Search Results (6,243)

Background: Propolis possesses many bioactive compounds that could modulate the gut microbiota and reduce the production of uremic toxins in patients with chronic kidney disease (CKD) undergoing hemodialysis (HD). This clinical trial aimed to evaluate the effects of propolis on the gut microbiota profile and uremic toxin plasma levels in HD patients. These are secondary analyses from a previous double-blind, randomized clinical study, with 42 patients divided into two groups: the placebo and propolis group received 400 mg of green propolis extract/day for eight weeks. Indole-3 acetic acid (IAA), indoxyl sulfate (IS), and p-cresyl sulfate (p-CS) plasma levels were evaluated by reversed-phase liquid chromatography, and cytokines were investigated using the multiplex assay (Bio-Plex Magpix^®). The fecal microbiota composition was analyzed in a subgroup of patients (n = 6) using a commercial kit for fecal DNA extraction. The V4 region of the 16S rRNA gene was then amplified by the polymerase chain reaction (PCR) using short-read sequencing on the Illumina NovaSeq PE250 platform in a subgroup. Forty-one patients completed the study, 20 in the placebo group and 21 in the propolis group. There was a positive correlation between IAA and TNF-α (r = 0.53, p = 0.01), IL-2 (r = 0.66, p = 0.002), and between pCS and IL-7 (r = 0.46, p = 0.04) at the baseline. No significant changes were observed in the values of uremic toxins after the intervention. Despite not being significant, microbial evenness and observed richness increased following the propolis intervention. Counts of the Fusobacteria species showed a positive correlation with IS, while counts of Firmicutes, Lentisphaerae, and Proteobacteria phyla were negatively correlated with IS. Two months of propolis supplementation did not reduce the plasma levels of uremic toxins (IAA, IS, and p-CS) or change the fecal microbiota. Full article

During HIV-1 virus assembly, the genomic RNA (vRNA) is selected for packaging by the viral protein Gag because it contains a specific packaging signal, Psi. While there have been numerous studies of Gag–Psi interactions, there is almost no information on the kinetic aspects of this interaction. We investigated the kinetics of Gag binding to different RNAs using switchSENSE DRX² technology. We measured the association rate of Gag binding to monomeric Psi, to a “Multiple Binding Site Mutant” Psi that is inactive for genome packaging in vivo, and to a scrambled Psi. We discovered that Gag binds more rapidly to Psi RNA than to the mutant or scrambled RNAs. Furthermore, rapid Gag association kinetics are retained within sub-regions of Psi: Gag associates more rapidly with RNA containing only the 3′ two of the three Psi stem-loops than with monomeric RNA containing the 5′ two stem-loops or a scrambled RNA. No differences were detectable with individual Psi stem-loops. Interestingly, the rate of binding of Gag molecules to Psi increases with increasing Gag concentration, suggesting cooperativity in binding. The results are consistent with the hypothesis that selectivity in packaging derives from kinetic differences in initiation of particle assembly. Full article

Background: Assisted partner services (APS) is a recommended public health approach to promote HIV testing for sexual partners of individuals diagnosed with HIV. We evaluated the cost and cost-effectiveness of integrating oral HIV self-testing (HIVST) into existing APS programs. Methods: Within the APS-HIVST study conducted in western Kenya (2021–2022), we conducted micro-costing, time-and-motion, and provider surveys to determine incremental HIVST distribution cost (2022 USD). Using a decision tree model, we estimated the incremental cost per new diagnosis (ICND) for HIVST incorporated into APS, compared to APS with provider-delivered testing only. Scenario, parameter and probabilistic sensitivity analyses were conducted to explore influential assumptions. Results: The cost per HIVST distributed within APS was USD 8.97, largest component costs were testing supplies (38%) and personnel (30%). Under conditions of a facility-based testing uptake of <91%, or HIVST utilization rates of <27%, HIVST integration into APS is potentially cost-effective. At a willing-to-pay threshold of USD 1000, the net monetary benefit was sensitive to the effectiveness of HIVST in increasing testing rates, phone call rates, HIVST sensitivity, HIV prevalence, cost of HIVST, space allocation at facilities, and personnel time during facility-based testing. In a best-case scenario, the HIVST option was cheaper by USD 3037 and diagnosed 11 more cases (ICND = 265.82). Conclusions: Implementers and policy makers should ensure that HIVST programs are implemented under conditions that guarantee efficiency by focusing on facilities with low uptake for provider-delivered facility-based testing, while deliberately targeting HIVST utilization among the few likely to benefit from remote testing. Additional measures should focus on minimizing costs relating to personnel and testing supplies. Full article

As with all new fields of discovery, work on the biological role of G-quadruplexes (GQs) has produced a number of results that at first glance are quite baffling, sometimes because they do not fit well together, but mostly because they are different from commonly held expectations. Like other classes of flipons, those that form G-quadruplexes have a repeat sequence motif that enables the fold. The canonical DNA motif (G₃N_1–7)₃G₃, where N is any nucleotide and G is guanine, is a feature that is under active selection in avian and mammalian genomes. The involvement of G-flipons in genome maintenance traces back to the invertebrate Caenorhabditis elegans and to ancient DNA repair pathways. The role of GQs in transcription is supported by the observation that yeast Rap1 protein binds both B-DNA, in a sequence-specific manner, and GQs, in a structure-specific manner, through the same helix. Other sequence-specific transcription factors (TFs) also engage both conformations to actuate cellular transactions. Noncoding RNAs can also modulate GQ formation in a sequence-specific manner and engage the same cellular machinery as localized by TFs, linking the ancient RNA world with the modern protein world. The coevolution of noncoding RNAs and sequence-specific proteins is supported by studies of early embryonic development, where the transient formation of G-quadruplexes coordinates the epigenetic specification of cell fate. Full article

Objectives: Currently available research data points to COVID-19-related multi-organ system damage. This study aims to evaluate the impact of SARS-CoV-2 on the reproductive health, that is, plasma levels of FSH, LH, estradiol, AMH, and antral follicular count, of women undergoing level II ART techniques. Methods: This is a multicenter, prospective, and observational study by the reproductive medicine centers of Palermo’s Ospedali Riuniti Villa Sofia-Cervello Hospital and Vanvitelli University. From September 2022 to March 2024, 203 patients aged 24–43 were enrolled, all with diagnosed infertility and a history of SARS-CoV-2 infection. Symptomatic women, patients testing positive for HIV or other liver viruses, and patients with a history of ovarian cancer or who had taken gonadotoxic drugs were excluded. Plasma measurements of FSH, LH, estradiol, AMH, and antral follicular count were performed before and after infection. Results: The analysis accounting for the concentration of anti-Müllerian hormone (AMH) before and after COVID-19 infection shows an average concentration decrease from 1.33 ng/mL before SARS-CoV-2 infection to 0.97 ng/mL after infection. Average decrease after infection was −27.4%; average reduction of 1 follicle (95% CI: from −0.74 to −1.33) was reported following SARS-CoV-2 infection. Levels of E2 before and after SARS-CoV-2 infection did not vary significantly. Average FSH and LH levels before and after SARS-CoV-2 infection pointed to an increase. Conclusions: SARS-CoV-2 infection damages female reproductive health, causing significant reductions in AMH (−27.4%) and AFC (−1 antral follicle) values and an increase in FSH (+13.6%) and LH (+13.4%) values. No effect on E2 levels was reported. The pandemic has also affected the ability of infertile patients to access ART procedures, and that calls for a novel, updated blueprint designed to enhance our preparedness in the event that similar circumstances should occur again. Full article

Triggering receptor expressed on myeloid cells 2 (TREM2) is involved in neuroinflammation and HIV-associated neurocognitive impairment (NCI). People with HIV (PWH) using cannabis exhibit lower inflammation and neurological disorders. We hypothesized that TREM2 dysfunction mediates HIV neuropathogenesis and can be reversed by cannabinoids. EcoHIV-infected wildtype (WT) and TREM2^R47H mutant mice were used to study HIV’s impact on TREM2 and behavior. TREM2 and related gene expressions were examined in monocyte-derived macrophages (MDMs) from PWH (n = 42) and people without HIV (PWoH; n = 19) with varying cannabis use via RNA sequencing and qPCR. Differences in membrane-bound and soluble TREM2 (sTREM2) were evaluated using immunocytochemistry (ICC) and ELISA. EcoHIV increased immature and C-terminal fragment forms of TREM2 in WT mice but not in TREM2^R47H mice, with increased IBA1 protein in TREM2^R47H hippocampi, correlating with worse memory test performance. TREM2 mRNA levels increased with age in PWoH but not in PWH. Cannabidiol (CBD) treatment increased TREM2 mRNA alone and with IL1β. RNA-seq showed the upregulation of TREM2-related transcripts in cannabis-using PWH compared to naïve controls. IL1β increased sTREM2 and reduced membrane-bound TREM2, effects partially reversed by CBD. These findings suggest HIV affects TREM2 expression modulated by cannabis and CBD, offering insights for therapeutic strategies. Full article

The frequency of virus-associated cancers is growing worldwide, especially in resource-limited settings. One of the biggest challenges in cancer research among people living with HIV (PLWH) has been understanding how infection with both HIV and Kaposi sarcoma-associated herpesvirus (KSHV) promotes the pathogenesis of Kaposi sarcoma (KS), the most common cancer among PLWH worldwide and a significant public health problem in regions with high prevalence of HIV such as Sub-Saharan Africa (SSA). The AIDS and Cancer Specimen Resource (ACSR) provides samples for research, including dried blood spots (DBS) that were collected from large clinical epidemiology studies of KSHV and KS in PLWH conducted more than a decade ago in SSA. Here, we validated the quality of DNA derived from DBS samples from SSA studies and provided evidence of quantitative recovery of inflammatory cytokines using these DBS samples through comparison with paired frozen plasma. Significant differences in DNA, protein yields, and inflammatory biomarker levels were also observed between PLWH with/without KS. Establishing the fitness of DBS samples for studies of KS pathogenesis extends the number of projects that can be supported by these ACSR special collections and provides evidence that DBS collection for future KS research is a practical option in resource-limited settings. Full article

Community pharmacies have unparalleled potential to increase access to pre-exposure prophylaxis medications (PrEP) for HIV prevention; however, only 17 out of 50 states in the United States have statewide authority for pharmacists to provide PrEP at community pharmacies. Few studies have reported on how pharmacists overcome the legislative barrier and provide PrEP services in restrictive pharmacy prescription states. The objective of this article is to identify the existing primary literature describing pharmacist PrEP services in the community in states with restrictive prescription authority. Methods: A systemic literature review was conducted to identify the primary literature that involved community pharmacy service and PrEP conducted in states that do not have expanded pharmacist prescriptive authority between 2000 to 2024. Results: Ten publications were identified, describing nine studies, including four interview and survey studies, three intervention reports, and two ongoing clinical trials. None of these studies have a control group. Most pharmacists provide PrEP services in the community through a collaborative practice agreement with a primary care provider. Conclusions: Future clinical studies with randomized controlled designs are required to test novel strategies in the education and implementation of pharmacy-led PrEP services in a community pharmacy setting to increase PrEP access. Full article

The HIV-1 maturation inhibitor (MI) VH3739937 (VH-937) inhibits cleavage between capsid and spacer peptide 1 and exhibits an oral half-life in humans compatible with once-weekly dosing. Here, the antiviral properties of VH-937 are described. VH-937 exhibited potent antiviral activity against all HIV-1 laboratory strains, clinical isolates, and recombinant viruses examined, with half-maximal effective concentration (EC₅₀) values ≤ 5.0 nM. In multiple-cycle assays, viruses less susceptible to other MIs, including A364V, were inhibited at EC₅₀ values ≤ 8.0 nM and maximal percent inhibition (MPI) values ≥ 92%. However, VH-937 was less potent against A364V in single-cycle assays (EC₅₀, 32.0 nM; MPI, 57%) and A364V emerged in one of four resistance selection cultures. Other substitutions were selected by VH-937, although re-engineered viruses with these sequences were non-functional in multiple-cycle assays. Measured dissociation rates from wild-type and A364V-containing VLPs help explain resistance to the A364V mutation. Overall, the in vitro antiviral activity of VH-937 supports its continued development as a treatment for HIV-1. Full article

Our examination of RNA helicases for effects on HIV-1 protein production and particle assembly identified Rocaglamide (RocA), a known modulator of eIF4A1 function, as an inhibitor of HIV-1 replication in primary CD4⁺ T cells and three cell systems. HIV-1 attenuation by low-nM RocA doses was associated with reduced viral particle formation without a marked decrease in Gag production. Rather, the co-localization of Gag and HIV-1 genomic RNA (gRNA) assemblies was impaired by RocA treatment in a reversible fashion. Ribonucleoprotein (RNP) immunoprecipitation studies recapitulated the loss of Gag-gRNA assemblies upon RocA treatment. Parallel biophysical studies determined that neither RocA nor eIF4A1 independently affected the ability of Gag to interact with viral RNA, but together, they distorted the structure of the HIV-1 RNP visualized by electron microscopy. Taken together, several lines of evidence indicate that RocA induces stable binding of eIF4A1 onto the viral RNA genome in a manner that interferes with the ordered assembly of Gag along Gag-gRNA assemblies required to generate infectious virions. Full article

Since combination antiretroviral therapy (cART) was introduced to treat human immunodeficiency virus type-1 (HIV-1)/acquired immunodeficiency syndrome (AIDS), the AIDS mortality rate has markedly decreased, and convalescence in individuals with HIV has improved drastically. However, sexual transmission has made HIV-1 a global epidemic. Sacran is a megamolecular polysaccharide extracted from cyanobacterium Aphanothece sacrum that exhibits numerous desirable characteristics for transdermic applications, such as safety as a biomaterial, a high moisture retention effect, the ability to form a film and hydrogel, and an anti-inflammatory effect. In this study, we evaluated the anti-HIV-1 effects in sacran as a barrier to HIV-1 transmission. Sacran inhibited HIV-1 infection and envelope-dependent cell-to-cell fusion. Moreover, we used a Transwell assay to confirm that sacran inhibited viral diffusion and captured viruses. The synergistic effects of sacran and other anti-HIV infection drugs were also evaluated. HIV-1 infections can be reduced through the synergistic effects of sacran and anti-HIV-1 drugs. Our study suggests using sacran gel to provide protection against HIV-1 transmission. Full article

Background: Over the past two decades, intervention strategies to improve the use of the elimination of mother-to-child transmission (EMTCT) services have been implemented for several reasons. The reasons include elimination of HIV infections during pregnancy, delivery, breastfeeding, prevention of HIV, prevention of unintended pregnancies, and safer conception. Poor utilization of EMTCT services has been proven to put the child at risk of acquiring HIV, which could have been avoided. Objective: This study aims to explore and describe interventions to promote the elimination of mother-to-child transmission services among pregnant and nursing mothers in Africa. Method: A scoping literature review technique was undertaken on research papers published in English that focused on EMTCT, barriers, interventions, and methods to address challenges to EMTCT utilization. These were screened independently and coded. Results: The analysis comprised 14 out of approximately 9029 literature sources. Intervention strategies to improve EMTCT service utilization, according to the findings, include accessibility and affordability, healthcare worker training, integrating the elimination of mother-to-child transmission into maternal and child health services, community-based interventions, family-centred approaches, and the use of technology. Conclusions: Interventions that increase women’s use of EMTCT services will contribute to the aim of HIV-free generation by reducing new HIV infections in children and saving lives. Full article

Doravirine (DOR) is a non-nucleoside reverse transcriptase inhibitor (NNRTI) with efficacy against some NNRTI-resistant mutants. Although DOR resistance mutations are established for HIV-1 subtype B, it is less clear for non-B subtypes. This study investigated prevalent NNRTI resistance mutations on DOR susceptibility in HIV-1 subtype C. Prevalent drug resistance mutations were identified from a South African genotypic drug resistance testing database. Mutations, single or in combination, were introduced into replication-defective pseudoviruses and assessed for DOR susceptibility in vitro. The single V106M and Y188L mutations caused high-level resistance while others did not significantly impact DOR susceptibility. We observed an agreement between our in vitro and the Stanford HIVdb predicted susceptibilities. However, the F227L mutation was predicted to cause high-level DOR resistance but was susceptible in vitro. Combinations of mutations containing K103N, V106M or Y188L caused high-level resistance, in agreement with the predictions. These mutations are frequently observed in patients failing efavirenz- or nevirapine-based first-line regimens. However, they are also observed in those failing a protease inhibitor-based second-line regimen, as we have observed in our database. Genotypic drug resistance testing is therefore vital prior to the initiation of DOR-based treatment for those previously exposed to efavirenz or nevirapine. Full article

Over the past three years, new SARS-CoV-2 variants have continuously emerged, evolving to a point where an immune response against the original vaccine no longer provided optimal protection against these new strains. During this time, high-throughput neutralization assays based on pseudoviruses have become a valuable tool for assessing the efficacy of new vaccines, screening updated vaccine candidates against emerging variants, and testing the efficacy of new therapeutics such as monoclonal antibodies. Lentiviral vectors derived from HIV-1 are popular for developing pseudo and chimeric viruses due to their ease of use, stability, and long-term transgene expression. However, the HIV-based platform has lower transduction rates for pseudotyping coronavirus spike proteins than other pseudovirus platforms, necessitating more optimized methods. As the SARS-CoV-2 virus evolved, we produced over 18 variants of the spike protein for pseudotyping with an HIV-based vector, optimizing experimental parameters for their production and transduction. In this article, we present key parameters that were assessed to improve such technology, including (a) the timing and method of collection of pseudovirus supernatant; (b) the timing of host cell transduction; (c) cell culture media replenishment after pseudovirus adsorption; and (d) the centrifugation (spinoculation) parameters of the host cell+ pseudovirus mix, towards improved transduction. Additionally, we found that, for some pseudoviruses, the addition of a cationic polymer (polybrene) to the culture medium improved the transduction process. These findings were applicable across variant spike pseudoviruses that include not only SARS-CoV-2 variants, but also SARS, MERS, Alpha Coronavirus (NL-63), and bat-like coronaviruses. In summary, we present improvements in transduction efficiency, which can broaden the dynamic range of the pseudovirus titration and neutralization assays. Full article

Introduction: Post-menopausal women living with Human Immunodeficiency Virus (WLHIV) face an increased risk of bone fractures due to the relationship between HIV-related factors and menopause. This narrative review aims to summarise the current knowledge about fracture risk among post-menopausal WLHIV in particular looking at hormonal changes, combined antiretroviral therapy (cART), lifestyle factors, and psychosocial implications. We also profiled a summary of the significant, recent studies of post-menopausal WLHIV residing in low-income countries (LIC). Methods: A thorough search of the literature was performed across PubMed, Medline, Scopus, and Google Scholar, focussing on studies published between 2000 and 2024. Inclusion criteria entailed original research, reviews, and meta-analyses addressing bone mineral density (BMD), fracture incidence, and related risk factors in post-menopausal WLHIV. Results: The review identified 223 relevant studies. Post-menopausal WLHIV exhibit significantly lower BMD and higher fracture rates compared to both HIV-negative post-menopausal women and pre-menopausal WLHIV. cART, particularly tenofovir disoproxil fumarate (TDF), contributes to reduced BMD. Menopausal status exacerbates this risk through decreased oestrogen levels, leading to increased bone resorption. Moreover, lifestyle choices such as smoking, alcohol consumption, and low physical activity are more prevalent in PWHIV, which further elevates fracture risk. Different psychosocial factors may make WLWHIV more vulnerable at this stage of their life, such as depression, isolation, stigma, and housing and nutritional issues. Women living in LICs face a variety of challenges in accessing HIV care. There are gaps in research related to the prevalence of osteoporosis and bone loss in post-menopausal WLHIV in LICs. Conclusion: Post-menopausal women living with HIV face a significantly higher risk of bone loss and fractures due to the combined effects of HIV and menopause. Antiretroviral therapy (particularly TDF), lifestyle factors, and psychosocial challenges exacerbate this risk. There is a need for careful selection of cART, hormone replacement therapy (HRT), and emerging treatments such as Abaloparatide. A holistic approach including lifestyle changes and psychosocial support is crucial to reduce fracture risk in WLHIV, especially in low-income countries. Full article