Rhesus macaque TRIM5␣ (rhTRIM5␣) is a retroviral restriction factor that inhibits HIV-1 infection. Previous studies have revealed that TRIM5␣ restriction occurs via a two-step process. The first step is restriction factor binding, which is sufficient to inhibit infection. The second step, which is sensitive to proteasome inhibition, prevents the accumulation of reverse transcription products in the target cell. However, because of the pleotropic effects of proteasome inhibitors, the molecular mechanisms underlying the individual steps in the restriction process have remained poorly understood. In this study, we have fused the small catalytic domain of herpes simplex virus UL36 deubiquitinase (DUb) to the N-terminal RING domain of rhTRIM5␣, which results in a ubiquitination-resistant protein. Cell lines stably expressing this fusion protein inhibited HIV-1 infection to the same degree as a control fusion to a catalytically inactive DUb. However, reverse transcription products were substantially increased in the DUb-TRIM5␣ fusion relative to the catalytically inactive control or the wild-type (WT) TRIM5␣. Similarly, expression of DUb-rhTRIM5␣ resulted in the accumulation of viral cores in target cells following infection, while the catalytically inactive control and WT rhTRIM5␣ induced the abortive disassembly of viral cores, indicating a role for ubiquitin conjugation in rhTRIM5␣-mediated destabilization of HIV-1 cores. Finally, DUb-rhTRIM5␣ failed to activate NF-B signaling pathways compared to controls, demonstrating that this ubiquitination-dependent activity is separable from the ability to restrict retroviral infection. IMPORTANCEThese studies provide direct evidence that ubiquitin conjugation to rhTRIM5␣-containing complexes is required for the second step of HIV-1 restriction. They also provide a novel tool by which the biological activities of TRIM family proteins might be dissected to better understand their function and underlying mechanisms of action. TRIM5␣ is a retroviral restriction factor that mediates a postentry block to infection (1, 2). The best-studied example of this restriction is the ability of the TRIM5␣ protein from rhesus macaques (rhTRIM5␣) to potently inhibit HIV-1 infection (1, 2). As a member of the TRIM family of proteins, TRIM5␣ possesses the canonical RING, B-Box, and coiled-coil (CC) domains that comprise the tripartite motif (TRIM) that define this family of proteins (3). The N-terminal RING domain acts as an E3 ubiquitin ligase (4-6), and together with the B-Box domain, also functions to mediate the self-association of TRIM5␣ dimers (7-9). The CC domain, in cooperation with the Linker2 (L2) region, mediates the dimerization of TRIM5␣ monomers and the formation of higher-order assemblies (10-14). TRIM5␣ also possesses a C-terminal SPRY domain which is known to recognize determinants in the assembled viral core to mediate restriction (15-17). Following core binding, TRIM5␣ induces the abortive disassembly of the viral core (18,19). The mechanism by which core disruption o...

ObjectiveTo conduct a systematic review of the literature regarding approaches to staff training in dual diagnosis competencies.MethodsA search was conducted using eight databases: Informit, Taylor & Francis, Springer, Proquest, Expand, Sage, Psych info, Elsevier and Cinahl. The year range was 2005 to April 2015. An additional manual search of reference lists was conducted to ensure relevant articles were not overlooked.ResultsOf 129 potential results, there were only 11 articles regarding staff training in dual diagnosis. The limited studies included problems: small sample sizes, selection biases, and questions as to validity of some capability instruments, and low inclusion of service user perspectives. Organisational challenges to greater uptake of staff training including agency size, agency willingness to change, and a need to change policies.ConclusionsThere is a pressing need for more research, and quality research, in this important area of knowledge translation, dissemination and implementation of evidence-based practices. In particular there is limited literature regarding the efficacy of dual diagnosis competency resources, and a gap as to use of the mentoring in dual diagnosis capacity building.

Background During the COVID-19 pandemic, we saw telehealth rapidly become the primary way to receive mental health care. International research has validated many of the benefits and challenges of telehealth known beforehand for specific population groups. However, if telehealth is to assume prominence in future mental health service delivery, greater understanding of its capacity to be used to provide psychosocial support to people with complex and enduring mental health conditions is needed. Objective We focused on an Australian community-managed provider of psychosocial intervention and support. We aimed to understand service user and worker experiences of psychosocial support via telehealth throughout the COVID-19 pandemic. Methods This study was jointly developed and conducted by people with lived experience of mental ill health or distress, mental health service providers, and university-based researchers. Semistructured interviews were conducted between August and November 2020 and explored participant experiences of receiving or providing psychosocial support via telehealth, including telephone, text, and videoconferencing. Qualitative data were analyzed thematically; quantitative data were collated and analyzed using descriptive statistics. Results Service users (n=20) and workers (n=8) completed individual interviews via telephone or videoconferencing platform. Service users received psychosocial support services by telephone (12/20, 60%), by videoconferencing (6/20, 30%), and by both telephone and videoconferencing (2/20, 10%). Of note, 55% (11/20) of service user participants stated a future preference for in-person psychosocial support services, 30% (6/20) preferred to receive a mixture of in-person and telehealth, and 15% (3/20) elected telehealth only. Two meta-themes emerged as integral to worker and service user experience of telehealth during the pandemic: (1) creating safety and comfort and (2) a whole new way of working. The first meta-theme comprises subthemes relating to a sense of safety and comfort while using telehealth; including trusting in the relationship and having and exercising choice and control. The second meta-theme contains subthemes reflecting key challenges and opportunities associated with the shift from in-person psychosocial support to telehealth. Conclusions Overall, our findings highlighted that most service users experienced telehealth positively, but this was dependent on them continuing to get the support they needed in a way that was safe and comfortable. While access difficulties of a subgroup of service users should not be ignored, most service users and workers were able to adapt to telehealth by focusing on maintaining the relationship and using choice and flexibility to maintain service delivery. Although most research participants expressed a preference for a return to in-person psychosocial support or hybrid in-person and telehealth models, there was a general recognition that intentional use of telehealth could contribute to flexible and responsive service delivery. Challenges to telehealth provision of psychosocial support identified in this study are yet to be fully understood.

Summary HIV-1 recruits cellular Endosomal Sorting Complexes Required for Transport (ESCRTs) to bud virions from the membrane. Disruption of the viral nucleocapsid (NC) domain integrity affects HIV-1 budding. However, the molecular mechanisms of NC’s involvement in HIV budding remain unclear. We find that NC mimics the PDZ domains of syntenin, a membrane-binding adaptor involved in cell-to-cell contact/communication, to capture the Bro1 domain of ALIX, which is an ESCRTs recruiting cellular adaptor. NC binds membranes via basic residues in either the distal or proximal zinc fingers and NC-membrane binding is essential for Bro1 capture and HIV-1 budding. Removal of RNA enhances NC membrane binding suggesting a dynamic competition between membrane lipids and RNA for same binding sites in NC. Remarkably, syntenin PDZ can substitute for NC function in HIV-1 budding. Thus, NC mimics syntenin PDZs to function as a membrane-binding adaptor critical for HIV-1 budding at microdomains of the membrane.

Clinicians are routinely subjected to intense and stressful working environments, and the current COVID-19 crisis increases their risk of psychological distress. Mindfulness has been shown to improve life satisfaction, resilience to stress, self-compassion, compassion and general well-being in healthcare workers. Based on their clinical experience, the authors present mindfulness moments for clinicians (MMFC), a selection of short, simple and accessible mindfulness practices to promote resilience and compassion among clinicians working in this pandemic. The practices can be used on the job and are accessible to both novice and experienced meditators. Most of these practices are extracted from evidence-based mindfulness programmes. Further research is indicated to assess the effectiveness of using MMFC to support clinicians in their work and to promote resilience.