High Provider Trust Associates with High HIV Antiretroviral Adherence Among Women Living with HIV in a Metropolitan Washington, DC Cohort.

Trust in providers and health care systems (HCSs) has been associated with higher HIV antiretroviral (ART) adherence; however, most previous studies enrolled primarily men and did not concurrently assess provider trust, HCS distrust, and clinical/biological outcomes. We enrolled 239 Washington, DC Women's Interagency HIV Study (WIHS) women: 167 with HIV (WWH) and 72 without HIV. In 2006 and 2017-2018, women completed surveys on provider trust and HCS distrust. Clinical, social, and demographic covariates were obtained during the 2017-2018 WIHS study visit. Descriptive analyses included chi-squared and Mann-Whitney tests. Wilcoxon signed-rank tests assessed trust measure change over time. Logistic (provider trust) and linear (HCS distrust) models were constructed in R. The majority of women were African American/Black (76.9%) with a median age of 52 (interquartile range 48, 58) and currently insured (99.6%). In multi-variable analyses, women with HIV (WWH) had higher odds of high provider trust [adjusted odds ratio (aOR) 2.90, 95% confidence interval (CI) 1.34, 6.45], with ≥95% ART adherence associated with high provider trust among only WWH (aOR 4.13, 95% CI 1.14, 15.92). Multi-variable models also showed 3.40-point higher HCS distrust scores among WWH who reported ≥95% ART adherence (p = 0.03). CD4 count and HIV viral load were not associated with provider trust or HCS distrust. Provider (p = 0.67) and HCS (p = 0.65) trust did not significantly change in this population at two time points for 10 years. Self-reported antiretroviral therapy adherence significantly associated with high provider trust, yet also with high HCS distrust, revealing a nuanced relationship to providers and the HCS among WWH.

Viral Suppression Is Associated with HIV Treatment Self-Efficacy in a Cohort of Women in Washington, DC.

The goal of HIV treatment is viral suppression as it is linked with improved health outcomes and decreased risk of viral transmission. We assessed the sociodemographic, behavioral, and patient-provider interaction associations with viral suppression with an administered survey to HIV-seropositive women in the metropolitan Washington, DC, site of the Women's Interagency HIV Study (WIHS) between 2017 and 2018. Logistic and mixed models were used to explore related factors between HIV viral suppression groups and HIV treatment self-efficacy, respectively. Higher HIV treatment self-efficacy and disclosure concerns were positively associated with viral suppression, while illicit drug use had a negative association. In mixed models, more health care provider trust was associated with higher HIV treatment self-efficacy, while depressive symptoms were associated with lower HIV treatment self-efficacy. Depression, illicit substance use, and HIV treatment self-efficacy are potentially modifiable factors that can influence viral suppression. Implementation studies are needed to determine whether interventions to manage depression or self-efficacy and improve trust in health care providers will influence treatment outcomes.

Select gp120 V2 domain specific antibodies derived from HIV and SIV infection and vaccination inhibit gp120 binding to α4ß7.

The GI tract is preferentially targeted during acute/early HIV-1 infection. Consequent damage to the gut plays a central role in HIV pathogenesis. The basis for preferential targeting of gut tissues is not well defined. Recombinant proteins and synthetic peptides derived from HIV and SIV gp120 bind directly to integrin α4ß7, a gut-homing receptor. Using both cell-surface expressed α4ß7 and a soluble α4ß7 heterodimer we demonstrate that its specific affinity for gp120 is similar to its affinity for MAdCAM (its natural ligand). The gp120 V2 domain preferentially engages extended forms of α4ß7 in a cation -sensitive manner and is inhibited by soluble MAdCAM. Thus, V2 mimics MAdCAM in the way that it binds to α4ß7, providing HIV a potential mechanism to discriminate between functionally distinct subsets of lymphocytes, including those with gut-homing potential. Furthermore, α4ß7 antagonists developed for the treatment of inflammatory bowel diseases, block V2 binding to α4ß7. A 15-amino acid V2 -derived peptide is sufficient to mediate binding to α4ß7. It includes the canonical LDV/I α4ß7 binding site, a cryptic epitope that lies 7-9 amino acids amino terminal to the LDV/I, and residues K169 and I181. These two residues were identified in a sieve analysis of the RV144 vaccine trial as sites of vaccine -mediated immune pressure. HIV and SIV V2 mAbs elicited by both vaccination and infection that recognize this peptide block V2-α4ß7 interactions. These mAbs recognize conformations absent from the ß- barrel presented in a stabilized HIV SOSIP gp120/41 trimer. The mimicry of MAdCAM-α4ß7 interactions by V2 may influence early events in HIV infection, particularly the rapid seeding of gut tissues, and supports the view that HIV replication in gut tissue is a central feature of HIV pathogenesis.

ß-arrestin-2-biased agonism of delta opioid receptors sensitizes transient receptor potential vanilloid type 1 (TRPV1) in primary sensory neurons.

Despite advances in understanding the signaling mechanisms involved in the development and maintenance of chronic pain, the pharmacologic treatment of chronic pain has seen little advancement. Agonists at the mu opioid receptor (MOPr) continue to be vital in the treatment of many forms of chronic pain, but side-effects limit their clinical utility and range from relatively mild, such as constipation, to major, such as addiction and dependence. Additionally, chronic activation of MOPr results in pain hypersensitivity known as opioid-induced hyperalgesia (OIH), and we have shown recently that recruitment of ß-arrestin2 to MOPr, away from transient potential vanilloid eceptor type 1 (TRPV1) in primary sensory neurons contributes to this phenomenon. The delta opioid receptor (DOPr) has become a promising target for the treatment of chronic pain, but little is known about the effects of chronic activation of DOPr on nociceptor sensitivity and OIH. Here we report that chronic activation of DOPr by the DOPr-selective agonist, SNC80, results in the sensitization of TRPV1 and behavioral signs of OIH via ß-arrestin2 recruitment to DOPr and away from TRPV1. Conversely, chronic treatment with ARM390, a DOPr-selective agonist that does not recruit ß-arrestin2, neither sensitized TRPV1 nor produced OIH. Interestingly, the effect of SNC80 to sensitize TRPV1 is species-dependent, as rats developed OIH but mice did not. Taken together, the reported data identify a novel side-effect of chronic administration of ß-arrestin2-biased DOPr agonists and highlight the importance of potential species-specific effects of DOPr agonists.

Nasal secretion concentrations of IL-5, IL-6, and IL-10 in children with and without upper respiratory tract viruses.

OBJECTIVE: To determine if levels of interleukin (IL) 5, IL-6, and IL-10 or their ratios in nasal secretion are diagnostic of viral upper respiratory tract infections (vURTIs) and coldlike illnesses (CLIs) in children. DESIGN: Longitudinal study of children for vURTIs, CLIs, and concentrations and ratios of nasal cytokines. SETTING: Outpatient assessments of children. PARTICIPANTS: A total of 224 children, aged 1 to 9 years. MAIN OUTCOME MEASURES: Concentrations of IL-5, IL-6, and IL-10 in nasal secretions, vURTIs diagnosed by polymerase chain reaction (PCR) detection of upper respiratory tract viruses, and concurrent CLIs diagnosed by parents. RESULTS: Of 1269 secretion samples, 552 (43.5%) were collected during a vURTI (PCR findings positive for an assayed virus [PCR(+)]). A concurrent CLI was diagnosed for 34% of the PCR(+) samples and for 18% of the samples found to be negative by PCR analysis (PCR(-)). Cytokine concentrations and ratios were highly variable and skewed to the lower values. The significance of the cytokine concentrations and ratios as discriminators of groups defined by the presence or absence of virus and of subgroups defined by the presence or absence of a CLI was evaluated using receiver operating characteristic curves. All measures were significant discriminators of the PCR(+) vs PCR(-) groups, and most were significant discriminators of the paired CLI subgroups. The concentration of IL-6 and the IL-5/IL-6 ratio were the best discriminators across all groups and subgroups. However, the sensitivities and specificities of those discriminators at the best cutoff values were on the order of 0.7 for the most extreme pairwise comparison (PCR(+)CLI(+) vs PCR(-)CLI(-)) and lower for the other comparison groups. CONCLUSION: The low sensitivities and specificities for cytokine-based assignment of specimens to the paired groups and subgroups limit their usefulness for diagnosis of infection or illness.

The interleukin 6 -174 C/C genotype predicts greater rhinovirus illness.

BACKGROUND: In adults and children with respiratory syncytial virus (RSV) infection, a polymorphism in the interleukin 6 (IL-6) promoter at position -174 predicts illness magnitude. In addition, polymorphisms in the interleukin 10 (IL-10), tumor necrosis factor alpha (TNF-alpha), and interferon gamma (IFN-gamma) genes are associated with immune responsiveness and the frequency of complications. Here, the effect of these polymorphisms on illness and seroconversion during infection with rhinovirus type 39 (RV39) was evaluated. METHODS: Seventy-two adults were genotyped for the selected polymorphisms, experimentally exposed to RV39, and followed to track infection, seroconversion, and symptoms and signs of illness. Regression analysis was used to determine whether these polymorphisms predicted seroconversion and illness magnitude in 57 infected subjects. RESULTS: The low-production IL-6 -174 phenotype (C/C genotype) was associated with greater symptom magnitudes, and the IFN-gamma phenotype +874 predicted the frequency of seroconversion. No relationship between the IL-10 or TNF-alpha polymorphisms and any measured outcome was documented. The concentration of IL-6 protein, as measured in nasal wash fluids from subjects, was positively correlated with symptom magnitude, but it was independent of the IL-6 -174 genotypes representing the high- and low-production phenotypes. CONCLUSIONS: These results document statistically significant associations between the IL-6 -174 and IFN-gamma +874 polymorphisms and specific responses to experimental RV39 infection. For the IL-6 -174 polymorphism, the results replicate those for experimental RSV infection.