial Nerve Dysfunction: A Mental Health and Quality of Life Analysis.

Background: Facial muscle dysfunction can have drastic psychosocial effects. Objectives: To evaluate the impacts of customized neuromuscular retraining on mental health, quality of life (QoL), facial muscle function, and synkinesis. Methods: Thirty patients with facial nerve dysfunction completed a course of neuromuscular retraining. Patients' mental health, QoL, facial muscle function, and synkinesis were evaluated using Patient Health Questionnaire (PHQ-9), Facial Clinimetric Evaluation (FaCE) scale, electronic, clinician-graded facial function scale (eFACE), and Synkinesis Assessment Questionnaire (SAQ) at the initial and final visits. Scores were compared before and after treatment. Results: Patients (n = 30) included had a mean age of 59.4 ± 13.4 years (range 32.3-82.8) and were mostly female (22/30, 73.3%). The most common etiology was Iatrogenic facial nerve paralysis (11/20, 36.7%). Most patients had postfacial paralysis synkinesis (15/30, 50%), while 10 had complete flaccid paralysis. The median house-Brackmann score was 2 (range 1-6). The mean duration of facial palsy was 39.5 ± 106.9 (range 1-576 months). The duration of follow-up after the initial treatment session was 5.5 months, including 10 sessions. After neuromuscular retraining median PHQ-9 scores improved from 5 (range 0-25) to 3 (range 0-20) (p = 0.002). Mean FaCE PROM scores increased from 47.7 ± 11.5 to 56.5 ± 8.8 (p = 0.001). The mean eFACE score increased from 55.8 ± 15.1 to 71.7 ± 13.6 (p < 0.001). Median SAQ score was lower at the final visit (34.6 ± 13.4) compared to the initial visit (47.7 ± 17.8; p < 0.001). Conclusion: Customized neuromuscular retraining may improve patient-reported mental health, QoL, and facial muscle function and reduce synkinesis in facial nerve dysfunction.

The Impact of the Post-Traumatic Facial Reconstruction on Postoperative Weight Loss.

Objectives: To identify risk factors and evaluate the impact of various facial fractures and reconstruction surgeries on postoperative weight change. Methods: Retrospective, monocentric study was performed at a tertiary care center. Medical history, type and mechanism of fracture, operative factors, and postoperative weights at follow-up appointments for 145 adult patients undergoing surgical repair for maxillofacial fractures were collected. Further information was obtained on postoperative diet and whether patients received maxillomandibular fixation (MMF). Univariate and multivariate analyses were utilized to evaluate effects of surgical reconstruction after facial trauma on postoperative weight loss. Results: Patients lost 3.2 ± 4.9 kg (95% confidence interval = 2.7-4.1, P < .0001) on average, with maximum loss between date of surgery and first follow-up. Univariate analysis demonstrated that intensive care unit admission (5.9 kg, SD 5.4, P = .001), nasogastric tube placement (5.1 kg, SD 4.6, P = .012), and MMF (4.4 kg, SD 5.4, P < .0001) were associated with more severe weight loss. Multivariate analyses showed that only MMF remained a significant risk factor for increased weight loss (avg. 6.0, standard error 1.93, t value 3.11, P = .0024). Conclusions: We report significant weight loss following facial trauma and reconstruction, which emphasizes the need to perform further studies on nutrition protocols for this patient population to optimize wound healing.

Variability in Minimal Clinically Important Difference Calculation and Reporting in the Otolaryngology Literature.

OBJECTIVE: Best practices for calculation of the minimal clinically important difference (MCID) of outcome measures include the use of complementary methodologies (broadly classified as anchor-based and distribution-based) and reporting of the MCID's predictive ability. We sought to determine MCID calculation and reporting patterns within the otolaryngology literature. METHODS: A systematic search strategy of Embase, PubMed, and Web of Science databases was developed and implemented to identify studies reporting the determination of an MCID for an outcome measure. Studies specifically within the otolaryngology literature (defined as journals classified as "otorhinolaryngology" in the Journal Citation Reports database) were included. All those journals were additionally searched for relevant articles. RESULTS: There were 35 articles that met the inclusion criteria. Of these studies, 88.6% reported MCID of a patient-reported outcome measure and the remainder were for objective outcome measurements. Anchor-based methods were used by 82.9% of studies and distribution-based methods were used by 68.6% of studies. Of all studies, 31.4% utilized anchor-based methods alone, 17.1% utilized distribution-based methods alone, and 51.4% used both methods. Only 25.7% of studies reported the sensitivity (median: 60.8%, range: 40.5%-86.7%) and specificity (median: 80.4%, range: 63.5%-88.0%) of the MCID to detect patients experiencing clinically important change. CONCLUSION: Deviation from best practices in MCID calculation and reporting exists within the otolaryngology literature, with almost half of all studies only using one method of MCID calculation and almost three-quarters not reporting the predictive ability (sensitivity/specificity) of the calculated MCID. When predictive ability is reported, however, MCIDs appear to be more specific than sensitive. LEVEL OF EVIDENCE: NA Laryngoscope, 134:2059-2069, 2024.

A Comprehensive Analysis of Tobacco Smoking History as a Risk for Outcomes after Endoscopic Transsphenoidal Resection of Pituitary Adenoma.

Objectives This study seeks to comprehensively analyze the impact of smoking history on outcomes after endoscopic transsphenoidal hypophysectomy (TSH) for pituitary adenoma. Design This was a retrospective study. Setting This study was done at the tertiary care center. Participants Three hundred and ninety-eight adult patients undergoing TSH for a pituitary adenoma. Main Outcome Measures Clinical and tumor characteristics and operative factors were collected. Patients were categorized as never, former, or active smokers, and the pack-years of smoking history was collected. Years since cessation of smoking was obtained for former smokers. Specific outcomes included postoperative cerebrospinal fluid (CSF) leak, length of hospitalization, 30-day return to the operating room, and 30-day readmission. Smoking history details were comprehensively analyzed for association with outcomes. Results Any history of smoking tobacco was associated with return to the operating room (odds ratio [OR] = 2.67, 95% confidence interval [CI]: 1.05-6.76, p = 0.039), which was for persistent CSF leak in 58.3%. Among patients with postoperative CSF leak, any history of smoking was associated with need for return to the operating room to repair the CSF leak (OR = 5.25, 95% CI: 1.07-25.79, p = 0.041). Pack-years of smoking was positively associated with a return to the operating room (OR = 1.03, 95% CI: 1.01-1.06, p = 0.048). In all multivariable models, all negative outcomes were significantly associated with the covariate: occurrence of intraoperative CSF leak. Conclusion This is the first study to show smoking may have a negative impact on healing of CSF leak repairs after TSH, requiring a return to the operating room. This effect appears to be dose dependent on the smoking history. Secondarily, intraoperative CSF leak as covariate in multivariable models was significantly associated with all negative outcomes.

Anti-V2 antibodies virus vulnerability revealed by envelope V1 deletion in HIV vaccine candidates.

The efficacy of ALVAC-based HIV and SIV vaccines in humans and macaques correlates with antibodies to envelope variable region 2 (V2). We show here that vaccine-induced antibodies to SIV variable region 1 (V1) inhibit anti-V2 antibody-mediated cytotoxicity and reverse their ability to block V2 peptide interaction with the α4ß7 integrin. SIV vaccines engineered to delete V1 and favor an α helix, rather than a ß sheet V2 conformation, induced V2-specific ADCC correlating with decreased risk of SIV acquisition. Removal of V1 from the HIV-1 clade A/E A244 envelope resulted in decreased binding to antibodies recognizing V2 in the ß sheet conformation. Thus, deletion of V1 in HIV envelope immunogens may improve antibody responses to V2 virus vulnerability sites and increase the efficacy of HIV vaccine candidates.

HIV vaccine delayed boosting increases Env variable region 2-specific antibody effector functions.

In the RV144 HIV-1 phase III trial, vaccine efficacy directly correlated with the magnitude of the variable region 2-specific (V2-specific) IgG antibody response, and in the presence of low plasma IgA levels, with the magnitude of plasma antibody-dependent cellular cytotoxicity. Reenrollment of RV144 vaccinees in the RV305 trial offered the opportunity to define the function, maturation, and persistence of vaccine-induced V2-specific and other mAb responses after boosting. We show that the RV144 vaccine regimen induced persistent V2 and other HIV-1 envelope-specific memory B cell clonal lineages that could be identified throughout the approximately 11-year vaccination period. Subsequent boosts increased somatic hypermutation, a critical requirement for antibody affinity maturation. Characterization of 22 vaccine-induced V2-specific mAbs with epitope specificities distinct from previously characterized RV144 V2-specific mAbs CH58 and CH59 found increased in vitro antibody-mediated effector functions. Thus, when inducing non-neutralizing antibodies, one method by which to improve HIV-1 vaccine efficacy may be through late boosting to diversify the V2-specific response to increase the breadth of antibody-mediated anti-HIV-1 effector functions.

Blocking α4ß7 integrin binding to SIV does not improve virologic control.

A study in nonhuman primates reported that infusions of an antibody against α4ß7 integrin, in combination with antiretroviral therapy, showed consistent, durable control of simian immunodeficiency virus (SIV) in rhesus macaques. The antibody used has pleiotropic effects, so we set out to gain insight into the underlying mechanism by comparing this treatment to treatment with non-neutralizing monoclonal antibodies against the SIV envelope glycoprotein that only block α4ß7 binding to SIV Env but have no other host-directed effects. Similar to the initial study, we used an attenuated strain of SIV containing a stop codon in nef. The study used 30 macaques that all began antiretroviral therapy and then were divided into five groups to receive different antibody treatments. Unlike the published report, we found no sustained virologic control by these treatments in vivo.