Antiretroviral therapy (ART) suppresses viral replication in people living with HIV. Yet, infected cells persist for decades on ART and viremia returns if ART is stopped. Persistence has been ...attributed to viral replication in an ART sanctuary and long-lived and/or proliferating latently infected cells. Using ecological methods and existing data, we infer that >99% of infected cells are members of clonal populations after one year of ART. We reconcile our results with observations from the first months of ART, demonstrating mathematically how a fossil record of historic HIV replication permits observed viral evolution even while most new infected cells arise from proliferation. Together, our results imply cellular proliferation generates a majority of infected cells during ART. Therefore, reducing proliferation could decrease the size of the HIV reservoir and help achieve a functional cure.
The advent of antiretroviral therapy (ART) has seen a dramatic decrease in the morbidity and mortality of individuals infected with human immunodeficiency virus (HIV). However, ART is not curative ...and HIV persists in treated individuals within a pool of infected CD4
memory T cells. The targeting and elimination of these cells, termed the latent HIV reservoir, may be essential in establishing a cure for HIV. Current HIV reservoir research is focused on identifying cells that harbor latent, replication-competent, HIV provirus using specific cell surface markers. Recently, studies have turned to immune checkpoint (IC) molecules, such as programmed cell death protein 1 (PD-1). IC molecules are regulators of the immune system and have previously been linked to HIV infection. Furthermore, cells isolated from treated individuals co-expressing PD-1 alongside other IC molecules are enriched for HIV DNA. Administration of a IC blocking antibodies resulted in an increase of cell-associated HIV RNA within an individual, indicating the potential for this therapeutic to be utilized as a latency reversing agent. IC inhibitors could target CD4
T cells expressing IC molecules and possibly enhance HIV transcription, allowing for the elimination of these cells by either ART or the immune system. However, treatment with IC inhibitors has been associated with toxicities such as immune-related adverse events and therefore future studies should proceed with caution.
Traumatic experiences contribute significantly to behavioral and mood dysregulation syndromes presenting for treatment to behavioral health settings. Individuals with Autism Spectrum Disorder (ASD), ...Intellectual Disability (ID) and developmental delay experience traumatic events more frequently than their typically developing peers. However, measures used to identify trauma related disorders and treatment thereof are based on typically developing individuals. Regardless of the baseline characteristics of individuals who experience trauma, trauma exposure is the result of multiple interdependent environmental, social, and familial characteristics. We used the "ecological systems analysis approach" to structure our review of the impact of trauma on those with ASD and ID. In addition, the COVID-19 pandemic which exposed the global population to a collective trauma, has also catalyzed investigations into the challenges faced by members of society most dependent on social services. Children with ASD and ID were among those vulnerable individuals, and the COVID-19 pandemic has allowed researchers to better understand the impact of a collective trauma on those individuals. It is imperative that we understand current research and recommendations for identifying and treating trauma-related disorders in individuals with developmental disorders to best inform clinical practice and directions for future research in this area.
Antiretroviral therapy effectively suppresses, but does not eradicate HIV-1 infection. Persistent low-level HIV-1 can still be detected in plasma and cellular reservoirs even after years of effective ...therapy, and cessation of current treatments invariably results in resumption of viral replication. Efforts to eradicate persistent HIV-1 require a comprehensive examination of the quantity and genetic composition of HIV-1 within the plasma and infected cells located in the peripheral blood and tissues throughout the body. Single-molecule techniques, such as the single-copy assay and single-genome/proviral sequencing assays, have been employed to further our understanding of the source and viral dynamics of persistent HIV-1 during long-term effective therapy. The application of the single-copy assay, which quantifies plasma HIV-1 RNA down to a single copy, has revealed that viremia persists in the plasma and CSF after years of effective therapy. This low-level HIV-1 RNA also persists in the plasma following treatment intensification, treatment with latency reversing agents, cancer-related therapy, and bone marrow transplantation. Single-genome/proviral sequencing assays genetically characterise HIV-1 populations after passing through different selective pressures related to cell type, tissue type, compartment, or therapy. The application of these assays has revealed that the intracellular HIV-1 reservoir is stable and mainly located in CD4+ memory T cells. Moreover, this intracellular HIV-1 reservoir is primarily maintained by cellular proliferation due to homeostasis and antigenic stimulation, although cryptic replication may take place in anatomic sites where treatment is sub-optimal. The employment of single-genome/proviral sequencing showed that latency reversing agents broadly activate quiescent proviruses but do not clear the intracellular reservoir. Recently, full-length individual proviral sequencing assays have been developed and the application of these assays has revealed that the majority of intracellular HIV-1 DNA is genetically defective. In addition, the employment of these assays has shown that genetically intact proviruses are unequally distributed in memory T cell subsets during antiretroviral therapy. The application of single-molecule assays has enhanced the understanding of the source and dynamics of persistent HIV-1 in the plasma and cells of HIV-infected individuals. Future studies of the persistent HIV-1 reservoir and new treatment strategies to eradicate persistent virus will benefit from the utilization of these assays.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
This study investigated how emotional valence of a perceived emotional state impacted performance on the Reading the Mind in the Eyes task (RMET) in adolescents with autism spectrum disorder (ASD) ...and typically developing (TD) controls. Valence of items on the RMET, Adult (RMET-A) and Child (RMET-C) versions, was first classified in a survey of 113 medical students. Adolescents with ASD (N = 33) and TD adolescents (N = 30) were administered both RMET versions. Individuals with ASD made more errors than TD controls on positive and negative, but not neutral, valence items. The difference in performance was accentuated on the RMET-A compared to the RMET-C. Both emotional valence and complexity of language contribute to RMET performance in individuals with ASD.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Viral rebound upon stopping combined antiretroviral therapy poses a major barrier toward an HIV cure. Cellular and anatomical sources responsible for reinitiating viral replication remain a subject ...of ardent debate, despite extensive research efforts. To unravel the source of rebounding viruses, we conducted a large-scale HIV-STAR (HIV-1 sequencing before analytical treatment interruption to identify the anatomically relevant HIV reservoir) clinical trial. We collected samples from 11 participants and compared the genetic composition of (pro)viruses collected under treatment from different cellular and anatomical compartments with that of plasma viruses sampled during analytical treatment interruption. We found a remarkably heterogeneous source of viral rebound. In addition, irrespective of the compartment or cell subset, genetically identical viral expansions played a significant role in viral rebound. Our study suggests that although there does not seem to be a primary source for rebound HIV, cellular proliferation is an important driver of HIV persistence and should therefore be considered in future curative strategies.
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•HIV-1 sequences sampled from different reservoirs were compared to rebound viruses in 11 individuals•Rebound viruses can originate from various cellular and anatomical compartments•Cellular proliferation is an important driver of HIV persistence•Cure strategies should take into account the lack of a prominent HIV rebound origin
De Scheerder et al. conduct an in-depth investigation into the origins of HIV rebound. They show that viral rebound originates from multiple compartments and cell proliferation is a driver of viral persistence. Future HIV cure strategies will need to overcome the challenges associated with heterogeneous viral rebound.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Latent replication-competent HIV-1 persists in individuals on long-term antiretroviral therapy (ART). We developed the Full-Length Individual Proviral Sequencing (FLIPS) assay to determine the ...distribution of latent replication-competent HIV-1 within memory CD4+ T cell subsets in six individuals on long-term ART. FLIPS is an efficient, high-throughput assay that amplifies and sequences near full-length (∼9 kb) HIV-1 proviral genomes and determines potential replication competency through genetic characterization. FLIPS provides a genome-scale perspective that addresses the limitations of other methods that also genetically characterize the latent reservoir. Using FLIPS, we identified 5% of proviruses as intact and potentially replication competent. Intact proviruses were unequally distributed between T cell subsets, with effector memory cells containing the largest proportion of genetically intact HIV-1 proviruses. We identified multiple identical intact proviruses, suggesting a role for cellular proliferation in the maintenance of the latent HIV-1 reservoir.
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•FLIPS utilizes NGS to sequence and genetically characterize HIV-1 proviruses•FLIPS identifies genetically intact and likely replication-competent HIV-1 proviruses•Identical HIV-1 proviruses suggest maintenance of reservoir by cellular proliferation•Demonstrate the advantages of FLIPS over other common HIV-1 sequencing assays
Latent, replication-competent HIV-1 proviruses pose a significant barrier to an HIV-1 cure. Hiener et al. present the Full-Length Individual Proviral Sequencing (FLIPS) assay to reveal the distribution of genetically intact and potentially replication-competent HIV-1 proviruses in different T cell subsets isolated from individuals on long-term antiretroviral therapy.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The yeast dynamin-like protein Vps1 has roles at multiple stages of membrane trafficking including Golgi to vacuole transport, endosomal recycling, endocytosis and in peroxisomal fission. While the ...majority of the Vps1 amino acid sequence shows a high level of identity with the classical mammalian dynamins, it does not contain a pleckstrin homology domain (PH domain). The Dyn1 PH domain has been shown to bind to lipids with a preference for PI(4,5)P2 and it is considered central to the function of Dyn1 in endocytosis. The lack of a PH domain in Vps1 has raised questions as to whether the protein can function directly in membrane fusion or fission events. Here we demonstrate that the region Insert B, located in a position equivalent to the dynamin PH domain, is able to bind directly to lipids and that mutation of three lysine residues reduces its capacity to interact with lipids, and in particular with PI(4,5)P2. The Vps1 KKK-AAA mutant shows more diffuse staining but does still show some localization to compartments adjacent to vacuoles and to endocytic sites suggesting that other factors are also involved in its recruitment. This mutant selectively blocks endocytosis, but is functional in other processes tested. While mutant Vps1 can localise to endocytic sites, the mutation results in a significant increase in the lifetime of the endocytic reporter Sla2 and a high proportion of defective scission events. Together our data indicate that the lipid binding capacity of the Insert B region of Vps1 contributes to the ability of the protein to associate with membranes and that its capacity to interact with PI(4,5)P2 is important in facilitating endocytic scission.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Research investigating the relationships among the Dark Triad traits (narcissism, Machiavellianism, and psychopathy) and well-being has shown narcissism to be functionally distinct from the other two ...dark traits. Across two studies, the relationship between these three traits and well-being was investigated, using first broad and then more nuanced measures of the Dark Triad. Results of Study 1 indicated that narcissism differed from the other Dark Triad traits in that it was positively associated with well-being. Additionally, narcissism provided a buffering effect on the relationship between these traits and well-being. Study 2 results found that the grandiose subtype of narcissism was positively associated with well-being and provided a buffering effect on the relationship between the other Dark Triad traits and well-being.
•Assessing Dark Triad subtypes resulted in unique relationships not seen when using unidimensional measures.•Grandiose narcissism was positively associated with well-being; the other Dark Triad subtypes were negatively associated.•Grandiose narcissism provided a buffering effect on the relationship between some Dark Triad traits and well-being.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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