In owl monkeys, a retrotransposition event replaced the gene encoding the retroviral restriction factor TRIM5alpha with one encoding TRIMCyp, a fusion between the RING, B-box 2 and coiled-coil domains of TRIM5 and cyclophilin A. TRIMCyp restricts human immunodeficiency virus (HIV-1) infection by a mechanism dependent on the interaction of the cyclophilin A moiety and the HIV-1 capsid protein. Here, we show that infection by retroviruses other than HIV-1 can be restricted by TRIMCyp, providing an explanation for the evolutionary retention of the TRIMCyp gene in owl monkey lineages. The TRIMCyp-mediated block to HIV-1 infection occurs before the earliest step of reverse transcription. TRIMCyp-mediated restriction involves at least two functions: (1) capsid binding, which occurs most efficiently for trimeric TRIMCyp proteins that retain the coiled-coil and cyclophilin A domains, and (2) an effector function that depends upon the B-box 2 domain.

BackgroundMost currently approved anti-HIV drugs (e.g., reverse transcriptase inhibitors, protease inhibitors and fusion/entry inhibitors) must act inside or on surface of the target cell to inhibit HIV infection, but none can directly inactivate virions away from cells. Although soluble CD4 (sCD4) can inactivate laboratory-adapted HIV-1 strains, it fails to reduce the viral loads in clinical trials because of its low potency against primary isolates and tendency to enhance HIV-1 infection at low concentration. Thus, it is essential to design a better HIV inactivator with improved potency for developing new anti-HIV therapeutics that can actively attack the virus in the circulation before it attaches to and enter into the target cell.ResultsWe engineered a bivalent HIV-1 inactivator, designated 2DLT, by linking the D1D2 domain of CD4 to T1144, the next generation HIV fusion inhibitor, with a 35-mer linker. The D1D2 domain in this soluble 2DLT protein could bind to the CD4-binding site and induce the formation of the gp41 prehairpin fusion-intermediate (PFI), but showed no sCD4-mediated enhancement of HIV-1 infection. The T1144 domain in 2DLT then bound to the exposed PFI, resulting in rapid inactivation of HIV-1 virions in the absence of the target cell. Beside, 2DLT could also inhibit fusion of the virus with the target cell if the virion escapes the first attack of 2DLT.ConclusionThis bivalent molecule can serve as a dual barrier against HIV infection by first inactivating HIV-1 virions away from cells and then blocking HIV-1 entry on the target cell surface, indicating its potential for development as a new class of anti-HIV drug.

Accessible Summary What is known on the subject? A growing body of qualitative and quantitative research has investigated the experiences of affiliated stigma for family members of PWMI. Some findings are contradictory and have not been considered systematically. What does the paper adds to existing knowledge? Family caregivers of PWMI may encounter affiliate stigma, but no systematic review or meta‐analysis has been conducted to evaluate affiliate stigma among them. We identified eight variables significantly related to affiliate stigma among caregivers of PWMI. The findings can be used to help clinical practice to develop health promotion and prevention strategies. What are the implications for practice? Affiliate stigma was prevalent among the family caregivers of PWMI and is important for clinicians to consider. Health‐focused interventions for family caregivers can mediate the impact of affiliated stigma through provision of social support by practitioners, such as respite care based on the “Senses Framework,” self‐help groups and online support program. And the caregivers of PWMI might benefit from further support (e.g., psychoeducation) to improve their knowledge about mental illness. Abstract IntroductionMany studies have investigated the correlates of affiliate stigma among family caregivers of people with mental illness (PWMI). Thus far, no systematic review or meta‐analysis has been conducted to synthesize these results. Aims/QuestionThis review aims to identify the correlates of affiliate stigma among family caregivers of PWMI. MethodWe searched four databases including PubMed, PsycINFO, EMBASE and Web of Science for studies that investigated the association of affiliate sigma with socio‐demographic, psychosocial and disease‐related factors. ResultsTwenty‐two studies including 3,381 participants met the inclusion criteria. Eighteen variables were included for the meta‐analysis. For disease‐related characteristics, only “disease attribution” and “care time/day” were associated with affiliate stigma. For psychosocial characteristics, “support from others,” “burden,” “depression,” “stress,” “distress” and “face concern” were related to affiliate stigma. DiscussionThis review is the first to assess the association of affiliate stigma with other characteristics of interest. However, the findings are limited due to a very small number of studies. Researchers should conduct in‐depth study in this area and improve the quality of the literature. Implications for practiceHealth‐focused interventions for family caregivers such as respite care, self‐help groups, online support program and psychosocial education can mediate the impact of affiliated stigma.