No abstract

A rare subset of IL-10-producing B cells, named regulatory B cells (Bregs), suppresses adaptive immune responses and inflammation in mice. In this study, we examined the role of IL-10-producing B cells in HIV-1 infection. Compared to uninfected controls, IL-10-producing B cell frequencies were elevated in both blood and sigmoid colon during the early and chronic phase of untreated HIV-1 infection. Ex vivo IL-10-producing B cell frequency in early HIV-1 infection directly correlated with viral load. IL-10-producing B cells from HIV-1 infected individuals were enriched in CD19+TIM-1+ B cells and were enriched for specificity to trimeric HIV-1 envelope protein. Anti-retroviral therapy was associated with reduced IL-10-producing B cell frequencies. Treatment of B cells from healthy donors with microbial metabolites and Toll-like receptor (TLR) agonists could induce an IL-10 producing phenotype, suggesting that the elevated bacterial translocation characteristic of HIV-1 infection may promote IL-10-producing B cell development. Similar to regulatory B cells found in mice, IL-10-producing B cells from HIV-1-infected individuals suppressed HIV-1-specific T cell responses in vitro, and this suppression is IL-10-dependent. Also, ex vivo IL-10-producing B cell frequency inversely correlated with contemporaneous ex vivo HIV-1-specific T cell responses. Our findings show that IL-10-producing B cells are induced early in HIV-1 infection, can be HIV-1 specific, and are able to inhibit effective anti-HIV-1 T cell responses. HIV-1 may dysregulate B cells toward Bregs as an immune evasion strategy.

Type 1 long-interspersed nuclear elements (L1s) are autonomous retrotransposable elements that retain the potential for activity in the human genome but are suppressed by host factors. Retrotransposition of L1s into chromosomal DNA can lead to genomic instability, whereas reverse transcription of L1 in the cytosol has the potential to activate innate immune sensors. We hypothesized that HIV-1 infection would compromise cellular control of L1 elements, resulting in the induction of retrotransposition events. Here, we show that HIV-1 infection enhances L1 retrotransposition in Jurkat cells in a Vif-and Vpr-dependent manner. In primary CD4؉ cells, HIV-1 infection results in the accumulation of L1 DNA, at least the majority of which is extrachromosomal. These data expose an unrecognized interaction between HIV-1 and endogenous retrotransposable elements, which may have implications for the innate immune response to HIV-1 infection, as well as for HIV-1-induced genomic instability and cytopathicity. L 1 element DNA sequences comprise approximately 17% of the human genome (1, 2). Although the bulk of these sequences are in the form of short 5= truncated insertions, an estimated 100 full-length intact elements are present (3, 4). These intact L1 elements represent the only retrotransposons encoded by the human genome known to be capable of autonomous replication (4-7). Full-length L1 elements are ϳ6 kb in length, comprising a 5=-untranslated region (5=UTR) two open reading frames (ORF1 and ORF2) and a 3=UTR ending in a poly(A) tail (8). ORF1 encodes a 40-kDa protein with RNA chaperone activity, while ORF2 encodes a 150-kDa protein which possesses the reverse transcriptase (RT) and endonuclease functions required for retrotransposition (6,(9)(10)(11)(12)(13)(14)(15)(16)(17). Productive retrotransposition is thought to occur by a mechanism termed target-primed reverse transcription (TPRT), where reverse transcription is primed against genomic DNA at the insertion site and thus occurs in concert with integration (18)(19)(20).Several cases of genetic disease have been traced to gene disruptions caused by L1 retrotransposition events in germ line cells, and L1 retrotransposition in somatic cells has been implicated in oncogenesis and cancer progression (21-26). L1 retrotransposition may also play a role in normal physiology. Previous studies have demonstrated the ability for tagged, engineered L1 elements to retrotranspose in neural progenitor cells, and this, supported by quantitative PCR (qPCR) data showing elevated copy numbers of L1 elements in the adult human brain, has led to the suggestion that L1 retrotransposition may play a role in the generation of neuronal somatic mosaicism (27, 28). The vast amount of L1 element sequence fixed in the human genome has, however, presented a technical challenge to the isolation of novel endogenous L1 genomic insertions in somatic cells.Although TPRT appears to be the primary mechanism by which novel genomic L1 insertions are generated, there is considerable evidence that cytosolic...

This article examines the history of Asian migration and exclusion in the Americas by focusing on the intersections of national histories, transnational migration, and the globality of race. Beginning in the mid-nineteenth century, a transnational conversation about race, migration, and national security circulated throughout North and South America. The subject was the global migration of Asians and the alleged threat they posed. By examining the circularity of Asian migration within the Americas as well as the transnational nature of anti-Asian racism, this article seeks to revise our understandings of transnationalism and contribute to the larger global history of race.

1 Selection of relevant articles: journal articles covering the main topics of VM. 2 A pre-test: 10 multiple choice questions (MCQs) to evaluate baseline knowledge and trigger interest in common vascular problems. 3 A teaching log (TL): a list of relevant topics in VM, with extra empty lines, displayed in the conference room. TRs were encouraged to mark their preferred topics, and to add other topics they were interested in to the TL, so they could be prioritised. Attending physicians were encouraged to pick topics from the TL for teaching sessions and mark when they were done. 4 Post-test and discussion: 20 MCQs designed to cover the most relevant topics. This was followed by a dedicated session to go over each question, discuss topics not covered during the rotation and answer any final questions. The results of the tests were for internal use; individual results were not shared, except with the TR, in order to focus on teaching and not on evaluating.What lessons were learned? Seventy-four TRs were exposed to the intervention, 80% were male and 76% were on internal medicine, neurology or medical paediatric subspecialty rotations. Mean scores of the pre-and post-tests were significantly different (52% and 65%, respectively; p < 0.01). The survey was sent to 57 trainees; 70% responded and 51% had rotated more than 6 months prior to the survey. Most (70%) encountered vascular diseases at least weekly in their practice. The perception of VM improved: all trainees felt more confident in managing vascular diseases and would recommend the rotation to their colleagues. In comparison with other internal medicine rotations, interventions were considered effective by 92% of responders. The preferred intervention was the distribution of selected articles, followed by the post-test and discussion. The TL allowed them to have a personalised and diverse rotation. The median number of topics from the TL discussed per month was 5.5 (IQR,. The average number of topics per month discussed by the two instructors was very similar (5.8 and 5.1 each). Within 23 months (IQR, 12-32) after the rotation the mean score on VM knowledge questions was persistently above the baseline (67% mean score, p < 0.01).Our interventions had a positive impact on the training and increased awareness of vascular pathology as well as the comfort level when treating such patients.