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HIV targets the gut mucosa early in infection, causing immune and epithelial barrier dysfunction and disease progression. However, gut mucosal sensing and innate immune signaling through mucosal pattern recognition receptors (PRRs) during HIV infection and disease progression are not well defined. Using the simian immunodeficiency virus (SIV)-infected rhesus macaque model of AIDS, we found a robust increase in PRRs and inflammatory cytokine gene expression during the acute SIV infection in both peripheral blood and gut mucosa, coinciding with viral replication. PRR expression remained elevated in peripheral blood following the transition to chronic SIV infection. In contrast, massive dampening of PRR expression was detected in the gut mucosa, despite the presence of detectable viral loads. Exceptionally, expression of Toll-like receptor 4 (TLR4) and TLR8 was downmodulated and diverged from expression patterns for most other TLRs in the gut. Decreased mucosal PRR expression was associated with increased abundance of several pathogenic bacterial taxa, including Pasteurellaceae members, Aggregatibacter and Actinobacillus, and Mycoplasmataceae family. Early antiretroviral therapy led to viral suppression but only partial maintenance of gut PRRs and cytokine gene expression. In summary, SIV infection dampens mucosal innate immunity through PRR dysregulation and may promote immune activation, gut microbiota changes, and ineffective viral clearance.

Coinfection can markedly alter the response to a pathogen, thereby changing its clinical presentation. For example, non-typhoidal Salmonella (NTS) serotypes are associated with gastroenteritis in immunocompetent individuals. In contrast, individuals with severe pediatric malaria can develop bacteremic infections with NTS, during which symptoms of gastroenteritis are commonly absent. Here we report that, in both a ligated ileal loop model and a mouse colitis model, malaria parasites caused a global suppression of gut inflammatory responses and blunted the neutrophil influx that is characteristic of NTS infection. Further, malaria parasite infection led to increased recovery of Salmonella enterica serotype Typhimurium from the draining mesenteric lymph node (MLN) of mice. In the mouse colitis model, blunted intestinal inflammation during NTS infection was independent of anemia but instead required parasite-induced synthesis of interleukin (IL)-10. Blocking of IL-10 in coinfected mice reduced dissemination of S. Typhimurium to the MLN, suggesting that induction of IL-10 contributes to development of disseminated infection. Thus IL-10 produced during the immune response to malaria in this model contributes to suppression of mucosal inflammatory responses to invasive NTS, which may contribute to differences in the clinical presentation of NTS infection in the setting of malaria.

Background: Women and men have diverse responses to many infectious diseases. These differences are amplified following menopause. However, despite extensive information regarding the effects of sex hormones on immune cells, our knowledge is limited regarding the effects of sex and gender on the function of the mucosal immune system. Sex differences also manifest in the prevalence of gut associated inflammatory and autoimmune disorders, including Crohn's disease, ulcerative colitis and Celiac disease. It is thus hypothesized that a baseline sex-associated difference in immune activation may predispose women to inflammation-associated disease. Methods: Peripheral blood samples and small intestinal biopsies were obtained from 34 healthy men and women. Immunophenotypic analysis of isolated lymphocytes was performed by flow cytometry. Oligonucleotide analysis was used to study the transcriptional profile in the gut mucosal microenvironment while real-time PCR analysis was utilized to identify differential gene expression in isolated CD4+ T cells. Transcriptional analysis was confirmed by protein expression levels for genes of interest using fluorescent immunohistochemistry. Data was analyzed using the GraphPad software package. Results: Women had higher levels of immune activation and inflammation-associated gene expression in gut mucosal samples. CD4+ and CD8+ T cells had a significantly higher level of immune activation-associated phenotype in peripheral blood as well as in gut associated lymphoid tissue along with higher levels of proliferating T cells. CD4+ T cells that showed upregulation of IL1β as well as the TH17 pathway-associated genes contributed a large part of the inflammatory profile. Conclusion: In this study, we demonstrated an upregulation in gene expression related to immune function in the gut microenvironment of women compared to men, in the absence of disease or pathology. Upon closer investigation, CD4+ T cell activation levels were higher in the LPLs in women than in men. Sex differences in the mucosal immune system may predispose women to inflammation-associated diseases that are exacerbated following menopause. Our study highlights the need for more detailed analysis of the effects of sex differences in immune responses at mucosal effector sites. © 2013 Sankaran-Walters et al.; licensee BioMed Central Ltd.

Background: While there are methods to prevent HIV infection, there is still a need for a prevention device that is effective, user-controlled, easily transported without refrigeration, inexpensive and discreet. Importantly, such a device should be attractive to the user to avoid the problem of low adherence, particularly among at-risk youth. We have developed the silk fibroin (SF) platform to encapsulate and release a single or combination of HIV inhibitors, including the lectin Griffithsin (Grft), that does not need refrigeration. These small silk devices can be inserted vaginally and rectally, and be formulated either for quick-dissolve or sustained release. Methods: We have used silk-Grft inserts in female rhesus macaques (n=11), placing them vaginally and rectally. These compartments were swabbed to test for amount of Grft released and changes in local microbiome. Tissue biopsies were obtained and tested for protection against SHIV infection. To determine the user acceptability of silk inserts, we held four focus groups in California during summer 2020. These groups were composed of sexually active women and men, both straight and gay, who were shown a variety of silk fibroin inserts. Participants discussed HIV prevention knowledge and practices in the context of varying relationship statuses, impacts of COVID-19 on their sexual activity, and their perceptions of the silk inserts. Results: The Silk-Grft inserts readily dissolved in the vaginal and rectal compartments in macaques, where Grft levels were substantially above 100-fold [IC.sub.50], indicating effective release of Grft inhibitor. Tissue biopsies from both compartments were fully protected against ex vivo SHIV infection, with neither inflammation nor change in micro-biome. In focus groups, young, sexually active adults uniformly expressed positive sentiments and high interest when presented with silk inserts in an array of shapes and colors. These opinions included repeated preference for silk inserts over oral PrEP, due to the utility of silk inserts as spontaneous protection that did not require daily dosing. Conclusions: Together, these recently obtained results show that silk fibroin is an excellent candidate for formulating HIV inhibitors, being both highly effective in preventing infection and also attractive to young, sexually active adults, which may lead to higher adherence and protection., OA19.04LB P. LiWang (1); K. Crakes (2); C. Herrera (3); J. Morgan (1); A. Lopez (4); M. Palupi Rasajan (4); S. Dandekar (2) and N. Burke (4) (1) University of [...]