Posts Tagged ‘HIV/AIDS’

A global network of researchers? Not really – small worlds.

Thursday, April 17th, 2014

As science evolves, important scientific achievements require the collaborative effort of an increasing number of researchers. The study of patterns of scientific collaboration allows us to gain further understanding of innovation and knowledge production. Scientific collaboration networks have been the subject of growing interest in the past few years. Collaborative scientific publications have a long history. The first collaborative research paper was published in 1665 in the Philosophical Transactions of the Royal Society. To date, the most multi-authored scientific paper was published in 2010, when 3,222 researchers from 32 different countries contributed to a study of charged-particle multiplicities performed in the Large Hadron Collider at CERN.

A new study finds that the United States was the country with the largest number of international collaborations, particularly with South Africa, Uganda and Brazil. The high global clustering coefficient coupled with a short average distance between nodes suggests a “small-world phenomenon” among HIV and HPV researchers. Researchers from high-income countries seem to have a high number of research collaborations among them and to cluster together in densely connected communities, particularly those from the US. There is a large well-connected community, which encompasses 70% of researchers, and other much smaller communities, including the UK.

Small worlds

International Scientific Collaboration in HIV and HPV: A Network Analysis. (2014) PLoS ONE 9(3): e93376. doi:10.1371/journal.pone.0093376
Research endeavours require the collaborative effort of an increasing number of individuals. International scientific collaborations are particularly important for HIV and HPV co-infection studies, since the burden of disease is rising in developing countries, but most experts and research funds are found in developed countries, where the prevalence of HIV is low. The objective of our study was to investigate patterns of international scientific collaboration in HIV and HPV research using social network analysis. Through a systematic review of the literature, we obtained epidemiological data, as well as data on countries and authors involved in co-infection studies. The collaboration network was analysed in respect to the following: centrality, density, modularity, connected components, distance, clustering and spectral clustering. We observed that for many low- and middle-income countries there were no epidemiological estimates of HPV infection of the cervix among HIV-infected individuals. Most studies found only involved researchers from the same country (64%). Studies derived from international collaborations including high-income countries and either low- or middle-income countries had on average three times larger sample sizes than those including only high-income countries or low-income countries. The high global clustering coefficient (0.9) coupled with a short average distance between researchers (4.34) suggests a “small-world phenomenon.” Researchers from high-income countries seem to have higher degree centrality and tend to cluster together in densely connected communities. We found a large well-connected community, which encompasses 70% of researchers, and 49 other small isolated communities. Our findings suggest that in the field of HIV and HPV, there seems to be both room and incentives for researchers to engage in collaborations between countries of different income-level. Through international collaboration resources available to researchers in high-income countries can be efficiently used to enroll more participants in low- and middle-income countries.

HIV cure research – advances and prospects

Thursday, March 20th, 2014

HIV reservoirs 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.

Highlights:

  • 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.

 

HIV cure research: Advances and prospects. (2014) Virology pii: S0042-6822(14)00065-8. doi: 10.1016/j.virol.2014.02.021

Remember what happened last time we “cured” AIDS?

Thursday, March 6th, 2014

Immune Timothy Brown, the “Berlin patient” was freed of HIV infection via a bone marrow transfusion from a compatible CCR5Δ32 donor in 2007.

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.

 

Up close and three-dimensional: HIV inside the gut

Wednesday, February 5th, 2014

HIV HIV/AIDS remains a global public health problem with over 33 million people infected worldwide. High-resolution imaging of infected tissues by three-dimensional electron microscopy can reveal details of the structure of HIV-1, how it infects cells, and how and where the virus accumulates within different tissue sub-structures.

Three-dimensional electron microscopy had previously only been performed to image infected cultured cells or purified virus. This paper uses electron tomography (ET) to examine an active infection in the gastrointestinal tract of HIV-1–infected mice with humanized immune systems, allowing visualization of the interplay between the virus and host immune cells. Not only does it reveal details on how the virus quickly infects immune cells in the gut, using them as virus-producing factories, but it also highlights where the virus “hides out” deep within the intestinal tissue.

Three-dimensional imaging of an HIV-1 infection in tissue uncovers differences between cultured cell and tissue models of HIV-1 infection and in vivo infections and furthers our understanding of HIV-1/AIDS as a disease of mucosal tissues.

Electron Tomography of HIV-1 Infection in Gut-Associated Lymphoid Tissue. (2014) PLoS Pathog 10(1): e1003899. doi:10.1371/journal.ppat.1003899

 

Making sense of microbiology

Wednesday, October 30th, 2013

In a discussion on Twitter earlier this week I made an off the cuff remark which turned out to be unexpectedly telling. Discussing online science writing, I said:

We need sense-making, not more coverage.

Later that day I came across this post by Nathalia Holt - The Goldilocks Approach to Vaccines. I was already considering featuring this story in MicrobiologyBytes this week. Now, I feel I don’t need to (as long as you promise to go and read the full story on her blog):

“On Tuesday, Louis Picker began his talk to a packed room at the AIDS Vaccine meeting in Barcelona, Spain with the line, “The trick to making a vaccine is to be humble and accept the fact that viruses are smarter than we are.” He wasn’t referring just to HIV. Instead he was talking about CMV, or cytomegalovirus. CMV is very clever. A member of the herpes virus family, it’s over 200 million years old. This long evolution means that the virus has become adept in surviving within mammals. While the virus is found in roughly 45% of people, it rarely causes disease. Given its benign nature, Picker calls it “a parasite not a pathogen.” With these characteristics, perhaps it’s surprising that no one has attempted to use CMV in vaccines before now. What makes Picker’s approach unique is not how it manipulates HIV. In fact, the parts of HIV used in his vaccine are far from exceptionable. The vaccine uses pieces of an HIV protein called gag, a group of proteins that make up the basic structure of the virus. The gag protein has been a component of many failed vaccine attempts. What makes this vaccine different is not the innards of HIV it contains but instead how these pieces are delivered.”

This is exactly the sort of approach to science writing I had in mind when I mentioned sense-making on Twitter. Nathalia is not an average blogger. She is a talented and very experienced author for who her blog is merely a sideline. I have plenty of academic colleagues who would cringe and quibble at some of the terms Nathalia uses in this post, and the way in which she puts across some of the ideas. In spite of that, this is exactly the sort of approach I was thinking of when I tweeted. And it is exactly what I am trying to do when I write MicrobiologyBytes.

I honour of Nathalia, and all the other great science writers online, you’ll notice that I have changed the tagline at the top of MicrobiologyBytes. No longer does it say “The latest news about microbiology”, although that’s what you’ll get if you follow MicrobiologyBytes on Twitter, Facebook or Google+. The new tagline on the site better reflects what MicrobiologyBytes is about.

 

Vaccines & Correlates of Immune Protection - AIDS Vaccine 2013

Vaccines & Correlates of Immune Protection – AIDS Vaccine 2013

 

HIV thirty years on

Thursday, August 29th, 2013

HIV It has been thirty years since human immunodeficiency virus (HIV) was first identified as the cause of acquired immunodeficiency syndrome (AIDS), a landmark discovery that has led to tremendous progress in understanding and combating infection by this life-threatening retrovirus. The most notable achievement during this time has been the development of antiretroviral therapies that substantially improve the quality and length of life in infected individuals. Nevertheless, to date neither a complete cure nor a protective vaccine have been found, and new infections continue to occur at a rate of 6,850 people per day.

This collection of articles takes stock of where we are now, with a collection of articles that discuss different aspects of HIV infection, the progress made towards eradicating the virus, and the challenges of fundamental science and clinical management that remain.

BioMed Central: HIV thirty years on (2013)

How JC virus causes PML

Monday, June 17th, 2013

JC Virus The human JC polyomavirus is a bit of a mystery. Many people are infected with it, but few become ill as a result. This virus bides its time, waiting for your immune systen to let its guard down, then wham! People infected with HIV, those who have AIDS, or those receiving immunomodulatory therapies for autoimmune diseases are at serious risk for progressive multifocal leukoencephalopathy (PML), where the virus can spread from the kidney to the central nervous system and cause a fatal, demyelinating disease.

Recent reports have shown that virus isolates from PML patients often have distinct changes within the major capsid protein. This paper shows that that these mutations result in abolished engagement of the carbohydrate receptor motif necessary for infection. Viruses with PML-associated mutations are not infectious in glial cells, suggesting that they may play an alternative role in PML. Interesting stuff, suggesting that interaction with cell surface receptors is an important determinant of tissue tropism and JC virus pathogenesis for PML, even though the best defence remains a healthy immune system.

 

Progressive Multifocal Leukoencephalopathy-Associated Mutations in the JC Polyomavirus Capsid Disrupt Lactoseries Tetrasaccharide c Binding. (2013) mBio 4(3): e00247-13 doi: 10.1128/mBio.00247-13
The human JC polyomavirus (JCPyV) is the causative agent of the fatal, demyelinating disease progressive multifocal leukoencephalopathy (PML). The Mad-1 prototype strain of JCPyV uses the glycan lactoseries tetrasaccharide c (LSTc) and serotonin receptor 5-HT2A to attach to and enter into host cells, respectively. Specific residues in the viral capsid protein VP1 are responsible for direct interactions with the α2,6-linked sialic acid of LSTc. Viral isolates from individuals with PML often contain mutations in the sialic acid-binding pocket of VP1 that are hypothesized to arise from positive selection. We reconstituted these mutations in the Mad-1 strain of JCPyV and found that they were not capable of growth. The mutations were then introduced into recombinant VP1 and reconstituted as pentamers in order to conduct binding studies and structural analyses. VP1 pentamers carrying PML-associated mutations were not capable of binding to permissive cells. High-resolution structure determination revealed that these pentamers are well folded but no longer bind to LSTc due to steric clashes in the sialic acid-binding site. Reconstitution of the mutations into JCPyV pseudoviruses allowed us to directly quantify the infectivity of the mutants in several cell lines. The JCPyV pseudoviruses with PML-associated mutations were not infectious, nor were they able to engage sialic acid as measured by hemagglutination of human red blood cells. These results demonstrate that viruses from PML patients with single point mutations in VP1 disrupt binding to sialic acid motifs and render these viruses noninfectious.

 

Getting rid of HIV for good

Wednesday, June 5th, 2013

HIV-infected cell The eradication of HIV-1 from infected individuals is prevented by the persistence of the virus in a stable reservoir of latently infected CD4+ T cells. Latently infected cells can be found in all HIV-1 infected individuals at a very low frequency and allow the virus to persist despite antiretroviral therapy for the lifetime of an infected patient. Current efforts are focused on identifying small molecules or immune strategies to eliminate these latently infected cells. To assess the efficacy of these elimination strategies in HIV-1 infected patients, we must be able to measure the size of the remaining latent reservoir. While a previous assay can measure the size of this latent reservoir, it is too laborious and costly to be utilized in large-scale HIV-1 eradication trials. A new paper in PLoS Pathogens describes a rapid assay to measure the size of the HIV-1 latent reservoir more amenable to eradication trials.

 

Rapid Quantification of the Latent Reservoir for HIV-1 Using a Viral Outgrowth Assay. (2013) PLoS Pathog 9(5): e1003398. doi:10.1371/journal.ppat.1003398
HIV-1 persists in infected individuals in a stable pool of resting CD4+ T cells as a latent but replication-competent provirus. This latent reservoir is the major barrier to the eradication of HIV-1. Clinical trials are currently underway investigating the effects of latency-disrupting compounds on the persistence of the latent reservoir in infected individuals. To accurately assess the effects of such compounds, accurate assays to measure the frequency of latently infected cells are essential. The development of a simpler assay for the latent reservoir has been identified as a major AIDS research priority. We report here the development and validation of a rapid viral outgrowth assay that quantifies the frequency of cells that can release replication-competent virus following cellular activation. This new assay utilizes bead and column-based purification of resting CD4+ T cells from the peripheral blood of HIV-1 infected patients rather than cell sorting to obtain comparable resting CD4+ T cell purity. This new assay also utilizes the MOLT-4/CCR5 cell line for viral expansion, producing statistically comparable measurements of the frequency of latent HIV-1 infection. Finally, this new assay employs a novel quantitative RT-PCR specific for polyadenylated HIV-1 RNA for virus detection, which we demonstrate is a more sensitive and cost-effective method to detect HIV-1 replication than expensive commercial ELISA detection methods. The reductions in both labor and cost make this assay suitable for quantifying the frequency of latently infected cells in clinical trials of HIV-1 eradication strategies.

 

Microbiology Today: HIV and the ‘functional’ cure

Tuesday, June 4th, 2013



Microbiology Today: HIV and the ‘functional’ cure

http://www.sgm.ac.uk/en/publications/microbiology-today/current-issue.cfm