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2.  Risk and prognosis of Staphylococcus aureus bacteremia among individuals with and without end-stage renal disease: a Danish, population-based cohort study 
Staphylococcus aureus is a leading cause of bloodstream infections among hemodialysis patients and of exit-site infections among peritoneal dialysis patients. However, the risk and prognosis of Staphylococcus aureus bacteremia among end-stage renal disease patients have not been delineated.
In this Danish nationwide, population-based cohort study patients with end-stage renal disease and matched population controls were observed from end-stage renal disease diagnosis/sampling until first episode of Staphylococcus aureus bacteremia, death, or end of study period. Staphylococcus aureus positive blood cultures, hospitalization, comorbidity, and case fatality were obtained from nationwide microbiological, clinical, and administrative databases. Incidence rates and risk factors were assessed by regression analysis.
The incidence rate of Staphylococcus aureus bacteremia was very high for end-stage renal disease patients (35.7 per 1,000 person-years; 95% CI, 33.8-37.6) compared to population controls (0.5 per 1,000 person-years; 95% CI, 0.5-0.6), yielding a relative risk of 65.1 (95% CI, 59.6-71.2) which fell to 28.6 (95% CI, 23.3-35.3) after adjustment for sex, age, and comorbidity. After stratification for type of renal replacement therapy, we found the highest incidence rate of Staphylococcus aureus bacteremia among hemodialysis patients (46.3 per 1,000 person-years) compared to peritoneal dialysis patients (22.0 per 1,000 person-years) and renal transplant recipients (8.9 per 1,000 person-years). In persons with Staphylococcus aureus bacteremia, ninety-day case fatality was 18.2% (95% CI, 16.2%-20.3%) for end-stage renal disease patients and 33.7% (95% CI, 30.3-37.3) for population controls.
Patients with end-stage renal disease, and hemodialysis patients in particular, have greatly increased risk of Staphylococcus aureus bacteremia compared to population controls. Future challenges will be to develop strategies to reduce Staphylococcus aureus bacteremia-related morbidity and death in this high-risk population.
Electronic supplementary material
The online version of this article (doi:10.1186/s12879-014-0740-8) contains supplementary material, which is available to authorized users.
PMCID: PMC4296555  PMID: 25566857
Bacteremia; Staphylococcus aureus; End-stage renal disease; Dialysis
3.  Challenges facing HIV treatment in Guinea-Bissau: the benefits of international research collaborations 
The introduction of antiretroviral therapy (ART) for HIV infection in sub-Saharan Africa has improved the quality of life of millions of people and reduced mortality. However, substantial problems with the infrastructure for ART delivery remain.
Clinicians and researchers at an HIV clinic in Guinea-Bissau identified problems with the delivery of ART by establishing a clinical database and by collaborating with international researchers.
Local setting
The Bissau HIV cohort study group was established in 2007 as a collaboration between local HIV physicians and international HIV researchers. Patients were recruited from the HIV clinic at the country’s main hospital in the capital Bissau.
Relevant changes
Between 2005 and 2013, 5514 HIV-positive patients were treated at the clinic. Working together, local health-care workers and international researchers identified the main problems affecting ART delivery: inadequate drug supply; loss of patients to follow-up; and inadequate laboratory services. Solutions to these problems were devised. The collaborations encouraged local physicians to start their own research projects to find possible solutions to problems at the clinic.
Lessons learnt
The HIV clinic in Bissau faced numerous obstacles in delivering ART at a sufficiently high quality and patients’ lives were put in jeopardy. The effectiveness of ART could be enhanced by delivering it as part of an international research collaboration since such collaborations can help identify problems, find solutions and increase the capacity of the health-care system.
PMCID: PMC4264391  PMID: 25552775
4.  Dynamic Control of Auxin Distribution Imposes a Bilateral-to-Radial Symmetry Switch during Gynoecium Development 
Current Biology  2014;24(22):2743-2748.
Symmetry formation is a remarkable feature of biological life forms associated with evolutionary advantages and often with great beauty. Several examples exist in which organisms undergo a transition in symmetry during development [1–4]. Such transitions are almost exclusively in the direction from radial to bilateral symmetry [5–8]. Here, we describe the dynamics of symmetry establishment during development of the Arabidopsis gynoecium. We show that the apical style region undergoes an unusual transition from a bilaterally symmetric stage ingrained in the gynoecium due to its evolutionary origin to a radially symmetric structure. We also identify two transcription factors, INDEHISCENT [9] and SPATULA [10], that are both necessary and sufficient for the radialization process. Our work furthermore shows that these two transcription factors control style symmetry by directly regulating auxin distribution. Establishment of specific auxin-signaling foci and the subsequent development of a radially symmetric auxin ring at the style are required for the transition to radial symmetry, because genetic manipulations of auxin transport can either cause loss of radialization in a wild-type background or rescue mutants with radialization defects. Whereas many examples have described how auxin provides polarity and specific identity to cells in a range of developmental contexts, our data presented here demonstrate that auxin can also be recruited to impose uniform identity to a group of cells that are otherwise differentially programmed.
Graphical Abstract
•Apex of the Arabidopsis gynoecium undergoes a bilateral-to-radial symmetry transition•Transcription factors IND/SPT are necessary and sufficient for organ radialization•IND and SPT regulate auxin transport to achieve radial symmetry•Spatiotemporal auxin dynamics control growth and symmetry of the gynoecium
Symmetry transitions in nature are common and occur almost exclusively via a change from radial to bilateral symmetry. Here, Moubayidin and Østergaard reveal how control of auxin transport by SPATULA and INDEHISCENT imposes a rare bilateral-to-radial symmetry switch during Arabidopsis gynoecium development.
PMCID: PMC4245708  PMID: 25455035
5.  Differences in coreceptor specificity contribute to alternative tropism of HIV-1 subtype C for CD4+ T-cell subsets, including stem cell memory T-cells 
Retrovirology  2014;11(1):97.
CD4+ memory T-cells are a major target for infection by HIV-1, whereby latent provirus can establish and endure suppressive antiretroviral therapies. Although HIV-1 subtype C strains (C-HIV) account for the majority of HIV-1 infections worldwide, the susceptibility of CD4+ memory T-cells to infection by CCR5- (R5) and CXCR4-using (X4) C-HIV is unknown. Here, we quantified the susceptibility of naïve and memory CD4+ T-cell subsets, including stem cell memory T-cells (TSCM), to infection by HIV-1 subtype C (C-HIV) strains from treatment-naïve subjects who progressed from chronic to advanced stages of disease whilst either maintaining CCR5-using (R5) viruses (subjects 1503 and 1854), or who experienced emergence of dominant CXCR4-using (X4) strains (subject 1109).
We show that R5 and X4 C-HIV viruses preferentially target memory and naïve CD4+ T-cell subsets, respectively. While TSCM were susceptible to infection by both R5 and X4 C-HIV viruses, the proportion of infected CD4+ T-cells that were TSCM was higher for R5 strains. Mutagenesis studies of subject 1109 viruses established the V3 region of env as the determinant underlying the preferential targeting of naïve CD4+ T-cells by emergent X4 C-HIV variants in this subject. In contrast, the tropism of R5 C-HIV viruses for CD4+ T-cell subsets was maintained from chronic to advanced stages of disease in subjects 1503 and 1854.
This study provides new insights into the natural history of tropism alterations for CD4+ T-cell subsets by C-HIV strains during progression from chronic to advanced stages of infection. Although not preferentially targeted, our data suggest that TSCM and other memory CD4+ T-cells are likely to be viral reservoirs in subjects with X4 C-HIV infection.
Electronic supplementary material
The online version of this article (doi:10.1186/s12977-014-0097-5) contains supplementary material, which is available to authorized users.
PMCID: PMC4236466  PMID: 25387392
HIV-1; Subtype C; T-cell; CD4+; TSCM
6.  LCoMotion – Learning, Cognition and Motion; a multicomponent cluster randomized school-based intervention aimed at increasing learning and cognition - rationale, design and methods 
BMC Public Health  2014;14(1):967.
The aim of the study; LCoMotion – Learning, Cognition and Motion was to develop, document, and evaluate a multi-component physical activity (PA) intervention in public schools in Denmark. The primary outcome was cognitive function. Secondary outcomes were academic skills, body composition, aerobic fitness and PA. The primary aim of the present paper was to describe the rationale, design and methods of the LCoMotion study.
LCoMotion was designed as a cluster-randomized controlled study. Fourteen schools from all five regions in Denmark participated. All students from 6th and 7th grades were invited to participate (n = 869) and consent was obtained for 87% (n = 759). Baseline measurements were obtained in November/December 2013 and follow-up measurements in May/June 2014. The intervention lasted five months and consisted of a “package” of three main components: PA during academic lessons, PA during recess and PA homework. Furthermore a cycling campaign was conducted during the intervention period. Intervention schools should endeavor to ensure that students were physically active for at least 60 min every school day. Cognitive function was measured by a modified Eriksen flanker task and academic skills by a custom made mathematics test. PA was objectively measured by accelerometers (ActiGraph, GT3X and GT3X+) and aerobic fitness assessed by an intermittent shuttle-run test (the Andersen intermittent running test). Furthermore, compliance with the intervention was assessed by short message service (SMS)-tracking and questionnaires were delivered to students, parents and teachers.
LCoMotion has ability to provide new insights on the effectiveness of a multicomponent intervention on cognitive function and academic skills in 6th and 7th grade students.
Trial registration NCT02012881 (10/10/2013)
PMCID: PMC4192295  PMID: 25236478
Cognition; Academic achievement; Physical activity; Children; Adolescents; School-based intervention; Fitness; RCT
7.  Hepatitis B and Delta Virus Are Prevalent but Often Subclinical Co-Infections among HIV Infected Patients in Guinea-Bissau, West Africa: A Cross-Sectional Study 
PLoS ONE  2014;9(6):e99971.
Co-infection with human immunodeficiency virus (HIV) and hepatitis B virus (HBV) may lead to accelerated hepatic disease progression with higher rates of liver cirrhosis and liver-related mortality compared with HBV mono-infection. Co or super-infection with hepatitis Delta virus (HDV) may worsen the liver disease and complicate treatment possibilities.
In this cross-sectional study we included HIV-infected individuals who had a routine blood analysis performed at an HIV clinic in Bissau, Guinea-Bissau between the 28th of April and 30th of September 2011. All patients were interviewed, had a clinical exam performed and had a blood sample stored. The patients' samples were tested for HBV and HDV serology, and HBV/HDV viral loads were analyzed using in-house real-time PCR methods.
In total, 576 patients (417 HIV-1, 104 HIV-2 and 55 HIV-1/2) were included in this study. Ninety-four (16.3%) patients were HBsAg positive of whom 16 (17.0%) were HBeAg positive. In multivariable logistic regression analysis, CD4 cell count <200 cells/ µl and animist religion were significantly associated with HBsAg positivity. Due to scarcity of available plasma, virological analyses were not performed for eight patients. HBV DNA was detected in 42 of 86 samples (48.8%) positive for HBsAg and genotyping was performed in 26 patients; 25 of whom had genotype E and one genotype D. Among 9 patients on antiretroviral treatment (ART), one patient had the [L180M, M204V] mutation associated with lamivudine resistance. Among the HBsAg positive patients 25.0% were also positive for anti-HDV and 4/9 (44.4%) had detectable HDV RNA.
HBV and HDV were frequent co-infections among HIV positive patients in Guinea-Bissau and chronic infection was associated with severe immunosuppression. Lamivudine was widely used among HBsAg positive patients with the risk of developing resistant HBV.
PMCID: PMC4051771  PMID: 24915064
8.  Anti-inflammatory effect of a retrovirus-derived immunosuppressive peptide in mouse models 
BMC Immunology  2013;14:51.
Short dimeric or mulitmeric peptides derived from a highly conserved stretch of amino acids from gammaretroviral envelope proteins has been found to have immunosuppressive properties in vitro. Here we test the hypothesis that such immunosuppressive peptides may serve as immunomodulatory reagents for treatment of inflammatory disorders.
The anti-inflammatory effect of a synthetic retrovirus-derived immunosuppressive peptide of 17 amino acids was tested in two murine skin inflammation models, a TPA-induced acute toxic contact eczema model and an oxazolone-induced allergic contact dermatitis. Overall, mice (n = 24) treated with a topically applied cream containing the dimeric immunosuppressive peptide exhibited a reduction of 28.8% in ear thickness (range 20.1-42.5), whereas the application of a scrambled peptide dimer or a monomer of the immunosuppressive peptide remained without effect (p = 0.028). Furthermore, ear biopsies from mice treated with the dimeric immunosuppressive peptide showed a significant reduction in mRNA of the pro-inflammatory cytokines TNF-α, IL-17C, and IL-6 as well as the chemokine CXCL2 compared to mice treated with control peptides.
Using two murine skin inflammation models, we show that an immunosuppressive retroviral peptide is capable of reducing inflammatory disorders. The results indicate that virus-derived immunosuppressive peptides capable of down-regulating several proinflammatory cytokines may represent a novel class of drugs for the treatment of excess inflammation.
PMCID: PMC3840592  PMID: 24245569
9.  Loss to follow-up occurs at all stages in the diagnostic and follow-up period among HIV-infected patients in Guinea-Bissau: a 7-year retrospective cohort study 
BMJ Open  2013;3(10):e003499.
To describe loss to follow-up (LTFU) at all stages of the HIV programme.
A retrospective cohort study.
The HIV clinic at Hospital National Simão Mendes in Bissau, Guinea-Bissau.
A total of 4080 HIV-infected patients.
Outcome measures
Baseline characteristics, percentages and incidence rates of LTFU as well as LTFU risk factors at four different stages: immediately after HIV diagnosis (stage 1), after the first CD4 cell count and before a follow-up consultation (stage 2), after a follow-up consultation for patients not eligible for antiretroviral treatment (ART; stage 3) and LTFU among patients on ART (stage 4).
Almost one-third of the patients were lost to the programme before the first consultation where ART initiation is decided; during the 7-year observation period, more than half of the patients had been lost to follow-up (overall incidence rate=51.1 patients lost per 100 person-years). Age below 30 years at inclusion was a risk factor for LTFU at all stages of the HIV programme. The biggest risk factors were body mass index <18.5 kg/m2 (stage 1), male gender (stage 2), HIV-2 infection (stage 3) and CD4 cell count <200 cells/μL (stage 4).
In this study, LTFU constituted a major problem, and this may apply to other similar ART facilities. More than half of the patients were lost to follow-up shortly after enrolment, possibly implying a high mortality. Thus, retention should be given a high priority.
PMCID: PMC3808780  PMID: 24163204
10.  Cross sectional analysis of the association between mode of school transportation and physical fitness in children and adolescents 
To investigate the associations between body composition, cardiorespiratory and muscular fitness in relation to travel mode to school in children and adolescents.
Children and adolescents from 40 elementary schools and 23 high schools representing all regions in Norway were invited to participate in the study. Anthropometry, cardiorespiratory and muscular fitness were tested at the school location. Questionnaires were used in order to register mode of transport to school, age, gender and levels of leisure time physical activity.
A total of 1694 (i.e. 60% of all invited participants) children and adolescents at a mean age of 9.6 and 15.6 respectively (SD = 0.4 for both groups) were analyzed for associations with physical fitness variables. Males cycling to school had lower sum of skin folds than adolescents walking to school. Higher cardiorespiratory fitness in adolescents and male cyclists compared to walkers and passive commuters were observed. Among children, cycling and walking to school, higher isometric muscle endurance in the back extensors compared to passive commuters was observed.
Based on this national representative cross-sectional examination of randomly selected children and adolescents there is evidence that active commuting, especially cycling, is associated with a favourable body composition and better cardiorespiratory and muscular fitness as compared to passive commuting.
PMCID: PMC3724579  PMID: 23866826
Walking; Cycling; Commuting; Transport; Adiposity; BMI
11.  Risk of human papillomavirus-related cancers among kidney transplant recipients and patients receiving chronic dialysis - an observational cohort study 
BMC Nephrology  2013;14:137.
Individuals with end-stage renal disease (ESRD) have excess risk of various cancer types. However, the total burden of human papillomavirus-related cancers remains unknown.
We performed a nationwide observational cohort study during 1994–2010.
For each person with ESRD, we sampled 19 population controls (without ESRD) matched on age, gender and municipality. Participants were followed until first diagnosis of human papillomavirus-related cancer, death, emigration, or 31 December 2010, whichever came first.
Human papillomavirus-related cancers were extracted from Danish medical administrative databases. We considered cancers of the cervix, vulva, vagina, penis, anus, and subsets of head and neck cancers as human papillomavirus-related. We calculated incidence rates of human papillomavirus-related cancer and used Poisson regression to identify risk factors for human papillomavirus-related cancer.
Among 12,293 persons with ESRD and 229,524 population controls we identified 62 and 798 human papillomavirus-related cancers, respectively. Incidence rates of human papillomavirus-related- cancer were 102 per 100,000 person-years (95% confidence interval [CI]; 79.5-131) among persons with ESRD and 40.8 per 100,000 person-years (95% CI; 38.1-43.7) among population controls. ESRD patients had 4.54 (95% CI, 2.48-8.31) fold increased risk of anal cancer and 5.81 fold (95% CI; 3.36-10.1) increased risk of vulvovaginal cancer. Adjusted for age, comorbidity, and sex, ESRD patients had 2.41 (95% CI; 1.83-3.16) fold increased risk of any human papillomavirus-related cancer compared with population controls. Compared with dialysis patients renal transplant recipients had an age-adjusted non-significant 1.53 (95% CI, 0.91-2.58) fold higher risk of human papillomavirus-related cancer.
Persons with ESRD have excess risk of potentially vaccine-preventable human papillomavirus-related cancers.
PMCID: PMC3710213  PMID: 23834996
12.  Characteristics of HIV-2 and HIV-1/HIV-2 Dually Seropositive Adults in West Africa Presenting for Care and Antiretroviral Therapy: The IeDEA-West Africa HIV-2 Cohort Study 
Ekouevi, Didier K. | Balestre, Eric | Coffie, Patrick A. | Minta, Daouda | Messou, Eugene | Sawadogo, Adrien | Minga, Albert | Sow, Papa Salif | Bissagnene, Emmanuel | Eholie, Serge P. | Gottlieb, Geoffrey S. | Dabis, François | Zannou, Djimon Marcel | Ahouada, Carin | Akakpo, Jocelyn | Ahomadegbé, Christelle | Bashi, Jules | Gougounon-Houéto, Alice | Azon-Kouanou, Angèle | Houngbé, Fabien | Koumakpaï, Sikiratou | Alihonou, Florence | d’Almeida, Marcelline | Hodonou, Irvine | Hounhoui, Ghislaine | Sagbo, Gracien | Tossa-Bagnan, Leïla | Adjide, Herman | Drabo, Joseph | Bognounou, René | Dienderé, Arnaud | Traore, Eliezer | Zoungrana, Lassane | Zerbo, Béatrice | Sawadogo, Adrien Bruno | Zoungrana, Jacques | Héma, Arsène | Soré, Ibrahim | Bado, Guillaume | Tapsoba, Achille | Yé, Diarra | Kouéta, Fla | Ouedraogo, Sylvie | Ouédraogo, Rasmata | Hiembo, William | Gansonré, Mady | Messou, Eugène | Gnokoro, Joachim Charles | Koné, Mamadou | Kouakou, Guillaume Martial | Bosse, Clarisse Amani | Brou, Kouakou | Assi, Achi Isidore | Chenal, Henri | Hawerlander, Denise | Soppi, Franck | Minga, Albert | Abo, Yao | Bomisso, Germain | Eholié, Serge Paul | Amego, Mensah Deborah Noelly | Andavi, Viviane | Diallo, Zelica | Ello, Frédéric | Tanon, Aristophane Koffi | Koule, Serge Olivier | Anzan, Koffi Charles | Guehi, Calixte | Aka, Edmond Addi | Issouf, Koffi Ladji | Kouakou, Jean-Claude | N’Gbeche, Marie-Sylvie | Touré, Pety | Avit-Edi, Divine | Kouakou, Kouadio | Moh, Magloire | Yao, Valérie Andoblé | Folquet, Madeleine Amorissani | Dainguy, Marie-Evelyne | Kouakou, Cyrille | Méa-Assande, Véronique Tanoh | Oka-Berete, Gladys | Zobo, Nathalie | Acquah, Patrick | Kokora, Marie-Berthe | Eboua, Tanoh François | Timité-Konan, Marguerite | Ahoussou, Lucrèce Diecket | Assouan, Julie Kebé | Sami, Mabéa Flora | Kouadio, Clémence | Renner, Lorna | Goka, Bamenla | Welbeck, Jennifer | Sackey, Adziri | Owiafe, Seth Ntiri | Wejse, Christian | Silva, Zacarias José Da | Paulo, Joao | Rodrigues, Amabelia | da Silva, David | Medina, Candida | Oliviera-Souto, Ines | Østergaard, Lars | Laursen, Alex | Sodemann, Morten | Aaby, Peter | Fomsgaard, Anders | Erikstrup, Christian | Eugen-Olsen, Jesper | Maïga, Moussa Y | Diakité, Fatoumata Fofana | Kalle, Abdoulaye | Katile, Drissa | Traore, Hamar Alassane | Minta, Daouda | Cissé, Tidiani | Dembelé, Mamadou | Doumbia, Mohammed | Fomba, Mahamadou | Kaya, Assétou Soukho | Traoré, Abdoulaye M | Traoré, Hamady | Toure, Amadou Abathina | Dicko, Fatoumata | Sylla, Mariam | Berthé, Alima | Traoré, Hadizatou Coulibaly | Koïta, Anta | Koné, Niaboula | N'Diaye, Clémentine | Coulibaly, Safiatou Touré | Traoré, Mamadou | Traoré, Naïchata | Charurat, Man | Ajayi, Samuel | Dapiap, Stephen | Otu,  | Igbinoba, Festus | Benson, Okwara | Adebamowo, Clément | James, Jesse | Obaseki,  | Osakede, Philip | Olasode, John | Sow, Papa Salif | Diop, Bernard | Manga, Noël Magloire | Tine, Judicael Malick | Signate Sy, Haby | Ba, Abou | Diagne, Aida | Dior, Hélène | Faye, Malick | Gueye, Ramatoulaye Diagne | Mbaye, Aminata Diack | Patassi, Akessiwe | Kotosso, Awèrou | Kariyare, Benjamin Goilibe | Gbadamassi, Gafarou | Komi, Agbo | Mensah-Zukong, Kankoé Edem | Pakpame, Pinuwe | Lawson-Evi, Annette Koko | Atakouma, Yawo | Takassi, Elom | Djeha, Améyo | Ephoévi-gah, Ayoko | Djibril, Sherifa El-Hadj | Dabis, François | Bissagnene, Emmanuel | Arrivé, Elise | Coffie, Patrick | Ekouevi, Didier | Jaquet, Antoine | Leroy, Valériane | Lewden, Charlotte | Sasco, Annie | Azani, Jean-Claude | Allou, Gérard | Balestre, Eric | Bohossou, Franck | Karcher, Sophie | Gonsan, Jules Mahan | Carrou, Jérôme Le | Lenaud, Séverin | Nchot, Célestin | Malateste, Karen | Yao, Amon Roseamonde | Siloué, Bertine | Clouet, Gwenaelle | Djetouan, Hugues | Doring, Alexandra | Kouakou, Adrienne | Rabourdin, Elodie | Rivenc, Jean | Anglaret, Xavier | Ba, Boubacar | Essanin, Jean Bosco | Ciaranello, Andrea | Datté, Sébastien | Desmonde, Sophie | Diby, Jean-Serge Elvis | Gottlieb, Geoffrey S. | Horo, Apollinaire Gninlgninrin | Kangah, Serge N'zoré | Malvy, Denis | Meless, David | Mounkaila-Harouna, Aida | Ndondoki, Camille | Shiboski, Caroline | Thiébaut, Rodolphe | PAC-CI,  | Abidjan,
PLoS ONE  2013;8(6):e66135.
HIV-2 is endemic in West Africa. There is a lack of evidence-based guidelines on the diagnosis, management and antiretroviral therapy (ART) for HIV-2 or HIV-1/HIV-2 dual infections. Because of these issues, we designed a West African collaborative cohort for HIV-2 infection within the framework of the International epidemiological Databases to Evaluate AIDS (IeDEA).
We collected data on all HIV-2 and HIV-1/HIV-2 dually seropositive patients (both ARV-naive and starting ART) and followed-up in clinical centres in the IeDEA-WA network including a total of 13 clinics in five countries: Benin, Burkina-Faso Côte d’Ivoire, Mali, and Senegal, in the West Africa region.
Data was merged for 1,754 patients (56% female), including 1,021 HIV-2 infected patients (551 on ART) and 733 dually seropositive for both HIV-1 and HIV 2 (463 on ART). At ART initiation, the median age of HIV-2 patients was 45.3 years, IQR: (38.3–51.7) and 42.4 years, IQR (37.0–47.3) for dually seropositive patients (p = 0.048). Overall, 16.7% of HIV-2 patients on ART had an advanced clinical stage (WHO IV or CDC-C). The median CD4 count at the ART initiation is 166 cells/mm3, IQR (83–247) among HIV-2 infected patients and 146 cells/mm3, IQR (55–249) among dually seropositive patients. Overall, in ART-treated patients, the CD4 count increased 126 cells/mm3 after 24 months on ART for HIV-2 patients and 169 cells/mm3 for dually seropositive patients. Of 551 HIV-2 patients on ART, 5.8% died and 10.2% were lost to follow-up during the median time on ART of 2.4 years, IQR (0.7–4.3).
This large multi-country study of HIV-2 and HIV-1/HIV-2 dual infection in West Africa suggests that routine clinical care is less than optimal and that management and treatment of HIV-2 could be further informed by ongoing studies and randomized clinical trials in this population.
PMCID: PMC3688850  PMID: 23824279
13.  Longitudinal Analysis of CCR5 and CXCR4 Usage in a Cohort of Antiretroviral Therapy-Naïve Subjects with Progressive HIV-1 Subtype C Infection 
PLoS ONE  2013;8(6):e65950.
HIV-1 subtype C (C-HIV) is responsible for most HIV-1 cases worldwide. Although the pathogenesis of C-HIV is thought to predominantly involve CCR5-restricted (R5) strains, we do not have a firm understanding of how frequently CXCR4-using (X4 and R5X4) variants emerge in subjects with progressive C-HIV infection. Nor do we completely understand the molecular determinants of coreceptor switching by C-HIV variants. Here, we characterized a panel of HIV-1 envelope glycoproteins (Envs) (n = 300) cloned sequentially from plasma of 21 antiretroviral therapy (ART)-naïve subjects who experienced progression from chronic to advanced stages of C-HIV infection, and show that CXCR4-using C-HIV variants emerged in only one individual. Mutagenesis studies and structural models suggest that the evolution of R5 to X4 variants in this subject principally involved acquisition of an “Ile-Gly” insertion in the gp120 V3 loop and replacement of the V3 “Gly-Pro-Gly” crown with a “Gly-Arg-Gly” motif, but that the accumulation of additional gp120 “scaffold” mutations was required for these V3 loop changes to confer functional effects. In this context, either of the V3 loop changes could confer possible transitional R5X4 phenotypes, but when present together they completely abolished CCR5 usage and conferred the X4 phenotype. Our results show that the emergence of CXCR4-using strains is rare in this cohort of untreated individuals with advanced C-HIV infection. In the subject where X4 variants did emerge, alterations in the gp120 V3 loop were necessary but not sufficient to confer CXCR4 usage.
PMCID: PMC3688867  PMID: 23824043
14.  Eliminating the latent HIV reservoir by reactivation strategies 
Combination antiretroviral therapy (cART) has transformed HIV from a deadly to a chronic disease, but HIV patients are still burdened with excess morbidity and mortality, long-term toxicities from cART, stigmatization, and insufficient access to cART worldwide. Thus, a cure for HIV would have enormous impact on society as well as the individual. As the complexity and mechanisms of HIV persistence during therapy are being unraveled, new therapeutic targets for HIV eradication are discovered. Substances that activate HIV production in the latently infected cells have recently received much attention. By turning on expression of latent HIV proviruses, reactivation strategies could contribute to the eradication HIV infection. Compounds that are currently being or soon to be tested in clinical trials are emphasized. The results from these trials will provide important clues as to whether or not reactivating strategies could become significant components of a cure for HIV.
PMCID: PMC3903897  PMID: 23563519
HIV; immune modulation; histone deacetylase inhibitors; experimental research; cure
15.  Comparison of HDAC inhibitors in clinical development 
Objective: We aimed to compare the potential for inducing HIV production and the effect on T-cell activation of potent HDAC inhibitors undergoing clinical investigation.
Design: In vitro study
Methods: The latently infected cell lines ACH2 and U1 were treated with the HDAC inhibitors panobinostat, givinostat, belinostat, vorinostat and valproic acid. Viral induction was estimated by p24 production. Peripheral blood mononuclear cells from uninfected donors were treated with the HDAC inhibitors and the expression of activation markers on T-cell phenotypes was measured using flow cytometry. Finally, the ability of givinostat, belinostat and panobinostat to reactivate latent HIV-1 expression in primary T-cells was investigated employing a CCL19-induced latent primary CD4+ T cell infection model.
Results: The various HDAC inhibitors displayed significant potency differences in stimulating HIV-1 expression from the latently infected cell lines with panobinostat > givinostat ≈belinostat > vorinostat > valproic acid. Panobinostat was significantly more potent than all other HDAC inhibitors and induced virus production even in the very low concentration range 8–31 nM. The proportion of primary T-cells expressing the early activation marker CD69 increased moderately in all HDAC inhibitor-treated cells compared with untreated cells. Finally, proof was obtained that panobinostat, givinostat and belinostat induce virus production in latently infected primary cells at therapeutic concentrations with panobinostat being the most potent stimulator.
Conclusion: At therapeutic concentrations panobinostat stimulate HIV-1 expression in latently infected cells with greater potency than other HDAC inhibitors undergoing clinical investigation. These findings warrant further investigation and panobinostat is now being advanced into clinical testing against latent HIV infection.
PMCID: PMC3899169  PMID: 23370291
HIV; histone deacetylase inhibitors; HIV eradication; HIV cure
16.  Characterization of HIV-1 Infection and Innate Sensing in Different Types of Primary Human Monocyte-Derived Macrophages 
Mediators of Inflammation  2013;2013:208412.
Macrophages play an important role in human immunodeficiency virus (HIV) pathogenesis and contribute to establishment of a viral reservoir responsible for continuous virus production and virus transmission to T cells. In this study, we investigated the differences between various monocyte-derived macrophages (MDMs) generated through different differentiation protocols and evaluated different cellular, immunological, and virological properties. We found that elevated and persistent HIV-1 pWT/BaL replication could be obtained only in MDMs grown in RPMI containing macrophage colony-stimulating factor (M-CSF). Interestingly, this MDM type was also most responsive to toll-like receptor stimulation. By contrast, all MDM types were activated to a comparable extent by intracellular DNA, and the macrophage serum-free medium-(Mac-SFM-)differentiated MDMs responded strongly to membrane fusion through expression of CXCL10. Finally, we found that HIV infection of RPMI/M-CSF-differentiated MDMs induced low-grade expression of two interferon-stimulated genes in some donors. In conclusion, our study demonstrates that the differentiation protocol used greatly influences the ability of MDMs to activate innate immune reactions and support HIV-1 replication. Paradoxically, the data show that the MDMs with the strongest innate immune response were also the most permissive for HIV-1 replication.
PMCID: PMC3569920  PMID: 23431237
17.  Structure of laccase from Streptomyces coelicolor after soaking with potassium hexacyanoferrate and at an improved resolution of 2.3 Å 
The structure of the small laccase from S. coelicolor is reported at improved resolution and in a different space group. The soaked ligand is bound between laccase molecules.
The paper reports the structure of the small laccase from Streptomyces coelicolor determined from a crystal soaked with potassium hexacyanoferrate [K4Fe(CN)6]. The decolorization of the natively blue crystal observed upon soaking indicates the reduction of the enzyme in the crystal. The ligand binds between laccase molecules and stabilizes the crystal. The increased diffraction limit of the diffraction data collected from this crystal enabled the refinement of the small laccase structure at 2.3 Å resolution, which is the highest resolution obtained to date.
PMCID: PMC3079965  PMID: 21206017
laccases; ligand soaking; oxidoreductases; multicopper blue proteins
18.  Timing of Toll-Like Receptor 9 Agonist Administration in Pneumococcal Vaccination Impacts Both Humoral and Cellular Immune Responses as Well as Nasopharyngeal Colonization in Mice 
Infection and Immunity  2012;80(5):1744-1752.
Synthetic oligodeoxynucleotides (ODN) containing unmethylated CpG motifs, CpG ODN, are Toll-like receptor 9 agonists (TLR9a), which have been used as adjuvants in pneumococcal vaccines to improve antibody responses in immunodeficient patients. Here, we examined whether the coadministration of TLR9a with pneumococcal CRM197-conjugate vaccine enhances protection against pneumococcal colonization, the levels of antipolysaccharide antibodies, and the CD4+ T-cell responses. Wild-type BALB/c mice and B-cell-deficient BALB/c Igh-Jtm1Dhu mice were immunized twice with the following: (i) PCV alone; (ii) simultaneous PCV and TLR9a; (iii) PCV and then TLR9a, after a 48-h delay; (iv) TLR9a alone; and (v) phosphate-buffered saline. Nasopharyngeal protection, serum antibodies, CD4+ T-cell responses, and clearance of bacteremia after intraperitoneal challenge with Streptococcus pneumoniae 6B were evaluated. We found decreased nasopharyngeal protection against S. pneumoniae 6B colonization after simultaneous immunization with PCV and TLR9a compared to immunization with PCV alone in wild-type BALB/c mice (P = 0.037). A similar trend was observed in B-cell-deficient BALB/c Igh-Jtm1Dhu mice. Simultaneous administration did not enhance antibody levels and lowered the CRM197-specific cytokine release of gamma interferon, interleukin-2 (IL-2), IL-5 and IL-13. Immunization with PCV and then TLR9a, after a 48-h delay, significantly improved nasopharyngeal protection compared to simultaneous administration (P = 0.011). Furthermore, delaying TLR9a delivery increased antibody titers compared to both simultaneous administration (P = 0.001) and PCV immunization alone (P = 0.026). In conclusion, the immunological and clinical impact of adjuvanting a pneumococcal conjugate vaccine (Prevnar; Pfizer) with a TLR9a is highly depended on timing of the adjuvant administration. Thus, careful timing of adjuvant administration may improve novel vaccine formulations.
PMCID: PMC3347424  PMID: 22371375
19.  Bicycling to school improves the cardiometabolic risk factor profile: a randomised controlled trial 
BMJ Open  2012;2(6):e001307.
To investigate whether bicycling to school improves cardiometabolic risk factor profile and cardiorespiratory fitness among children.
Prospective, blinded, randomised controlled trial.
Single centre study in Odense, Denmark
43 children previously not bicycling to school were randomly allocated to control group (n=20) (ie, no change in lifestyle) or intervention group (ie, bicycling to school) (n=23).
Primary and secondary outcome measures
Change in cardiometabolic risk factor score and change in cardiorespiratory fitness.
All participants measured at baseline returned at follow-up. Based upon intention-to-treat (ITT) analyses, clustering of cardiometabolic risk factors was lowered by 0.58 SD (95% CI −1.03 to −0.14, p=0.012) in the bicycling group compared to the control group. Cardiorespiratory fitness (l O2/min) per se did not increase significantly more in the intervention than in the control group (β=0.0337, 95% CI −0.06 to 0.12, p=0.458).
Bicycling to school counteracted a clustering of cardiometabolic risk factors and should thus be recognised as potential prevention of type 2 diabetes mellitus and cardiovascular disease (CVD). The intervention did, however, not elicit a larger increase in cardiorespiratory fitness in the intervention group as compared with the control group.
Trial registration
Registered at (NCT01236222).
PMCID: PMC3533114  PMID: 23117560
cardiometabolic; risk factors; bicycling; children; commuting
20.  HSV-1-induced chemokine expression via IFI16-dependent and IFI16-independent pathways in human monocyte-derived macrophages 
Herpesviridae  2012;3:6.
Innate recognition is essential in the antiviral response against infection by herpes simplex virus (HSV). Chemokines are important for control of HSV via recruitment of natural killer cells, T lymphocytes, and antigen-presenting cells. We previously found that early HSV-1-mediated chemokine responses are not dependent on TLR2 and TLR9 in human macrophages. Here, we investigated the role of the recently identified innate IFN-inducible DNA receptor IFI16 during HSV-1 infection in human macrophages.
Peripheral blood mononuclear cells were purified from buffy coats and monocytes were differentiated to macrophages. Macrophages infected with HSV-1 were analyzed using siRNA-mediated knock-down of IFI16 by real-time PCR, ELISA, and Western blotting.
We determined that both CXCL10 and CCL3 are induced independent of HSV-1 replication. IFI16 mediates CCL3 mRNA accumulation during early HSV-1 infection. In contrast, CXCL10 was induced independently of IFI16.
Our data provide the first evidence of HSV-1-induced innate immune responses via IFI16 in human primary macrophages. In addition, the data suggest that at least one additional unidentified receptor or innate sensing mechanism is involved in recognizing HSV-1 prior to viral replication.
PMCID: PMC3523049  PMID: 23062757
Herpes simplex virus; Innate; IFI16; Chemokine; PRR; DNA; Macrophages; Human
21.  TLR9-adjuvanted pneumococcal conjugate vaccine induces antibody-independent memory responses in HIV-infected adults 
Human Vaccines & Immunotherapeutics  2012;8(8):1042-1047.
HIV-patients have excess of pneumococcal infection. We immunized 40 HIV-patients twice with pneumococcal conjugate vaccine (Prevnar, Pfizer) +/− a TLR9 agonist (CPG 7909). Peripheral blood mononuclear cells were stimulated with pneumococcal polysaccharides and cytokine concentrations measured. The CPG 7909 adjuvant group had significantly higher relative cytokine responses than the placebo group for IL-1β, IL-2R, IL-6, IFN-γ and MIP-β, which, did not correlate with IgG antibody responses. These findings suggests that CPG 7909 as adjuvant to pneumococcal conjugate vaccine induces cellular memory to pneumococcal polysaccharides in HIV-patients, independently of the humoral response.
PMCID: PMC3551874  PMID: 22854665
pneumococcal vaccine; cellular memory; CpG-ODN; adjuvants; HIV; TLR9
22.  The Impact of B-Cell Perturbations on Pneumococcal Conjugate Vaccine Response in HIV-Infected Adults 
PLoS ONE  2012;7(7):e42307.
Untreated HIV infection results in severe perturbations of the B-cell population and hyporesponsiveness to vaccination. We studied associations between circulating B-cell subsets and antibody response to pneumococcal conjugate vaccine in treated and untreated HIV patients.
Ninety-five HIV-infected adults were grouped according to antiretroviral therapy (ART) and CD4+ cell count as follows: 20 ART-naïve (no prior ART), 62 ART-responders (received ART, and CD4 count >500 cells/µl), and 13 impaired responders (received ART for more than 3 years, and CD4 count <500 cells/µl). All subjects were immunized twice with double-dose 7-valent pneumococcal conjugate vaccine with or without 1 mg CPG 7909 (toll-like receptor 9 agonist) at baseline and after three months. Pre-vaccination B-cell subpopulations were assessed by flow cytometry. Serum IgG concentrations for vaccine serotypes were quantified by ELISA at baseline and 3, 4, and 9 months post-vaccination. ART responders had more isotype-switched memory B cells and more marginal-zone (MZ)-like B cells compared with impaired responders. Furthermore, ART-naïve patients had higher concentration of transitional B cells and plasmablasts compared with B cells of other patient groups. The concentration of MZ-like, isotype switched memory cells and plasmablasts correlated positively with post-vaccination IgG concentration at 3, 4, and 9 months. Low concentrations of isotype-switched memory B cells was the strongest independent predictor of poor pneumococcal conjugate vaccine responsiveness, emphasizing that B-cell subset disturbances are associated with poor vaccine response among HIV-infected patients
PMCID: PMC3408459  PMID: 22860110
23.  Comparison of Bone and Renal Effects In HIV-infected Adults Switching to Abacavir or Tenofovir Based Therapy in a Randomized Trial 
PLoS ONE  2012;7(3):e32445.
Our objective was to compare the bone and renal effects among HIV-infected patients randomized to abacavir or tenofovir-based combination anti-retroviral therapy.
In an open-label randomized trial, HIV-infected patients were randomized to switch from zidovudine/lamivudine (AZT/3TC) to abacavir/lamivudine (ABC/3TC) or tenofovir/emtricitabine (TDF/FTC). We measured bone mass density (BMD) and bone turnover biomarkers (osteocalcin, osteocalcin, procollagen type 1 N-terminal propeptide (P1NP), alkaline phosphatase, type I collagen cross-linked C-telopeptide (CTx), and osteoprotegerin). We assessed renal function by estimated creatinine clearance, plasma cystatin C, and urinary levels of creatinine, albumin, cystatin C, and neutrophil gelatinase-associated lipocalin (NGAL). The changes from baseline in BMD and renal and bone biomarkers were compared across study arms.
Of 40 included patients, 35 completed 48 weeks of randomized therapy and follow up. BMD was measured in 33, 26, and 27 patients at baseline, week 24, and week 48, respectively. In TDF/FTC-treated patients we observed significant reductions from baseline in hip and lumbar spine BMD at week 24 (−1.8% and −2.5%) and week 48 (−2.1% and −2.1%), whereas BMD was stable in patients in the ABC/3TC arm. The changes from baseline in BMD were significantly different between study arms. All bone turnover biomarkers except osteoprotegerin increased in the TDF/FTC arm compared with the ABC/3TC arm, but early changes did not predict subsequent loss of BMD. Renal function parameters were similar between study arms although a small increase in NGAL was detected among TDF-treated patients.
Switching to TDF/FTC-based therapy led to decreases in BMD and increases in bone turnover markers compared with ABC/3TC-based treatment. No major difference in renal function was observed.
Trial registration NCT00647244
PMCID: PMC3315554  PMID: 22479327
24.  Morbidity and Risk of Subsequent Diagnosis of HIV: A Population Based Case Control Study Identifying Indicator Diseases for HIV Infection 
PLoS ONE  2012;7(3):e32538.
Early identification of persons with undiagnosed HIV infection is an important health care issue. We examined associations between diseases diagnosed in hospitals and risk of subsequent HIV diagnosis.
In this population-based case control study, cases were persons with incident HIV infection diagnosed in Denmark between 1 January 1995 and 1 June 2008. Risk-set sampling was used to identify 19 age- and gender-matched population controls for each HIV case, using the HIV diagnosis date as the index date for both cases and controls. Prior hospital diagnoses obtained from Danish medical databases were first categorized into 22 major disease categories (excluding AIDS-defining diseases except tuberculosis) and then subdivided into 161 subcategories, allowing us to examine specific diseases as potential HIV indicators by conditional logistic regression.
The study included 2,036 HIV cases and 35,718 controls. Persons with the following disease categories had a high risk of HIV diagnosis during the subsequent 5-year period: sexually transmitted infections and viral hepatitis (adjusted odds ratio [aOR] = 12.3, 95% CI: 9.60–15.7), hematological diseases (aOR = 4.28, 3.13–5.85), lower respiratory tract infections (aOR = 3.98, 3.14–5.04)), CNS infections (aOR = 3.44, 1.74–6.80), skin infections (aOR = 3.05, 2.47–3.75), other infections (aOR = 4.64, 3.89–5.54), and substance abuse (aOR = 2.60, 2.06–3.29). Several specific diseases were associated with aORs >20 including syphilis, hepatitis A, non “A” viral hepatitis, herpes zoster, candida infection, endocarditis, thrombocytopenia, and opioid abuse.
Targeted testing for HIV in patients diagnosed with diseases associated with HIV may lead to earlier treatment and thereby reduced morbidity, mortality and HIV transmission.
PMCID: PMC3293814  PMID: 22403672
25.  MCP1 SNPs and Pulmonary Tuberculosis in Cohorts from West Africa, the USA and Argentina: Lack of Association or Epistasis with IL12B Polymorphisms 
PLoS ONE  2012;7(2):e32275.
The monocyte chemotactic protein-1 (MCP-1) is a chemokine that plays an important role in the recruitment of monocytes to M. tuberculosis infection sites, and previous studies have reported that genetic variants in MCP1 are associated with differential susceptibility to pulmonary tuberculosis (PTB). We examined eight MCP1 single nucleotide polymorphisms (SNPs) in a multi-ethnic, case-control design that included: 321 cases and 346 controls from Guinea-Bissau, 258 cases and 271 controls from The Gambia, 295 cases and 179 controls from the U.S. (African-Americans), and an additional set of 237 cases and 144 controls of European ancestry from the U.S. and Argentina. Two locus interactions were also examined for polymorphisms in MCP1 and interleukin 12B (IL12B), another gene implicated in PTB risk. Examination of previously associated MCP1 SNPs rs1024611 (−2581A/G), rs2857656 (−362G/C) and rs4586 (+900C/T) did not show evidence for association. One interaction between rs2857656 and IL12B SNP rs2288831 was observed among Africans but the effect was in the opposite direction in Guineans (OR = 1.90, p = 0.001) and Gambians (OR = 0.64, p = 0.024). Our data indicate that the effect of genetic variation within MCP1 is not clear cut and additional studies will be needed to elucidate its role in TB susceptibility.
PMCID: PMC3288089  PMID: 22384203

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