Human Immunodeficiency Virus (HIV) is the causative agent of AIDS, a disease which affects over 24 million people globally and for which there is neither curative treatment nor vaccine available. As an intracellular pathogen that encodes only 15 proteins HIV-1 is highly dependent upon its host's cellular machinery in order to complete its life cycle. Host-directed therapy thus represents a potentially lucrative strategy for the development of novel anti-HIV therapies. microRNAs (miRNAs) are short noncoding RNA molecules that function as part of the endogenous RNA interference system which governs post transcriptional gene regulation. Current knowledge has placed miRNAs at the crux of HIV-host interactions, yet the functional relevance of the majority of the human miRNAome with regards to HIV replication has remained unknown. A microscopy-based high content screening (HCS) approach was thus developed to systematically evaluate the significance of augmenting or inhibiting the function of individual host miRNAs on the replication dynamics of HIV. A bespoke image analysis and data mining pipeline recovered 56 host miRNAs associated with suppressed HIV replication and 28 host miRNAs associated with enhanced HIV replication. Notably, the HIV-modulating potential of 80 of these miRNAs was previously unknown. Furthermore, HCS also uncovered a novel role for the miR-200 family in the modulation of HIV replication. In silico miRNA target identification and pathway enrichment analysis identified 24 pathways associated exclusively with suppressed HIV replication, 10 pathways associated exclusively with enhanced HIV replication and 38 functional pathways enriched for both enhanced and suppressed viral replication. These included a number of pathways previously implicated in HIV replication such as the PI3K, MAPK, TNF and WNT signalling pathways but also revealed novel functional associations including that of the Hippo signalling pathway. Intriguingly pathway analysis revealed an enrichment for host factors associated with viral carcinogenesis and a convergence on host processes and functional targets classically associated with chemotherapy including host DNA damage repair, cell cycle and tyrosine kinase receptor-mediated signalling. Experimental validation confirmed that HIV replication induced an aberrant cell survival phenotype in response to chemically induced DNA damage but this effect was reversed when DNA damage was induced prior to HIV exposure. A series of compound-based validation screens were thus undertaken in order to verify the functional associations recovered by miRNA screening. A targeted collection of 293 small molecule inhibitors, including a number of FDA-approved chemotherapeutics, were screened for HIV modulating activity. Novel anti-HIV activity was recovered for over 40 compounds including a number of FDA-approved therapies. Compound-target enrichment analysis revealed a strong concordance with functional associations initially described by miRNA-based HCS including EGFR-mediated signalling and DNA damage repair. Concordant HIV-suppressive activity was also recovered for miRNAs and compounds with common functional targets. The outcomes of this study thus represent a significant and novel contribution to current knowledge on HIV-host interactions. Furthermore, these findings have characterised novel miRNA and small molecule candidates for the treatment of HIV and have successfully demonstrated the utility of miRNA-based HCS for novel-drug discovery and drug repositioning.

In 2008, 1.8 million children under the age of 15 were living with HIV/AIDS in sub-Saharan Africa. The same report estimates that in 2008, there were 390 000 new infections in children below the age of 15 in Sub- Saharan Africa. Children appear to be the generation most affected by the HIV/AIDS epidemic. With the introduction of Highly Active Antiretroviral therapy (HAART) more perinatally infected children are living into adolescence and beyond. They will have to learn to live with a stigmatising, potentially fatal chronic illness. Health care workers can no longer rely solely on traditionally used outcome measures, such as viral loads and CD4+ percentages, to monitor effectiveness of interventions and treatments. Quality of Life (QoL) has been suggested as an additional essential outcome measure in clinical practice and research involving children living with a chronic illness. In this research the concept of Health Related Quality of Life (HRQoL) is evaluated in HIV-infected children using the PedsQL 4.0 Generic Core Scale (child self-reports, ages five-seven). The PedsQL 4.0 Generic Core Scales has been found to be a valid and reliable HRQoL measurement tool in children with chronic diseases, school-going children and children infected with HIV. Domains of Physical, Emotional, Social and School Functioning were evaluated. The children in the comparison group scored significantly higher (p<0.01) indicating a better quality of life. The HIV-infected children scored significantly lower in all four domains, with Physical Functioning being most affected (p<0.01). The children with HIV were found to be shorter (p<0.01) and lighter (p<0.01) than those in the comparison group. This could be a contributing factor to the physical difficulties experienced by the HIV-infected children. No relationship could be established between total scores of HRQoL and CD4+ percentages, viral load and duration of HAART treatment. Demographic data collected indicate that the HIV-infected children were more likely to have a primary caregiver with a lower level of education (p=0.01) and more likely to be receiving a Dependency Care Grant (p=0.05). The HRQoL results of this study are similar to those conducted in other parts of the world. The results stress the need for a multi-disciplinary approach when treating HIV-infected children. It has become essential to focus on the medical, physical and psychosocial functioning of the HIV-infected child thereby promoting participation in the family, school and the broader community.

Mother-to-child transmission (MTCT) of HIV accounts for more than 90% of pediatric infections worldwide, yet the mechanism of vertical transfer remains unknown. The feline immunodeficiency virus (FIV)-infected cat is a cost-effective, small-animal model of HIV pathogenesis and MTCT, which produces a high rate of reproductive failure and fetal infection in litters delivered at early- and late-term gestation. Our previous data suggest that FIV infection may dysregulate placental cytokines and compromise pregnancy. We hypothesized that FIV-infection may cause dysregulation of placental cytokine expression, and aberrant expression of these cytokines may potentiate inflammation and transplacental infections. The purpose of this project was to evaluate feline placental immunopathology at the whole and cellular levels during early- and late-term gestation to understand how lentiviruses may perturb placental immune parameters. To determine whether placentas were vulnerable to FIV infection, we quantified the expression of the FIV receptors, CD134 and CXCR4, in RNA extracted from late-term placental tissue. We found higher expression of CD134 and CXCR4 in placentas from successful pregnancies. To evaluate relative cytokine expression in randomly-sampled, whole placental specimens, we quantified representative pro- and anti-inflammatory cytokines and a chemokine. IL-6 and IL-12p35 were increased in early-gestation, FIV-infected queens; IL-6 was increased in late-gestation, FIV-infected queens. To evaluate placental immunopathology at the cellular level, we developed a novel immunohistochemistry method to identify trophoblastic cells selectively. Trophoblasts were collected using laser capture microdissection, and RNA was extracted from captured cells. We detected expression of several anti- and pro-inflammatory cytokines and the chemokine receptor CXCR4 (the FIV co-receptor) in trophoblasts at both stages of gestation. However, we failed to detect expression of other cytokines and CD134, the FIV primary receptor. FIV infection slightly lowered expression of all cytokines at both early and late pregnancy, although only the decrease in IL-5, from early pregnancy, and IL-4 and IL-12p35, from late pregnancy, reached significant levels. Fetal non-viability was associated with decreased trophoblast expression of IL-4, IL-6, IL-12p35, and CXCR4 at early gestation and decreased expression of IL-4, IL-12p35, IL-12p40 at late gestation. Collectively, these data indicate that FIV infection negatively impacts pregnancy outcome and alters placental immunomodulation.

We are using the feline immunodeficiency virus (FIV)-infected cat to model HIV mother-to-child-transmission (MTCT). Vertical transmission of either virus may result not only in infected offspring, but also failed pregnancy.In HIV infections, maternal hematological and virological parameters predict MTCT.We hypothesized that such parameters would likewise be predictors of FIV vertical transfer. We inoculated ten cats with FIV-B-2542; 10 cats were uninoculated. Cats were allowed to breed naturally. Fetuses were delivered at approximately week 3 (early) gestation by cesarean section. Fetal and placental tissues were collected.Blood samples were collected from the day of inoculation through delivery. We quantified CD4:CD8 T cell ratios, proviral load, and plasma viremia, and monitored seroreactivity to FIV proteins in longitudinal sera from both groups of cats. We documented clinical and reproductive outcome. The infected group produced reduced litter size and more failed pregnancies; CD4:CD8 ratios were depressed by 3.5 months p.i.Proviral DNA was detected in 14 of 14 (100%) placentas tested and 12 of 14 (86%) fetuses. However, the parameters assessed were not predictive of reproductive outcome and suggested a role for placental immunopathology in compromised pregnancy.Regulatory T cells (Treg) are anti-inflammatory and essential in maintaining pregnancy.Th17 cells are pro-inflammatory and associated with pregnancy failure. The activation of these cell populations is regulated by the cytokines TGF-? and IL-6. We hypothesized that placental immunology may result from altered dynamics of these cell populations.Using immunofluorescence confocal microscopy to measure Treg and Th17 markers FoxP3 and ROR ? , respectively, we quantified these cells in placental specimens from FIV-infected and control cats at early and late (week 8) gestation.Significantly higher levels of ROR ? were measured in FIV-infected placentas at early pregnancy; these cells co-localized at the maternaletal interface. We quantified the expression of Treg immunomodulators by quantitative PCR, noting higher expression of TGF-? in infected queens.A positive correlation of ROR ? with IL-6 occurred in control placentas, as predicted, but not in infected placentas.Collectively, the data suggest that an inflammatory placental microenvironment at early pregnancy in infected queens may result, in part, from dysregulation of the Treg/Th17 balance.

Through humoral and cell-mediated mechanisms, the immune system plays a vital role in protecting every organ system. Disorders of the immune system may result in various cutaneous manifestations, including cutaneous malignancies. In patients with immunodeficiency, the risk of development of malignant cutaneous neoplasms is substantially increased. This increased risk may be due to oncogenic viruses that find a suitable microenvironment for tumorigenesis and cancer development. A subset of cutaneous malignancies that develop in patients with immunodeficiency may show aggressive clinical and biological behavior. Here, we report six cases of highly aggressive and deadly cutaneous neoplasms that arose in patients with a known history of immunodeficiency: two cases of Kaposi sarcoma in patients with immunosuppression due to human immunodeficiency virus infection; a case of Merkel cell carcinoma and a case of squamous cell carcinoma (SCC) in patients receiving immunosuppressive drugs after organ transplant; a case of multiple cutaneous tumors, including invasive melanoma, SCC, and sebaceous carcinoma, in a patient with hypogammaglobulinemia and a history of organ transplant; and a case of basal cell carcinoma and melanoma in situ in a patient with primary immunodeficiency.

Two studies were conducted on endurance horses predominantly of Arabian breeding participating in an 80 km ride dedicated to research in April 2001 (Trial 1) and April 2002 (Trial 2). Objectives were to determine effects of endurance exercise, antioxidant supplementation, and a feed rich in fiber and fat vs. a high fat sweet feed on immunoglobulin A and G concentrations as well as identify selective IgA deficiency in endurance horses of Arabian breeding. There were no effects of distance in Trial 1 on IgA (P = 0.73) or IgG (P = 0.18) concentrations. In Trial 2, IgA concentrations increased (P = 0.05) and IgG concentrations increased (P = 0.006) after the start of the race. There were no effects of antioxidant supplementation on IgA (P = 0.16), IgG (P = 0.16), and IgM (P = 0.70) concentrations. There were no diet effects on IgA (P = 0.80), IgG (P = 0.59), and IgM (P = 0.54) concentrations. There were horses in both trials that were deficient in IgA only. Concentrations of IgG and IgM were within normal ranges, and there were no differences in training, performance and transportation variables, IgG concentrations, antioxidant supplementation, and feed supplementation compared to the horses with normal IgA concentrations. The concentration of IgM was higher in IgA deficient horses in Trial 1 (P = 0.035) and Trial 2 (P = 0.017). Horses with deficient IgA tended to be associated with health problems commonly found in humans and dogs affected with selective IgA deficiency. / Master of Science

Purpose of the study - Identify predictors of mortality and develop a related care plan for patients who are on antiretroviral therapy (ART) in Gondar, Ethiopia. Design - A quantitative, retrospective cohort study was conducted analysing medical records of HIV patients who presented to Gondar University Hospital (GUH), Gondar, and started ART between 1 January 2007 and 30 June 2010. Results - In defining the predictors of mortality, the findings in bivariate analysis revealed: female sex, CD4 cell count ≤ 50/μl, CD4 cell count 51-199/μl, a haemoglobin concentration ≤8g/dl, a history of oral candidiasis, tuberculosis and Cryptococcus meningitis were all statistically significant. A female sex, CD4 cell count ≤ 50/μl and CD4 cell count 51-199/μl maintain their significance level in the multivariate analysis. Conclusions - The study therefore recommends that clinicians and case managers be vigilant of these predictors of mortality while managing HIV patients who are on ART. Key Concepts- ART, AIDS, HIV, predictors of mortality / Health Studies / (M.A. (Public Health))

No description available.

Background: Whether the non-inferior efficacy and safety results of switching virologically suppressed HIV-1-infected patients from nevirapine immediate-release (NVP-IR) to NVP extended-release (NVP-XR) demonstrated in the TRANxITION study conducted in Europe and North America are also applicable to virologically suppressed HIV-infected Taiwanese patients remains unknown. We evaluated the comparative safety and efficacy of continuing NVP-IR versus switching to NVP-XR in virologically suppressed HIV-infected Taiwanese adults receiving combined antiretroviral therapy (cART) regimens. Methods: We conducted a retrospective cohort study at Kaohsiung Veterans General Hospital from April 1, 2013, to March 31, 2015. Eighty-four virologically suppressed HIV-infected adults receiving NVP-IRcART were split into two groups: those continuing with NVP-IR (n = 49) and those being switched to NVP-XR (n = 35). Demographic characteristics, clinical variables, and laboratory findings were compared. Therapeutic drug monitoring of steady-state plasma NVP concentrations and genotype analysis of CYP2B6 516 were also performed in 22 participants. The primary endpoint was continued virological suppression at the end of the study. Secondary endpoints were time to loss of virological response and adverse events. Results: During a mean follow-up of 18.4 months, the NVP-XR group demonstrated similar success at maintaining virological response compared with the NVP-IR group (82.9% vs. 85.7%; P = 0.72). Cox regression analysis indicated that there were no significant differences between NVP regimens for time to loss of virological response (hazard ratio: 0.940; P = 0.754). Furthermore, there were no significant differences in adverse events between these two groups. In the 22 participants, there was a non-significantly lower level of steady-state plasma NVP concentrations in the NVP-XR group than in NVP-IR recipients (5145.0 ng/mL vs. 6775.0 ng/mL; P = 0.267). The prevalence of CYP2B6 516 GT was 86.6%, and there was no significant difference in the distribution of CYP2B6 516 between these two groups. Conclusions: We found that switching from NVP-IR to NVP-XR appeared to have similar safety and efficacy compared with continuing NVP-IR among virologically suppressed, HIV-infected Taiwanese patients. Our finding of higher C-trough levels in both groups compared with other studies conducted in Caucasian populations and the high prevalence of CYP2B6 516 GT requires further investigation in a larger Taiwanese cohort.

The aim o f the study w as to determ ine the know ledge and concerns about HIV/AIDS among childbearing w om en in M ahalapye, Botswana. A descriptive study design using an inri-view schedule was used. The sam ple o f 166 respondents (aged 18-29 years) w as draw n from a population o f w om en w ho attended M ahalapye clinics. D ata w ere analysed by use o f a com puter and descriptive statistics including frequencies and percentages. The dem ographic data showed that the m ajority (85.5%) o f the respondents w ere not m arried, o f w hom 78% had partners and 9% w ere cohabiting. Seventy percent had secondary education and 70.4% w ere unem ployed, hence their dependence on their partners and relatives for econom ic support. The results show ed that the respondents had a high level o f know ledge about HIV/AIDS including risk factors, m ode o f transm ission and prevention. A ll respondents (100%) seem to be aware that a person can contract H IV through having m ultiple sexual partners. The m ajority (98%) stated that H IV can be transm itted sexually and 97% said that infected pregnant w om en can transm it H IV to their babies. N inety seven percent o f w om en said that the spread o f H IV can be prevented by \ h g condom s, 21.1 % said by having sex less frequently and 98.8% said people can protect them selves from contracting H IV by through sharing utensils and food w ith an infected person, 38% believed that mosquitoes and insects can transm it H IV and 41.6% did not believe that a person infected with HIV m ight look healthy. Thirty six (21.7% ) w om en perceived them selves not to be at risk o f H IV ow ing to current m onogam ous relationships and their trust in their partners. Radio and health personnel w ere m entioned as the m ain sources o f inform ation about HIV/AIDS. All (100% ) respondents revealed that they w ere afraid o f becom ing infected w ith the virus and 98.2% said that they w ere concerned that m en do not like using condom s. Even though 93.4% said that they w ere free to discuss sexual activities w ith their partners, 83.7% said that they w ould not find it easy to reveal their H IV status to their partner for fear o f rejection and stigm atisation. The results show ed that know ledge was related to education level. A ll w om en w ho had post secondary education indicated that AIDS cannot be cured by consulting traditional doctors ( 9 -0 0v'7) and W estern doctors (p=0.046) as com pared w ith those w ho did /iOf hav-'-post secondary education. A ge and m arital status seem not to be related to know ledge (p>0.05). Educational program m es targeted at these w om en should address the m isconceptions about the m ode o f transm ission. W om en should be equipped w ith effective com m unication and decision m aking skills that w ill em power them to adopt behaviours that will protect them from becom ing infected or infecting others. Further research is needed to determ ine the extent to w hich concerns expressed by w om en in this study are expressed by other groups o f women.