Archive for the ‘Uncategorized’ Category
As we find out that Tamiflu is no more effective than paracetamol or ibuprofen in treating influenza infection (NHS Choices: Effectiveness of Tamiflu and Relenza questioned) – giving Ben Goldacre the right to say I told you so – maybe there is some reason to be more optimistic about treating influenza.
A new paper in Immunity [subscription] shows that prostaglandin E2 (PGE2) is upregulated during influenza A virus infection, and this inhibits macrophage recruitment to the lungs as well as interferon production and apoptosis in influenza virus-infected macrophages. This results in impaired macrophage antigen presentation and reduced adaptive immunity against influenza virus. The good news is that suppression of PGE2 with prostaglandin inhibitors protects against influenza infection. And we’ve got lots of prostaglandin inhibitors, including ibuprofen and other nonsteroidal anti-inflammatory drugs (NSAIDs) that work by inhibiting a molecule called cyclooxygenase (COX). The lung innate immune system has a critical role in limiting respiratory viral infections, particularly in the case of the nastier strains of flu such as the 1918 Spanish Influenza virus (and those still to come). So this is potentially very good news.
The catch? Well this paper refers to studies in mice and clinical trials will need to be done in humans to show the same effects. Clinical trials will be easy to do as many COX- and PGE-inhibitors are already approved for human use. All we need to do is avoid Roche doing the trial, or we may never find out the results.
Targeted Prostaglandin E2 Inhibition Enhances Antiviral Immunity through Induction of Type I Interferon and Apoptosis in Macrophages. Immunity, 10 April 2014 doi: http://dx.doi.org/10.1016/j.immuni.2014.02.013
Summary: Aspirin gained tremendous popularity during the 1918 Spanish Influenza virus pandemic, 50 years prior to the demonstration of their inhibitory action on prostaglandins. Here, we show that during influenza A virus (IAV) infection, prostaglandin E2 (PGE2) was upregulated, which led to the inhibition of type I interferon (IFN) production and apoptosis in macrophages, thereby causing an increase in virus replication. This inhibitory role of PGE2 was not limited to innate immunity, because both antigen presentation and T cell mediated immunity were also suppressed. Targeted PGE2 suppression via genetic ablation of microsomal prostaglandin E-synthase 1 (mPGES-1) or by the pharmacological inhibition of PGE2 receptors EP2 and EP4 substantially improved survival against lethal IAV infection whereas PGE2 administration reversed this phenotype. These data demonstrate that the mPGES-1-PGE2 pathway is targeted by IAV to evade host type I IFN-dependent antiviral immunity. We propose that specific inhibition of PGE2 signaling might serve as a treatment for IAV.
[Editorial comment: I can just imaging the authors and journal editors doing the happy dance that this paper came out on sthe same day as the Tamiflu news.]
Principles of Molecular Virology, Chapter 1 (Introduction to Viruses), describes the techniques used to study viruses, including bioinformatics. But molecular techniques have moved on a lot in the last few years, so the new edition will have an update on this.
I’m updating the bioinformatics section of Chapter 1 and collecting resources to illustrate recent advances in how nucleic acid technologies have moved on in the last few years. One of those advances has been digital PCR (dPCR), an amazingly sensitive technique used to measure tiny quantities in nucleic acid in clinical samples, as in this example…
See more: Pile_of_Viruses via xkcd
Whenever I write about phage therapy – using bacteriophages to treat bacterial infections – readers get overly enthusiastic about injecting patients with phages to produce a miracle cure. Look at it this way – that hasn’t worked for the last 100 years and it’s not likely to suddenly start working now. This short review is worth reading because it takes a much more thoughtful and holistic approach to the idea of phage therapy than the simple minded “phage as wonder cure” idea.
Exploiting gut bacteriophages for human health. Trends Microbiol. 20 Mar 2014 pii: S0966-842X(14)00045-6. doi: 10.1016/j.tim.2014.02.010
The human gut contains approximately 1015 bacteriophages (the ‘phageome’), probably the richest concentration of biological entities on earth. Mining and exploiting these potential ‘agents of change’ is an attractive prospect. For many years, phages have been used to treat bacterial infections in humans and more recently have been approved to reduce pathogens in the food chain. Phages have also been studied as drug or vaccine delivery vectors to help treat and prevent diseases such as cancer and chronic neurodegenerative conditions. Individual phageomes vary depending on age and health, thus providing a useful biomarker of human health as well as suggesting potential interventions targeted at the gut microbiota.
Thirty years after the identification of HIV, a cure for HIV infection is still to be achieved. Advances of combined antiretroviral therapy (cART) (=HAART) in recent years have transformed HIV infection into a chronic disease when treatment is available. However, in spite of the favorable outcomes provided by the newer therapies, cART is not curative and patients are at risk of developing HIV-associated disorders. Moreover, universal access to antiretroviral treatment is restricted by financial obstacles. This review discusses the most recent strategies that have been developed in the search for an HIV cure and to improve life quality of people living with HIV.
- Some cases of cure or remission of infection have boosted the search for an HIV cure.
- cART intensification has not shown significant impact in the reservoirs, but early cART may limit them.
- Strategies to purge the reservoirs face difficulties linked to the complexity of latency mechanisms and drug non-specificity.
- Repression of reservoirs or cell manipulation to render them less permissive to HIV may facilitate HIV remission.
- HIV cure/remission may require boosting immune responses while keeping inflammation in check.
Herpes Simplex Virus 1 (HSV-1) infects 40–80% of adults worldwide. HSV-1 initiates infection at mucosal surfaces and spreads along sensory neurons to establish a life-long latent infection that can lead to neurological diseases. Humans usually develop IgG antibodies that specifically recognize pathogens via fragment antigen binding (Fab) variable regions. HSV-1 can avoid the protective effects of antibodies by producing gE-gI, a receptor that binds to the constant portion of IgGs (Fc), tethering the antibody in a position where it cannot trigger downstream immune functions. A gE-gI–bound IgG can participate in antibody bipolar bridging (ABB) such that the Fabs bind a viral antigen and the Fc binds gE-gI. The fate of ABB complexes had been unknown. This paper uses used live cell fluorescent imaging to follow ABB complexes during their formation and transport within a cell. ABB assemblies were internalized into acidic intracellular compartments, where gE-gI dissociated from IgG–viral antigen complexes and the IgG and antigen were targeted for degradation within lysosomes. These results suggest that gE-gI mediates clearance of infected cell surfaces of both anti-viral IgGs and viral antigens, a general mechanism to facilitate latent infection by evading IgG-mediated responses.
Last year there was a report of a newborn baby cured by very early drug therapy. The news today carries reports of a second case in a baby which confirms that this approach can work in newborns, although not in adults with established HIV infections.
Also in the news today is the story of the phase I clinical trial of gene-editing technology to control (but not eliminate) HIV infection using autologous donation to create CCR5Δ32 in the patient’s own cells (Gene Editing of CCR5 in Autologous CD4 T Cells of Persons Infected with HIV. (2014) N Engl J Med 2014; 370: 901-910 doi: 10.1056/NEJMoa1300662). But as Nature News correctly points out, the big story here is the relatively crude zinc-finger nuclease (ZFN) technology used in this study as opposed to the much more powerful transcription activator-like effector nucleases (TALENs) and clustered regularly interspaced palindromic repeats (CRISPRs) technologies under development to edit the somatic genome.
Watch this space for further updates.