Tryptophan-kynurenine metabolic pathway and daytime dysfunction in women with HIV.

Sleep disturbances are prevalent in women with HIV (WWH). Tryptophan-kynurenine (T-K) pathway metabolites are associated with alterations in actigraphy derived sleep measures in WWH, although may not always correlate with functional impairment. We investigated the relationship between T-K pathway metabolites and self-reported daytime dysfunction in WWH and women without HIV (WWoH). 141 WWH on stable antiretroviral therapy and 140 demographically similar WWoH enrolled in the IDOze Study had targeted plasma T-K metabolites measured using liquid chromatography-tandem mass spectrometry. We utilized the daytime dysfunction component of the Pittsburgh Sleep Quality Index (PSQI) to assess functional impairment across HIV-serostatus. Lower levels of 5-hydroxytryptophan and serotonin were associated with greater daytime dysfunction in all women. In WWH, daytime dysfunction was associated with increased kynurenic acid (R = 0.26, p < 0.05), and kynurenic acid-tryptophan (KA-T) ratio (R = 0.28, p < 0.01). WWH with daytime dysfunction had a 0.7 log fold increase in kynurenic acid compared to WWH without daytime dysfunction. Kynurenic acid levels and the KA-T ratio were associated with daytime dysfunction in WWH but not in WWoH. Longitudinal studies are needed to establish a causal relationship and directionality between T-K metabolic changes and sleep impairment in WWH.

Overnight urinary melatonin levels in women with and without HIV: An observational cohort study.

INTRODUCTION: Despite significant improvements in longevity and quality of life associated with antiretroviral therapy, individuals with HIV still suffer from a higher burden of sleep and circadian disruption and inflammatory-based diseases than individuals without HIV. While melatonin is a hormone that has a role in sleep and circadian regulation and has anti-inflammatory properties, the overnight concentration of the urinary melatonin metabolite has not yet been reported in people with HIV. METHODS: The aim of this study was to compare the overnight urinary melatonin metabolite levels in women aged 35-70 years with HIV (n = 151) to a well-matched comparison group of women without HIV (n = 147). All women wore a wrist actigraphy monitor and completed daily diaries documenting sleep timing and use of medications and drugs or alcohol for 10 days. Participants collected their overnight urine near the end of the monitoring period. RESULTS: Melatonin levels did not differ between women with or without HIV, but more than 40% of women had low levels of melatonin. Higher body mass index predicted lower levels of melatonin, and lower levels of melatonin were associated with lower sleep efficiency as assessed with wrist actigraphy. CONCLUSION: These data lay the foundation for exploration of the longitudinal consequences of endogenous melatonin levels for inflammatory-based diseases in aging women with and without HIV. Future studies should consider the use of supplemental melatonin to improve sleep in women with lower levels of melatonin.

COVID-19 symptom relationship to antibody response and ACE2 neutralization in recovered health systems employees before and after mRNA BNT162b2 COVID-19 vaccine.

BACKGROUND: The humoral response to SARS-CoV-2 can provide immunity and prevent reinfection. However, less is known about how the diversity, magnitude, and length of the antibody response after a primary infection is associated with symptoms, post-infection immunity, and post-vaccinated immunity. METHODS: Cook County Health employees provided blood samples and completed an online survey 8-10 weeks after a PCR-confirmed positive SARS-CoV-2 test (pre-vaccinated, N = 41) and again, 1-4 weeks after completion of a 2-dose series mRNA BNT162b2 COVID-19 vaccine (post-vaccinated, N = 27). Associations were evaluated between SARS-CoV-2 antibody titers, participant demographics, and clinical characteristics. Antibody titers and angiotensin-converting enzyme 2 (ACE2) neutralization were compared before and after the mRNA BNT162b2 COVID-19 vaccine. RESULTS: Antibody titers to the spike protein (ST4), receptor binding domain (RBD), and RBD mutant D614G were significantly associated with anosmia and ageusia, cough, and fever. Spike protein antibody titers and ACE2 neutralization were significantly higher in participants that presented with these symptoms. Antibody titers to the spike protein N-terminal domain (NTD), RBD, and ST4, and ACE2 IC50 were significantly higher in all post-vaccinated participant samples compared to pre-vaccinated participant sample, and not dependent on previously reported symptoms. CONCLUSIONS: Spike protein antibody titers and ACE2 neutralization are associated with the presentation of anosmia and ageusia, cough, and fever after SARS-CoV-2 infection. Symptom response to previous SARS-CoV-2 infection did not influence the antibody response from subsequent vaccination. These results suggest a relationship between infection severity and the magnitude of the immune response and provide meaningful insights into COVID-19 immunity according to discrete symptom presentation.

The IDOze Study: The Link Between Sleep Disruption and Tryptophan-Kynurenine Pathway Activation in Women With Human Immunodeficiency Virus.

BACKGROUND: Poor sleep is associated with human immunodeficiency virus (HIV), particularly among women with HIV (WWH), although mechanisms are unclear. We explored cross-sectional associations between sleep disruption and tryptophan-kynurenine (T/K) pathway activation, measured by the kynurenine-to-tryptophan ratio (K:T). METHODS: HIV-uninfected women (HIV-) and WWH aged 35-70 years and on stable antiretroviral therapy were included. Sleep metrics were measured using wrist actigraphy. Plasma T/K pathway metabolites were measured using liquid chromatography-tandem mass spectrometry. Multivariate linear regression models examined relationships between K:T and actigraphy-based sleep metrics by HIV status. RESULTS: WWH (n = 153) and HIV- women (n = 151) were demographically similar. Among WWH, median CD4 was 751 cells/µL; 92% had undetectable HIV RNA. Compared to HIV- women, WWH had higher K:T (P < .001) and kynurenine (P = .01) levels but similar tryptophan levels (P = .25). Higher K:T was associated with more wake bouts (P = .001), more time awake after sleep onset (P = .01), and lower sleep efficiency (P = .03) in WWH only. CONCLUSIONS: HIV infection was associated with T/K pathway activation; this activation was associated with poorer sleep efficiency and more fragmented sleep. While longitudinal studies are needed to elucidate the directionality of these associations, these findings may help identify treatments to reduce sleep disruption in WWH by targeting residual inflammation and T/K pathway activation.

HIV Status Does Not Affect Rectal Microbiome Composition, Diversity, or Stability over Time: A Chicago Women's Interagency HIV Study.

It remains unclear whether differences in gut microbiota noted between HIV-infected and uninfected individuals are driven by HIV or sexual behavior. We evaluated rectal swab microbiota of HIV-infected and uninfected women with similar demographic, neighborhood, and diet characteristics enrolled in the Chicago Women's Interagency HIV Study (WIHS). DNA was amplified for sequencing of fragments of bacterial small subunit (SSU or 16S) ribosomal RNA (rRNA) genes. HIV-infected and uninfected women did not differ by Shannon diversity index (p = .14), non-metric multidimensional scaling (NMDS) plot of Bray-Curtis indices (p = .488, r = 0.0027), or copy number of individual taxa. Both groups demonstrated marked microbiome stability over time (p = .889).

Feasibility of Repurposing the Polyanionic Microbicide, PPCM, for Prophylaxis against HIV Transmission during ART.

HIV-serodiscordant couples wishing to conceive often seek assisted reproduction, during which spermatozoa from infected men are washed to minimize the risk of HIV transmission to partner and fetus. We sought to improve this method by adding a microbicide, PPCM, as an HIV prophylactic. HIV-1 (BaL) inhibition by PPCM appears irreversible and independent of added Ca(2+). Without added Ca(2+), PPCM (≤10 mg/mL, ≤90 min), a stimulus of Ca(2+)-dependent acrosomal loss, has no effect on sperm motility, forward progression, or acrosomal status. PPCM-treated (10 mg/mL) sperm retain their ability to acrosome react when Ca(2+) is added. Sperm DNA integrity/function is unaffected by PPCM (≤10 mg/mL). Adding PPCM (5 mg/mL, 30 min) to washing media reduces infectivity (viral antigen p24 and RNA) of ex-vivo HIV-infected semen by 3-4 Logs compared with washing alone. Sperm washing with appropriate extracellular Ca(2+) levels and PPCM is significantly more effective than washing alone at reducing HIV infectivity.

Comparison of two human immunodeficiency virus (HIV) RNA surrogate assays to the standard HIV RNA assay.

Human immunodeficiency virus (HIV) RNA testing is the gold standard for monitoring antiretroviral therapy in HIV-infected patients. However, equipment and reagent costs preclude widespread use of the assay in resource-limited settings. The Perkin-Elmer Ultrasensitive p24 assay and the Cavidi Exavir Load assay both offer potentially simpler, less costly technologies for monitoring viral load. These assays were compared to the Roche Amplicor HIV-1 Monitor Test, v1.5, using panels of clinical samples (subtype B) from HIV-positive subjects and HIV-spiked samples (subtypes A, C, D, CRF_01AE, CRF_02AG, and F). The Ultrasensitive p24 assay detected 100% of the spiked samples with virus loads of >250,000 copies/ml and 61% of the clinical samples with virus loads of 219 to 288,850 copies/ml. Detection rates were improved substantially if an external lysis buffer was added to the procedure. The Cavidi assay detected 54 to 100% of spiked samples with virus loads >10,000 copies/ml and 68% of the clinical samples. These detection rates were also greatly improved with a newly implemented version of this kit. Coefficients of variation demonstrate good reproducibility for each of these kits. The results from the Cavidi v1.0, Cavidi v2.0, and Perkin-Elmer, and the Perkin-Elmer Plus external buffers all correlated well with the results from the Roche Monitor Test (r = 0.83 to 0.96, r = 0.84 to 0.99, r = 0.58 to 0.67, and r = 0.59 to 0.95, respectively). Thus, the use of these two assays for monitoring patients, together with less-frequent confirmation testing, offers a feasible alternative to frequent HIV RNA testing in resource-limited settings.

Comparison of the sensitivities of the version 1.5 and version 1.0 ultrasensitive Roche AMPLICOR HIV-1 MONITOR kits at low concentrations of human immunodeficiency virus RNA.

The sensitivities of the version 1.5 and 1.0 Roche UltraSensitive AMPLICOR HIV-1 MONITOR tests were compared using panels of coded samples of subtype B human immunodeficiency virus type 1 spiked into plasma at predetermined concentrations. Results indicate that the version 1.5 kit is more sensitive than the version 1.0 kit.