The role of oxygen on the interaction of Candida albicans with intestinal epithelial cells

The opportunistic fungal pathogen Candida albicans frequently occurs as commensal in the gastrointestinal tract of humans. While it is known that intestinal epithelial cells are highly sensitive to ischemia-reperfusion (IR) injury, the exact role of oxygen for IR-mediated fungal translocation has however not been addressed so far. Thus, the aim of this study was to investigate C. albicans-enterocyte interactions in dependence of oxygen availability. Enterocytes were able to maintain barrier function across a range of oxygen concentrations. Their susceptibility to C. albicans infection was however significantly influenced by oxygen: The shift from low to high oxygen enhanced susceptibility to infection, likely mediated by increased intracellular oxidative stress and alterations of tight junctions facilitating increased invasion of the fungus. In contrast, low oxygen concentrations and especially hypoxic shock were associated with less damage and partially retained barrier function. Additionally, fungal translocation was reduced after hypoxic shock. HIF-1α contributed to the protective effect, independent of the antimicrobial cathelicidin LL-37. Furthermore, peracute hypoxic preconditioning, compared to enterocytes constantly cultured at low oxygen, led to enhanced adhesion but reduced invasion and reduced hyphal growth of C. albicans, suggesting that oxygen-mediated changes of enterocytes also directly influence the fungus. Fungal adaptation to oxygen availability contributes to these interactions, as a C. albicans TYE7 deletion mutant showed oxygen-dependent alterations in virulence. Finally, this study provides evidence that the early stages of the infection process determine the fate of enterocytes during their interaction with C. albicans in an oxygen-dependent manner. In summary, this study demonstrates that oxygen availability significantly influences the interaction between C. albicans and the intestinal barrier by affecting both host cells and pathogen

The predominance of Human Immunodeficiency Virus type 1 (HIV-1) circulating recombinant form 02 (CRF02_AG) in West Central Africa may be related to its replicative fitness

BACKGROUND: CRF02_AG is the predominant HIV strain circulating in West and West Central Africa. The aim of this study was to test whether this predominance is associated with a higher in vitro replicative fitness relative to parental subtype A and G viruses. Primary HIV-1 isolates (10 CRF02_AG, 5 subtype A and 5 subtype G) were obtained from a well-described Cameroonian cohort. Growth competition experiments were carried out at equal multiplicity of infection in activated T cells and monocyte-derived dendritic cells (MO-DC) in parallel. RESULTS: Dual infection/competition experiments in activated T cells clearly indicated that CRF02_AG isolates had a significant replication advantage over the subtype A and subtype G viruses. The higher fitness of CRF02_AG was evident for isolates from patients with CD4+ T cell counts >200 cells/μL (non-AIDS) or CD4+ T cell counts <200 cells/μL (AIDS), and was independent of the co-receptor tropism. In MO-DC cultures, CRF02_AG isolates showed a slightly but not significantly higher replication advantage compared to subtype A or G isolates. CONCLUSION: We observed a higher ex vivo replicative fitness of CRF02_AG isolates compared to subtype A and G viruses from the same geographic region and showed that this was independent of the co-receptor tropism and irrespective of high or low CD4+ T cell count. This advantage in replicative fitness may contribute to the dominant spread of CRF02_AG over A and G subtypes in West and West Central Africa

Improving 23-Valent Pneumococcal Polysaccharide (PPSV23) Vaccination in Pediatric HIV Patients

Background and Objectives: Children living with HIV are at increased risk for invasive pneumococcal disease. The American Academy of Pediatrics recommends all children with HIV infection receive 23-valent pneumococcal polysaccharide vaccine (PPSV23) after receiving the 13 valent pneumococcal conjugate (PCV13) vaccine series. Despite this recommendation, the rate of PPSV23 vaccination in children with HIV remains low. This quality improvement project aimed to increase the rate of PPSV23 vaccination rate among pediatric and adolescent high risk population attending Special Immunology Services (SIS) HIV specialty clinic at Children’s National. Methods: Eligible patients included children and adolescents receiving care at SIS clinic. A baseline assessment of PPSV23 vaccination rate was performed in April 2015. Interventions included proactive acquisition of updated vaccination records from primary care providers, determining need for PCV-13 vaccine series and PPSV-23 during clinic visits, and requesting primary care providers to administer required vaccinations or providing PPSV-23 at subsequent SIS appointments. A REDCap database was created to track documentation of PCV-13 and PPSV23 vaccination. Results: In April 2015, 184 children and adolescents were enrolled in care at SIS. Fifty-seven patients (40.0%) had immunization records available, and only 17 (9.2%) had documentation of completion of PCV-13 series and none (0.0%) had documentation of PPSV-23. After 2 Plan-Do-Study-Act cycles over a period of 8 months, there was an increase of total patients with immunization records to 95 (51.6%). Thirtysix (19.6%) had documentation of completion of PCV-13 series and 16 patients (8.7%) had documented PPSV-23 vaccine. Three (18%) PPSV23 vaccines were administered in SIS clinic. Conclusions: Obtaining patients’ current vaccination records from primary care providers and lack of prior administration of PCV-13 are two barriers to completing PPSV-23 vaccination in children with HIV receiving care in a specialty setting. Dedicated SIS staff time is required to consistently operationalize procuring updated immunization records and administering PCV-13 and PPSV-23 as recommended by national guidelines

Outcomes of integrase inhibitor-based antiretroviral therapy in a clinical cohort of treatment-experienced children, adolescents and young adults with HIV infection

Background: Data on integrase strand transfer inhibitor (INSTI) use in children, adolescents and young adults with HIV are limited. We evaluated virologic and safety outcomes following INSTI initiation among treatment-experienced children, adolescents and young adults. Methods: The DC Cohort is a multicenter observational study of individuals receiving HIV care in Washington, DC. This analysis included treatment-experienced participants 0-24 years of age who initiated an INSTI during 2011-2017. Viral suppression (VS) and safety outcomes were quantified. Differences in VS by age, sex and CD4 count were assessed using Kaplan-Meier curves. Results: Of 141 participants (median age 20 years; 35% \u3c18 years; 60% male; 89% Black; 62% perinatally-infected), 35% had VS and 65% lacked VS on INSTI initiation. Dolutegravir was the most commonly prescribed INSTI (55%). Among participants without VS at INSTI initiation, 46% achieved VS after a median of 2.7 months. Participants 13-24 (vs. 0-12) years old (P = 0.011) and participants with CD4 counts \u3c350 (vs. \u3e500) cells/μL were less likely to achieve VS (P \u3c 0.001). Among participants with VS at INSTI initiation, 51% sustained VS through a median of 11.0 months of follow-up; of the 49% with transient viremia, 77% later achieved VS again. There were no safety concerns associated with the use of INSTIs. Conclusions: More than half of treatment-experienced children, adolescents and young adults with detectable viremia at INSTI initiation did not achieve VS, while half of those with prior VS experienced transient viremia. Further evaluation of long-term outcomes associated with INSTI use among children, adolescents and young adults is warranted

Global and regional molecular epidemiology of HIV-1, 1990–2015: a systematic review, global survey, and trend analysis

International audienceGlobal genetic diversity of HIV-1 is a major challenge to the development of HIV vaccines. We aimed to estimate the regional and global distribution of HIV-1 subtypes and recombinants during 1990–2015.We searched PubMed, EMBASE (Ovid), CINAHL (Ebscohost), and Global Health (Ovid) for HIV-1 subtyping studies published between Jan 1, 1990, and Dec 31, 2015. We collected additional unpublished HIV-1 subtyping data through a global survey. We included prevalence studies with HIV-1 subtyping data collected during 1990–2015. We grouped countries into 14 regions and analysed data for four time periods (1990–99, 2000–04, 2005–09, and 2010–15). The distribution of HIV-1 subtypes, circulating recombinant forms (CRFs), and unique recombinant forms (URFs) in individual countries was weighted according to the UNAIDS estimates of the number of people living with HIV (PLHIV) in each country to generate regional and global estimates of HIV-1 diversity in each time period. The primary outcome was the number of samples designated as HIV-1 subtypes A, B, C, D, F, G, H, J, K, CRFs, and URFs. The systematic review is registered with PROSPERO, number CRD42017067164.This systematic review and global survey yielded 2203 datasets with 383 519 samples from 116 countries in 1990–2015. Globally, subtype C accounted for 46·6% (16 280 897/34 921 639 of PLHIV) of all HIV-1 infections in 2010–15. Subtype B was responsible for 12·1% (4 235 299/34 921 639) of infections, followed by subtype A (10·3%; 3 587 003/34 921 639), CRF02_AG (7·7%; 2 705 110/34 921 639), CRF01_AE (5·3%; 1 840 982/34 921 639), subtype G (4·6%; 1 591 276/34 921 639), and subtype D (2·7%; 926 255/34 921 639). Subtypes F, H, J, and K combined accounted for 0·9% (311 332/34 921 639) of infections. Other CRFs accounted for 3·7% (1 309 082/34 921 639), bringing the proportion of all CRFs to 16·7% (5 844 113/34 921 639). URFs constituted 6·1% (2 134 405/34 921 639), resulting in recombinants accounting for 22·8% (7 978 517/34 921 639) of all global HIV-1 infections. The distribution of HIV-1 subtypes and recombinants changed over time in countries, regions, and globally. At a global level during 2005–15, subtype B increased, subtypes A and D were stable, and subtypes C and G and CRF02_AG decreased. CRF01_AE, other CRFs, and URFs increased, leading to a consistent increase in the global proportion of recombinants over time.Global and regional HIV diversity is complex and evolving, and is a major challenge to HIV vaccine development. Surveillance of the global molecular epidemiology of HIV-1 remains crucial for the design, testing, and implementation of HIV vaccines

Global and regional molecular epidemiology of HIV-1, 1990-2015: a systematic review, global survey, and trend analysis

BACKGROUND: Global genetic diversity of HIV-1 is a major challenge to the development of HIV vaccines. We aimed to estimate the regional and global distribution of HIV-1 subtypes and recombinants during 1990-2015. METHODS: We searched PubMed, EMBASE (Ovid), CINAHL (Ebscohost), and Global Health (Ovid) for HIV-1 subtyping studies published between Jan 1, 1990, and Dec 31, 2015. We collected additional unpublished HIV-1 subtyping data through a global survey. We included prevalence studies with HIV-1 subtyping data collected during 1990-2015. We grouped countries into 14 regions and analysed data for four time periods (1990-99, 2000-04, 2005-09, and 2010-15). The distribution of HIV-1 subtypes, circulating recombinant forms (CRFs), and unique recombinant forms (URFs) in individual countries was weighted according to the UNAIDS estimates of the number of people living with HIV (PLHIV) in each country to generate regional and global estimates of HIV-1 diversity in each time period. The primary outcome was the number of samples designated as HIV-1 subtypes A, B, C, D, F, G, H, J, K, CRFs, and URFs. The systematic review is registered with PROSPERO, number CRD42017067164. FINDINGS: This systematic review and global survey yielded 2203 datasets with 383 519 samples from 116 countries in 1990-2015. Globally, subtype C accounted for 46·6% (16 280 897/34 921 639 of PLHIV) of all HIV-1 infections in 2010-15. Subtype B was responsible for 12·1% (4 235 299/34 921 639) of infections, followed by subtype A (10·3%; 3 587 003/34 921 639), CRF02_AG (7·7%; 2 705 110/34 921 639), CRF01_AE (5·3%; 1 840 982/34 921 639), subtype G (4·6%; 1 591 276/34 921 639), and subtype D (2·7%; 926 255/34 921 639). Subtypes F, H, J, and K combined accounted for 0·9% (311 332/34 921 639) of infections. Other CRFs accounted for 3·7% (1 309 082/34 921 639), bringing the proportion of all CRFs to 16·7% (5 844 113/34 921 639). URFs constituted 6·1% (2 134 405/34 921 639), resulting in recombinants accounting for 22·8% (7 978 517/34 921 639) of all global HIV-1 infections. The distribution of HIV-1 subtypes and recombinants changed over time in countries, regions, and globally. At a global level during 2005-15, subtype B increased, subtypes A and D were stable, and subtypes C and G and CRF02_AG decreased. CRF01_AE, other CRFs, and URFs increased, leading to a consistent increase in the global proportion of recombinants over time. INTERPRETATION: Global and regional HIV diversity is complex and evolving, and is a major challenge to HIV vaccine development. Surveillance of the global molecular epidemiology of HIV-1 remains crucial for the design, testing, and implementation of HIV vaccines. FUNDING: None.status: publishe