Infectious Diseases - Research Publications
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ItemPI3K Activation in Neural Stem Cells Drives Tumorigenesis which can be Ameliorated by Targeting the cAMP Response Element Binding (CREB) Protein(Oxford University Press, 2018-10)BACKGROUND: Hyperactivation of phosphoinositide 3-kinase (PI3K) signaling is common in cancers, but the precise role of the pathway in glioma biology remains to be determined. Some understanding of PI3K signaling mechanisms in brain cancer comes from studies on neural stem/progenitor cells (NSPCs), where signals transmitted via the PI3K pathway cooperate with other intracellular pathways and downstream transcription factors to regulate critical cell functions. METHODS: To investigate the role of the PI3K pathway in glioma initiation and development, we generated a mouse model targeting the inducible expression of a PIK3CAH1047A oncogenic mutant and deletion of the PI3K negative regulator, phosphatase and tensin homolog (PTEN), to NSPCs. RESULTS: Expression of a Pik3caH1047A was sufficient to generate tumors with oligodendroglial features, but simultaneous loss of PTEN was required for the development of invasive, high-grade glioma. Pik3caH1047A-PTEN mutant NSPCs exhibited enhanced neurosphere formation which correlated with increased Wnt signaling, while loss of cAMP response element binding protein (CREB) in Pik3caH1047A-Pten mutant tumors led to longer symptom-free survival in mice. CONCLUSION: Taken together, our findings present a novel mouse model for glioma demonstrating that the PI3K pathway is important for initiation of tumorigenesis and that disruption of downstream CREB signaling attenuates tumor expansion.
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ItemSexually Transmitted Infections Among Young Men Who Have Sex with Men: Experiences with Diagnosis, Treatment, and Reinfection(SPRINGER, 2018-06)Despite high rates of sexually transmitted infections (STIs) among young men who have sex with men (YMSM), little is known about their experiences with diagnosis, treatment, and reinfection. To fill this gap, we interviewed 17 YMSM ages 18-29 who participated in an online HIV prevention trial and tested positive for STIs at both the baseline and three-month follow-up assessments. Participants were asked about their reactions to testing positive, experiences with treatment, disclosure to partners, and changes in thinking and behavior. Reactions were diverse, the most common being surprise and concern. Most participants sought treatment, although type of provider varied (e.g., primary care physician, clinic that specialized in gay/bisexual men's health). Providers tended to re-test participants, but some did so at the incorrect anatomical site. Participants who felt comfortable talking to providers about STIs tended to use their regular provider or one who specialized in gay/bisexual men's health. Most participants described changes in their thinking and behavior (e.g., increased condom use, decreased sex partners, questioning their partners' trust). Most participants disclosed to at least one partner, but some did not remember or were not in contact with partners. Experiences were similar the first and second time participants tested positive for STIs during the study with a few exceptions (e.g., more self-blame and comfort talking to providers the second time). In sum, YMSM have diverse experiences with STI diagnosis and treatment. Implications for public policy and STI prevention are discussed.
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ItemEpigenetic modulation of inflammation and synaptic plasticity promotes resilience against stress in mice.(Springer Science and Business Media LLC, 2018-02-02)Major depressive disorder is associated with abnormalities in the brain and the immune system. Chronic stress in animals showed that epigenetic and inflammatory mechanisms play important roles in mediating resilience and susceptibility to depression. Here, through a high-throughput screening, we identify two phytochemicals, dihydrocaffeic acid (DHCA) and malvidin-3'-O-glucoside (Mal-gluc) that are effective in promoting resilience against stress by modulating brain synaptic plasticity and peripheral inflammation. DHCA/Mal-gluc also significantly reduces depression-like phenotypes in a mouse model of increased systemic inflammation induced by transplantation of hematopoietic progenitor cells from stress-susceptible mice. DHCA reduces pro-inflammatory interleukin 6 (IL-6) generations by inhibiting DNA methylation at the CpG-rich IL-6 sequences introns 1 and 3, while Mal-gluc modulates synaptic plasticity by increasing histone acetylation of the regulatory sequences of the Rac1 gene. Peripheral inflammation and synaptic maladaptation are in line with newly hypothesized clinical intervention targets for depression that are not addressed by currently available antidepressants.
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ItemEvolutionary study and phylodynamic pattern of human influenza A/H3N2 virus in Indonesia from 2008 to 2010.(Public Library of Science (PLoS), 2018)Influenza viruses are by nature unstable with high levels of mutations. The sequential accumulation of mutations in the surface glycoproteins allows the virus to evade the neutralizing antibodies. The consideration of the tropics as the influenza reservoir where viral genetic and antigenic diversity are continually generated and reintroduced into temperate countries makes the study of influenza virus evolution in Indonesia essential. A total of 100 complete coding sequences (CDS) of Hemagglutinin (HA) and Neuraminidase (NA) genes of H3N2 virus were obtained from archived samples of Influenza-Like Illness (ILI) surveillance collected from 2008 to 2010. Our evolutionary and phylogenetic analyses provide insight into the dynamic changes of Indonesian H3N2 virus from 2008 to 2010. Obvious antigenic drift with typical 'ladder-like' phylogeny was observed with multiple lineages found in each year, suggesting co-circulation of H3N2 strains at different time periods. The mutational pattern of the Indonesian H3N2 virus was not geographically related as relatively low levels of mutations with similar pattern of relative genetic diversity were observed in various geographical origins. This study reaffirms that the existence of a particular lineage is most likely the result of adaptation or competitive exclusion among different host populations and combination of stochastic ecological factors, rather than its geographical origin alone.
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ItemUndiagnosed HIV infections among gay and bisexual men increasingly contribute to new infections in Australia.(Wiley, 2018-04)INTRODUCTION: We determined the contribution of undiagnosed HIV to new infections among gay and bisexual men (GBM) over a 12-year period in Australia where there has been increasing focus on improving testing and HIV treatment coverage. METHODS: We generated annual estimates for each step of the HIV cascade and the number of new HIV infections for GBM in Australia over 2004 to 2015 using relevant national data. Using Bayesian melding we then fitted a quantitative model to the cascade and incidence estimates to infer relative transmission coefficients associated with being undiagnosed, diagnosed and not on ART, on ART with unsuppressed virus, or on ART with suppressed virus. RESULTS: Between 2004 and 2015, we estimated the percentage of GBM with HIV in Australia who were unaware of their status to have decreased from 14.5% to 7.5%. During the same period, there was a substantial increase in the number and proportion of GBM living with HIV on treatment and with suppressed virus, with the number of virally suppressed GBM increasing from around 3900 (30.2% of all GBM living with HIV) in 2004 to around 14,000 (73.7% of all GBM living with HIV) in 2015. Despite the increase in viral suppression, the annual number of new infections rose from around 660 to around 760 over this period. Our results have a wide range due to the uncertainty in the cascade estimates and transmission coefficients. Nevertheless, undiagnosed GBM increasingly appear to contribute to new infections. The proportion of new infections attributable to undiagnosed GBM almost doubled from 33% in 2004 to 59% in 2015. Only a small proportion (<7%) originated from GBM with suppressed virus. DISCUSSION: Our study suggests that an increase in HIV treatment coverage in Australia has reduced the overall risk of HIV transmission from people living with HIV. However, the proportion of infections and the rate of transmission from undiagnosed GBM has increased substantially. These findings highlight the importance of HIV testing and intensified prevention for Australian GBM at high risk of HIV.
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ItemSex-based differences in antiretroviral therapy initiation, switching and treatment interruptions: global overview from the International Epidemiologic Databases to Evaluate AIDS (IeDEA)(JOHN WILEY & SONS LTD, 2018-06-29)INTRODUCTION: In 2015, the World Health Organization recommended that all HIV-infected individuals consider ART initiation as soon as possible after diagnosis. Sex differences in choice of initial ART regimen, indications for switching, time to switching and choice of second-line regimens have not been well described. The aims of this study were to describe first-line ART and CD4 count at ART initiation by sex, calendar year and region, and to analyse time to change or interruption in first-line ART, according to sex in each region. METHODS: Participating cohorts included: Southern, East and West Africa (IeDEA-Africa), North America (NA-ACCORD), Caribbean, Central/South America (CCASAnet) and Asia-Pacific including Australia (IeDEA Asia-Pacific). The primary outcomes analysed for each region and according to sex were choice of initial ART, time to switching and time to discontinuation of the first-line regimen. RESULTS AND DISCUSSION: The combined cohort data set comprised of 715,252 participants across seven regions from low- to high-income settings. The median CD4 count at treatment initiation was lower in men compared with women in nearly all regions and time periods. Women from North America and Southern Africa were more likely to switch ART compared to men (p < 0.001) with approximately 90% of women reporting a major change after 10 years in North America. Overall, after 8 years on ART, >50% of HIV- positive men and women from Southern Africa, East Africa, South and Central America remained on their original regimen. Men were more likely to have a treatment interruption compared with women in low- and middle-income countries from the Asia/Pacific region (p < 0.001) as were men from Southern Africa (p < 0.001). Greater than 75% of men and women did not report a treatment interruption after 10 years on ART from all regions except North America and Southern Africa. CONCLUSIONS: There are regional variations in the ART regimen commenced at baseline and rates of major change and treatment interruption according to sex. Some of this is likely to reflect changes in local and international antiretroviral guideline recommendations but other sex-specific factors such as pregnancy may contribute to these differences.
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ItemMaternal immunisation: What have been the gains? Where are the gaps? What does the future hold?(F1000 Research Ltd, 2018)The vaccination of pregnant women has enormous potential to protect not only mothers from vaccine-preventable diseases but also their infants through the passive acquisition of protective antibodies before they are able to themselves acquire protection through active childhood immunisations. Maternal tetanus programmes have been in place since 1989, and as of March 2018, only 14 countries in the world were still to reach maternal neonatal tetanus elimination status. This has saved hundreds of thousands of lives. Building on this success, influenza- and pertussis-containing vaccines have been recommended for pregnant women and introduced into immunisation programmes, albeit predominantly in resource-rich settings. These have highlighted some important challenges when additional immunisations are introduced into the antenatal context. With new vaccine candidates, such as respiratory syncytial virus (RSV) and group B streptococcus (GBS), on the horizon, it is important that we learn from these experiences, identify the information gaps, and close these to ensure safe and successful implementation of maternal vaccines in the future, particularly in low- and middle-income countries with a high burden of disease.
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ItemSmoking and HIV: what are the risks and what harm reduction strategies do we have at our disposal?(BMC, 2018-12-12)The World Health Organization estimates that smoking poses one of the greatest global health risks in the general population. Rates of current smoking among people living with HIV (PLHIV) are 2-3 times that of the general population, which contributes to the higher incidence of non-AIDS-related morbidity and mortality in PLHIV. Given the benefit of smoking cessation, strategies to assist individuals who smoke to quit should be a primary focus in modern HIV care. Tobacco harm reduction focuses on reducing health risk without necessarily requiring abstinence. However, there remains uncertainty about the safety, policy and familiarity of specific approaches, particularly the use of vaporised nicotine products. Evidence suggests that vaporised nicotine products may help smokers stop smoking and are not associated with any serious side-effects. However, there is the need for further safety and efficacy data surrounding interventions to assist quitting in the general population, as well as in PLHIV specifically. In addition, official support for vaping as a harm reduction strategy varies by jurisdiction and this determines whether medical practitioners can prescribe vaporised products and whether patients can access vaporised nicotine products. When caring for PLHIV who smoke, healthcare workers should follow general guidelines to assist with smoking cessation. These include: asking the patient about their smoking status; assessing the patient's readiness to quit and their nicotine dependence; advising the patient to stop smoking; assisting the patient in their attempt to stop smoking through referral, counselling, pharmacotherapy, self-help resources and/or health education; and arranging follow-up with the patient to evaluate their progress.
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ItemIncreasing antigen presentation on HSV-1-infected cells increases lesion size but does not alter neural infection or latency.(Microbiology Society, 2018-05)CD8+ T cells have a role in the control of acute herpes simplex virus (HSV) infection and may also be important in the maintenance of latency. In this study we have explored the consequences of boosting the efficacy of CD8+ T cells against HSV by increasing the amount of an MHC I-presented epitope on the surface of infected cells. To do this we used HSVs engineered to express an extra copy of the immunodominant CD8+ T cell epitope in C57Bl/6 mice, namely gB498 (SSIEFARL). Despite greater presentation of gB498 on infected cells, CD8+ T cell responses to these viruses in mice were similar to those elicited by a control virus. Further, the expression of extra gB498 did not significantly alter the extent or stability of latency in our mouse model, and virus loads in skin and sensory ganglia of infected mice were not affected. Surprisingly, mice infected with these viruses developed significantly larger skin lesions than those infected with control viruses and notably, this phenotype was dependent on MHC haplotype. Therefore increasing the visibility of HSV-infected cells to CD8+ T cell attack did not impact neural infection or latency, but rather enhanced pathology in the skin.