BackgroundPeople living with HIV (PLWH), even when viral replication is controlled through antiretroviral therapy (ART), experience persistent inflammation. This inflammation is partly attributed... Show moreBackgroundPeople 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.ResultsPLWH 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.ConclusionsWe 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.1fCw832AZENtKENNTh8vkGVideo AbstractConclusionsWe 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.1fCw832AZENtKENNTh8vkGVideo Abstract Show less
Background: Digital triage tools for sexually transmitted infection (STI) testing can potentially be used as a substitute for the triage that general practitioners (GPs) perform to lower their work... Show moreBackground: Digital triage tools for sexually transmitted infection (STI) testing can potentially be used as a substitute for the triage that general practitioners (GPs) perform to lower their work pressure. The studied tool is based on medical guidelines. The same guidelines support GPs' decision-making process. However, research has shown that GPs make decisions from a holistic perspective and, therefore, do not always adhere to those guidelines. To have a high-quality digital triage tool that results in an efficient care process, it is important to learn more about GPs' decision-making process. Objective: The first objective was to identify whether the advice of the studied digital triage tool aligned with GPs' daily medical practice. The second objective was to learn which factors influence GPs' decisions regarding referral for diagnostic testing. In addition, this study provides insights into GPs' decision-making process. Methods: A qualitative vignette-based study using semistructured interviews was conducted. In total, 6 vignettes representing patient cases were discussed with the participants (GPs). The participants needed to think aloud whether they would advise an STI test for the patient and why. A thematic analysis was conducted on the transcripts of the interviews. The vignette patient cases were also passed through the digital triage tool, resulting in advice to test or not for an STI. A comparison was made between the advice of the tool and that of the participants. Results: In total, 10 interviews were conducted. Participants (GPs) had a mean age of 48.30 (SD 11.88) years. For 3 vignettes, the advice of the digital triage tool and of all participants was the same. In those vignettes, the patients' risk factors were sufficiently clear for the participants to advise the same as the digital tool. For 3 vignettes, the advice of the digital tool differed from that of the participants. Patient-related factors that influenced the participants' decision-making process were the patient's anxiety, young age, and willingness to be tested. Participants would test at a lower threshold than the triage tool because of those factors. Sometimes, participants wanted more information than was provided in the vignette or would like to conduct a physical examination. These elements were not part of the digital triage tool. Conclusions: The advice to conduct a diagnostic STI test differed between a digital triage tool and GPs. The digital triage tool considered only medical guidelines, whereas GPs were open to discussion reasoning from a holistic perspective. The GPs' decision-making process was influenced by patients' anxiety, willingness to be tested, and age. On the basis of these results, we believe that the digital triage tool for STI testing could support GPs and even replace consultations in the future. Further research must substantiate how this can be done safely. Show less
Astrocytes, the most abundant cells in the mammalian brain, perform key functions and are involved in several neurodegenerative diseases. The human immunodeficiency virus (HIV) can persist in... Show moreAstrocytes, the most abundant cells in the mammalian brain, perform key functions and are involved in several neurodegenerative diseases. The human immunodeficiency virus (HIV) can persist in astrocytes, contributing to the HIV burden and neurological dysfunctions in infected individuals. While a comprehensive approach to HIV cure must include the targeting of HIV-1 in astrocytes, dedicated tools for this purpose are still lacking. Here we report a novel Adeno-associated virus-based vector (AAV9P1) with a synthetic surface peptide for transduction of astrocytes. Analysis of AAV9P1 transduction efficiencies with single brain cell populations, including primary human brain cells, as well as human brain organoids demonstrated that AAV9P1 targeted terminally differentiated human astrocytes much more efficiently than neurons. We then investigated whether AAV9P1 can be used to deliver HIV-inhibitory genes to astrocytes. To this end we generated AAV9P1 vectors containing genes for HIV-1 proviral editing by CRISPR/Cas9. Latently HIV-1 infected astrocytes transduced with these vectors showed significantly diminished reactivation of proviruses, compared with untransduced cultures. Sequence analysis identified mutations/deletions in key HIV-1 transcriptional control regions. We conclude that AAV9P1 is a promising tool for gene delivery to astrocytes and may facilitate inactivation/destruction of persisting HIV-1 proviruses in astrocyte reservoirs. Show less
