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Abstract Background In Tanzania, little is known on the species distribution and antifungal susceptibility profiles of yeast isolates from HIV-infected patients with primary and recurrent oropharyngeal candidiasis. Methods A total of 296 clinical oral yeasts were isolated from 292 HIV-infected patients with oropharyngeal candidiasis at the Muhimbili National Hospital, Dar es Salaam, Tanzania. Identification of the yeasts was performed using standard phenotypic methods. Antifungal susceptibility to fluconazole, itraconazole, miconazole, clotrimazole, amphotericin B and nystatin was assessed using a broth microdilution format according to the guidelines of the Clinical and Laboratory Standard Institute (CLSI; M27-A2). Results Candida albicans was the most frequently isolated species from 250 (84.5%) patients followed by C. glabrata from 20 (6.8%) patients, and C. krusei from 10 (3.4%) patients. There was no observed significant difference in species distribution between patients with primary and recurrent oropharyngeal candidiasis, but isolates cultured from patients previously treated were significantly less susceptible to the azole compounds compared to those cultured from antifungal naïve patients. Conclusion C. albicans was the most frequently isolated species from patients with oropharyngeal candidiasis. Oral yeast isolates from Tanzania had high level susceptibility to the antifungal agents tested. Recurrent oropharyngeal candidiasis and previous antifungal therapy significantly correlated with reduced susceptibility to azoles antifungal agents.

Abstract Background The aim of the study was to compare the prevalence and types of HIV-related oral lesions between children and adult Tanzanian patients on HAART with those not on HAART and to relate the occurrence of the lesions with anti-HIV drug regimen, clinical stage of HIV disease and CD4+ cell count. Methods Participants were 532 HIV infected patients, 51 children and 481 adults, 165 males and 367 females. Children were aged 2–17 years and adults 18 and 67 years. Participants were recruited consecutively at the Muhimbili National Hospital (MNH) HIV clinic from October 2004 to September 2005. Investigations included; interviews, physical examinations, HIV testing and enumeration of CD4+ T cells. Results A total of 237 HIV-associated oral lesions were observed in 210 (39.5%) patients. Oral candidiasis was the commonest (23.5%), followed by mucosal hyperpigmentation (4.7%). There was a significant difference in the occurrence of oral candidiasis (χ2 = 4.31; df = 1; p = 0.03) and parotid enlargement (χ2 = 36.5; df = 1; p = 0.04) between children and adults. Adult patients who were on HAART had a significantly lower risk of; oral lesions (OR = 0.32; 95% CI = 0.22 – 0.47; p = 0.005), oral candidiasis (OR = 0.28; 95% CI = 0.18 – 0.44; p = 0.003) and oral hairy leukoplakia (OR = 0.18; 95% CI = 0.04 – 0.85; p = 0.03). There was no significant reduction in occurrence of oral lesions in children on HAART (OR = 0.35; 95% CI = 0.11–1.14; p = 0.15). There was also a significant association between the presence of oral lesions and CD4+ cell count < 200 cell/mm3 (χ2 = 52.4; df = 2; p = 0.006) and with WHO clinical stage (χ2 = 121; df = 3; p = 0.008). Oral lesions were also associated with tobacco smoking (χ2 = 8.17; df = 2; p = 0.04). Conclusion Adult patients receiving HAART had a significantly lower prevalence of oral lesions, particularly oral candidiasis and oral hairy leukoplakia. There was no significant change in occurrence of oral lesions in children receiving HAART. The occurrence of oral lesions, in both HAART and non-HAART patients, correlated with WHO clinical staging and CD4+ less than 200 cells/mm3.

Immunization of volunteers under chloroquine prophylaxis by bites of Plasmodium falciparum sporozoite (PfSPZ)-infected mosquitoes induces > 90% protection against controlled human malaria infection (CHMI). We studied intradermal immunization with cryopreserved, infectious PfSPZ in volunteers taking chloroquine (PfSPZ chemoprophylaxis vaccine [CVac]). Vaccine groups 1 and 3 received 3× monthly immunizations with 7.5 × 10(4) PfSPZ. Control groups 2 and 4 received normal saline. Groups 1 and 2 underwent CHMI (#1) by mosquito bite 60 days after the third immunization. Groups 3 and 4 were boosted 168 days after the third immunization and underwent CHMI (#2) 137 days later. Vaccinees (11/20, 55%) and controls (6/10, 60%) had the same percentage of mild to moderate solicited adverse events. After CHMI #1, 8/10 vaccinees (group 1) and 5/5 controls (group 2) became parasitemic by microscopy; the two negatives were positive by quantitative real-time polymerase chain reaction (qPCR). After CHMI #2, all vaccinees in group 3 and controls in group 4 were parasitemic by qPCR. Vaccinees showed weak antibody and no detectable cellular immune responses. Intradermal immunization with up to 3 × 10(5) PfSPZ-CVac was safe, but induced only minimal immune responses and no sterile protection against Pf CHMI.

Abstract Background Injecting drug use is an increasingly important cause of HIV transmission in most countries worldwide, especially in eastern Europe, South America, and east and southeast Asia. Among people actively injecting drugs, provision of clean needles and opioid substitution reduce HIV-transmission. However, former injecting drug users (fIDUs) are often overlooked as a high risk group for HIV transmission. We compared HIV risk behavior among current and former injecting drug users (IDUs) in Indonesia, which has a rapidly growing HIV-epidemic largely driven by injecting drug use. Methods Current and former IDUs were recruited by respondent driven sampling in an urban setting in Java, and interviewed regarding drug use and HIV risk behavior using the European Addiction Severity Index and the Blood Borne Virus Transmission Questionnaire. Drug use and HIV transmission risk behavior were compared between current IDUs and former IDUs, using the Mann-Whitney and Pearson Chi-square test. Results Ninety-two out of 210 participants (44%) were self reported former IDUs. Risk behavior related to sex, tattooing or piercing was common among current as well as former IDUs, 13% of former IDUs were still exposed to contaminated injecting equipment. HIV-infection was high among former (66%) and current (60%) IDUs. Conclusion Former IDUs may contribute significantly to the HIV-epidemic in Indonesia, and HIV-prevention should therefore also target this group, addressing sexual and other risk behavior.

Abstract Background Drug resistant malaria poses an increasing public health problem in Indonesia, especially eastern Indonesia, where malaria is highly endemic. Widespread chloroquine (CQ) resistance and increasing sulphadoxine-pyrimethamine (SP) resistance prompted Indonesia to adopt artemisinin-based combination therapy (ACT) as first-line therapy in 2004. To help develop a suitable malaria control programme in the district of West Sumba, the seasonal distribution of alleles known to be associated with resistance to CQ and SP among Plasmodium falciparum isolates from the region was investigated. Methods Plasmodium falciparum isolates were collected during malariometric surveys in the wet and dry seasons in 2007 using two-stage cluster sampling. Analysis of pfcrt, pfmdr1, pfmdr1 gene copy number, dhfr, and dhps genes were done using protocols described previously. Results and Discussion The 76T allele of the pfcrt gene is nearing fixation in this population. Pfmdr1 mutant alleles occurred in 72.8% and 53.3%, predominantly as 1042D and 86Y alleles that are mutually exclusive. The prevalence of amplified pfmdr1 was found 41.9% and 42.8% of isolates in the wet and dry seasons, respectively. The frequency of dhfr mutant alleles was much lower, either as a single 108N mutation or paired with 59R. The 437G allele was the only mutant dhps allele detected and it was only found during dry season. Conclusion The findings demonstrate a slighly higher distribution of drug-resistant alleles during the wet season and support the policy of replacing CQ with ACT in this area, but suggest that SP might still be effective either alone or in combination with other anti-malarials.

Toll-like receptor 4 (TLR4) is an important pathogen recognition receptor that recognizes mainly lipopolysaccharide (LPS) of Gramnegative bacteria, but also structures from fungal and mycobacterial pathogens, as well as endogenous ligands. Two nonsynonymous polymorphisms of TLR4, Asp299Gly and Thr399Ile, have been suggested to alter the function of the receptor. Some, but not all, studies have proposed that these polymorphisms lead to reduced cytokine response and increased susceptibility to Gram-negative infections. In this review, we compare studies that assessed the effect of the Asp299Gly and Thr399Ile polymorphisms on susceptibility to Gram-negative infections and examine the phenotypic consequences of these polymorphisms. In addition, we review the geographical distribution of TLR4 polymorphisms and present a model for evolutionary pressures on the TLR4 genetic make-up. [ABSTRACT FROM AUTHOR]

BACKGROUNDPeople living with HIV (PLHIV) receiving antiretroviral therapy (ART) exhibit persistent immune dysregulation and microbial dysbiosis, leading to development of cardiovascular diseases (CVDs). We initially compared plasma proteomic profiles between 205 PLHIV and 120 healthy control participants (HCs) and validated the results in an independent cohort of 639 PLHIV and 99 HCs. Differentially expressed proteins (DEPs) were then associated to microbiome data. Finally, we assessed which proteins were linked with CVD development in PLHIV.METHODSProximity extension assay technology was used to measure 1,472 plasma proteins. Markers of systemic inflammation (C-reactive protein, D-dimer, IL-6, soluble CD14, and soluble CD163) and microbial translocation (IFABP) were measured by ELISA, and gut bacterial species were identified using shotgun metagenomic sequencing. Baseline CVD data were available for all PLHIV, and 205 PLHIV were recorded for development of CVD during a 5-year follow-up.RESULTSPLHIV receiving ART had systemic dysregulation of protein concentrations, compared with HCs. Most of the DEPs originated from the intestine and lymphoid tissues and were enriched in immune- and lipid metabolism-related pathways. DEPs originating from the intestine were associated with specific gut bacterial species. Finally, we identified upregulated proteins in PLHIV (GDF15, PLAUR, RELT, NEFL, COL6A3, and EDA2R), unlike most markers of systemic inflammation, associated with the presence and risk of developing CVD during 5-year follow-up.CONCLUSIONOur findings suggest a systemic dysregulation of protein concentrations in PLHIV; some proteins were associated with CVD development. Most DEPs originated from the gut and were related to specific gut bacterial species.TRIAL REGISTRATIONClinicalTrials.gov NCT03994835.FUNDINGAIDS-fonds (P-29001), ViiV healthcare grant (A18-1052), Spinoza Prize (NWO SPI94-212), European Research Council (ERC) Advanced grant (grant 833247), and Indonesia Endowment Fund for Education.

Chronic inflammation and immune dysfunction play a key role in the development of non-AIDS-related comorbidities. The aim of our study was to characterize the functional phenotype of immune cells in people living with HIV (PLHIV). We enrolled a cross-sectional cohort study of PLHIV on stable antiretroviral therapy and healthy controls. We assessed ex vivo cytokine production capacity and transcriptomics of monocytes and T cells upon bacterial, fungal, and viral stimulation. PLHIV exhibited an exacerbated proinflammatory profile in monocyte-derived cytokines, but not in lymphocyte-derived cytokines. Particularly, the production of the IL-1β to imiquimod, E. coli LPS, and Mycobacterium tuberculosis was increased, and this production correlated with plasma concentrations of high-sensitivity C-reactive protein and soluble CD14. This increase in monocyte responsiveness remained stable over time in subsequent blood sampling after more than 1 year. Transcriptome analyses confirmed priming of the monocyte IL-1β pathway, consistent with a monocyte-trained immunity phenotype. Increased plasma concentrations of β-glucan, a well-known inducer of trained immunity, were associated with increased innate cytokine responses. Monocytes of PLHIV exhibited a sustained proinflammatory immune phenotype with priming of the IL-1β pathway. Training of the innate immune system in PLHIV likely plays a role in long-term HIV complications and provides a promising therapeutic target for inflammation-related comorbidities.