Limited impact of fingolimod treatment during the initial weeks of ART in SIV-infected rhesus macaques.

Antiretroviral therapy (ART) is not curative due to the persistence of a reservoir of HIV-infected cells, particularly in tissues such as lymph nodes, with the potential to cause viral rebound after treatment cessation. In this study, fingolimod (FTY720), a lysophospholipid sphingosine-1-phosphate receptor modulator is administered to SIV-infected rhesus macaques at initiation of ART to block the egress from lymphoid tissues of natural killer and T-cells, thereby promoting proximity between cytolytic cells and infected CD4+ T-cells. When compared with the ART-only controls, FTY720 treatment during the initial weeks of ART induces a profound lymphopenia and increases frequencies of CD8+ T-cells expressing perforin in lymph nodes, but not their killing capacity; FTY720 also increases frequencies of cytolytic NK cells in lymph nodes. This increase of cytolytic cells, however, does not limit measures of viral persistence during ART, including intact proviral genomes. After ART interruption, a subset of animals that initially receives FTY720 displays a modest delay in viral rebound, with reduced plasma viremia and frequencies of infected T follicular helper cells. Further research is needed to optimize the potential utility of FTY720 when coupled with strategies that boost the antiviral function of T-cells in lymphoid tissues.

Connections during crisis: Adolescents' social dynamics and mental health during COVID-19.

Adolescence is a critical period for social development, which COVID-19 has dramatically altered. Quarantined youths had limited in-person interactions with peers. The present study used an intensive longitudinal design to investigate changes in interpersonal dynamics and mental health during COVID-19. Specifically, we investigated whether the associations between different social contexts-that is, "spillover"-changed during COVID-19 and whether changes in social interactions during COVID-19 was associated with changes in depressive symptoms. Approximately 1 year prior to the onset of COVID-19, 139 youths reported depressive symptoms and daily interactions with parents, siblings, and friends, every day for 21 days via online questionnaires. Shortly after schools closed due to COVID-19, 115 of these youths completed a similar 28-day diary. Analyses included 112 youths (62 girls; 73% Caucasian; Mage = 11.77, range = 8 to 15 in Wave 1) who completed at least 13 diary days in each data wave. Our results show that younger adolescents experienced significant decreases in negative and positive interactions with friends, whereas older adolescents showed significant decreases in negative interactions with friends and significant increases in positive interactions with siblings. As predicted, within-day spillover of positive interactions and person-level association of negative interactions increased within the family during COVID-19, whereas within-day spillover of positive interactions between family and friends decreased. We also found a dramatic increase in depressive symptoms. More negative interactions and fewer positive interactions with family members were associated with changes in depressive symptoms. Our study sheds light on how youths' social development may be impacted by COVID-19. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Recurrent HBV Integration Targets as Potential Drivers in Hepatocellular Carcinoma.

Chronic hepatitis B virus (HBV) infection is the major etiology of hepatocellular carcinoma (HCC), frequently with HBV integrating into the host genome. HBV integration, found in 85% of HBV-associated HCC (HBV-HCC) tissue samples, has been suggested to be oncogenic. Here, we investigated the potential of HBV-HCC driver identification via the characterization of recurrently targeted genes (RTGs). A total of 18,596 HBV integration sites from our in-house study and others were analyzed. RTGs were identified by applying three criteria: at least two HCC subjects, reported by at least two studies, and the number of reporting studies. A total of 396 RTGs were identified. Among the 28 most frequent RTGs, defined as affected in at least 10 HCC patients, 23 (82%) were associated with carcinogenesis and 5 (18%) had no known function. Available breakpoint positions from the three most frequent RTGs, TERT, MLL4/KMT2B, and PLEKHG4B, were analyzed. Mutual exclusivity of TERT promoter mutation and HBV integration into TERT was observed. We present an RTG consensus through comprehensive analysis to enable the potential identification and discovery of HCC drivers for drug development and disease management.

Virion-associated phosphatidylethanolamine promotes TIM1-mediated infection by Ebola, dengue, and West Nile viruses.

Phosphatidylserine (PS) receptors contribute to two crucial biological processes: apoptotic clearance and entry of many enveloped viruses. In both cases, they recognize PS exposed on the plasma membrane. Here we demonstrate that phosphatidylethanolamine (PE) is also a ligand for PS receptors and that this phospholipid mediates phagocytosis and viral entry. We show that a subset of PS receptors, including T-cell immunoglobulin (Ig) mucin domain protein 1 (TIM1), efficiently bind PE. We further show that PE is present in the virions of flaviviruses and filoviruses, and that the PE-specific cyclic peptide lantibiotic agent Duramycin efficiently inhibits the entry of West Nile, dengue, and Ebola viruses. The inhibitory effect of Duramycin is specific: it inhibits TIM1-mediated, but not L-SIGN-mediated, virus infection, and it does so by blocking virus attachment to TIM1. We further demonstrate that PE is exposed on the surface of apoptotic cells, and promotes their phagocytic uptake by TIM1-expressing cells. Together, our data show that PE plays a key role in TIM1-mediated virus entry, suggest that disrupting PE association with PS receptors is a promising broad-spectrum antiviral strategy, and deepen our understanding of the process by which apoptotic cells are cleared.

ADAM17 activity and other mechanisms of soluble L-selectin production during death receptor-induced leukocyte apoptosis.

L-selectin is an adhesion molecule expressed by neutrophils that broadly directs their infiltration in to sites of inflammation. It is also present at relatively high levels in the serum of normal individuals. It is well established that L-selectin is efficiently shed from the surface of neutrophils upon their activation, a process that regulates its density and binding activity. Neutrophil programmed cell death is critical for the resolution of inflammation, and L-selectin downregulation is induced during this process as well. The mechanisms underpinning this latter process are much less understood, and were investigated in this study. Using a disintegrin and metalloprotease (ADAM)-17 radiation chimeric mice, we demonstrate for the first time that during early events of death receptor-mediated neutrophil apoptosis, L-selectin downregulation occurs primarily by ADAM17-mediated shedding. This was observed as well upon using shRNA to knock down ADAM17 expression in Jurkat cells, a well-studied cell line in terms of the molecular processes involved in the induction of apoptosis. These findings directly reveal that ADAM17 activity occurs during programmed cell death. Hence, the cleavage of particular ADAM17 substrates may be an additional component of the anti-inflammatory program initiated by apoptotic neutrophils. Of interest was that during later stages of induced leukocyte apoptosis, soluble L-selectin production occurred independent of ADAM17, as well as membrane events, such as blebbing and microparticle production. This process may provide an explanation for the lack of diminished serum L-selectin levels in ADAM17-null mice, and suggests a mechanism for the homeostatic maintenance of soluble L-selectin levels in the blood of healthy individuals.