15. 06. 24
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Exciting news!

A consortium to explore the roles human endogenous retroviruses (HERVs) has been selected by Genomics England to be a part of Genomics England Clinical Intepretation Partnership (GeCIP). GeCIP unites both NHS and academic researchers with the aim of translating data from the 100,000 Genomes Project to the healthcare setting, by forming collaborative communities around defined “domains”. The HERV consortium is one part of the functional cross cutting domain, in which genomic functions will be examined across all the 100,000 genomes, rather than concentrating on a specific disease, thus “cross-cutting” across all the available data sets. One focus of the functional cross cutting domain is to catalogue and characterise polymorphisms of ERVs in the whole human genomes of the 100,000 Genomes Project and assess the ways that ERVs are associated with phenotypes (specifically diseases) and other pathophysiological processes.

Read more about the 100,000 Genomes Project and its 30 research domains here: Genomics England Announce Lead Researchers

15. 03. 12
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Early HIV infection in an individual is characterised by the rapid viral replication and diversification alongside a powerful immune response that results in the destruction of immune cells. The viral load in the blood of the infected individual has its peak during this exponential growth phase of the virus. Furthermore, the newly infected individual is also likely to continue the same risky behaviors that lead to their infection. Consequently, the risk of transmitting HIV to an uninfected individual is also at the highest during this period. It is observed in diverse HIV epidemics with different affected populations – heterosexuals, men who have sex with men, and injection drug users – that early HIV infection is responsible for up to 50% of new cases of infection. TASP (HIV treatment as prevention) is aimed at providing antiretroviral therapy (ART) to HIV-infected individuals, reducing their blood viral load to near or undetectable levels, thus preventing the transmission of HIV to an uninfected person.
Unfortunately, a major obstacle of TASP implementation is the high risk of HIV transmission from recently infected individuals who do not know that they are infected. The early stage of HIV infection is marked by nonspecific symptoms such as a rash, flu-like symptoms, or general feelings of malaise. Social network-based interventions such as Transmission Reduction Intervention Project and Project Protect aim to educate about early HIV infection and locate those recently infected to get them in care with the goal of preventing onward transmission of HIV.
Mathematical modelling performed by Eaton and Hallett (2014) on data from the South African HIV epidemic led to the conclusion by the authors that ART given to early HIV-infected individuals does not significantly change the HIV prevalence in the long term.
In a recent PNAS letter, Tanya, Gkikas, and Sam, our colleague from the Institute of Infectious Disease Research argue that Eaton and Hallett’s results might be biased by the data used, taken from the South African HIV epidemic where the incidence of HIV infection has been on the decline in recent years. While their findings are true to those settings, they might not be relevant to the new HIV epidemics at the exponential stage of growth or those well-established HIV epidemics that experience a breakthrough into other population groups (such as HIV epidemics in Latvia, Ukraine, and Greece).
15. 02. 02
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By dating the integration of specific ERV loci in the genomes of 40 mammalian species, including the chimpanzee, dolphin, and even the nine-banded armadillo, Magiorkinis and colleagues found that humans and other primates have acquired far fewer ERVs compared to the other mammals surveyed. The authors observed a four-fold decline in ERV insertions in primate genomes over the last 10 million years. In humans, this major decline in ERVs is mainly due to the extinction of the massive HERV-H family, which is responsible for ~80% of ERV integrations in the human genome within the last 30 million years. Where the genomes of other primate species would acquire at least one new ERV lineage during this timeframe, the human genome is curiously absent of new ERVs.

Instead, the ancient HERV-K (HML-2) subfamily had continued to replicate in the human genome until at least a few hundred thousand years ago. HERV-K (HML-2) is potentially medically significant – it is polymorphic in the human population, meaning that some individuals have HERV-K (HML-2) loci that other individuals may not have – and the ERV itself and its gene products are expressed in HIV-1 infection and a number of cancers. It is currently unclear whether HERV-K (HML-2) has any direct role in human disease pathogenesis. The HERV-H family is also of particular interest – specific HERV-H long terminal repeats (LTRs) have recently been identified as having a functional role in maintaining pluripotency in human embryonic stem cells (hESCs). It is unknown if the extinction of HERV-H and the host appropriation of HERV-H sequences in hESC gene regulation is connected or a merely a coincidence.

The authors speculate that the lack of new ERVs in human genomes is partly due to a cultural shift in humans that prevented the acquisition and the transmission of novel retrovirus infections. This could be a result of decreased exposure to retrovirus-infected blood from consumption of infected meat, and from wounds gained during violent male-male conflict. This research also suggests that over the last few million years, the human immune system had become more effective in eradicating infection by exogenous retroviruses, compared to other mammals. The HIV-1 pandemic is relatively recent, and its high pathogenicity in humans contrasts sharply against the many SIVs that endemically infect non-human primates, reflecting the long evolutionary co-existence of non-human primates and retroviruses. This new study is published today in the journal Retrovirology.

 

Read the abstract here: The decline of human endogenous retroviruses: extinction and survival

University of Oxford press release: Fewer viral relics may be due to a less bloody evolutionary history

 

Other press:

Our Inner Viruses: Forty Million Years in the Making by Carl Zimmer

 

-- Audrey Lin

15. 01. 07
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Microbial invaders often have distinct molecular patterns (referred to as pathogen associated molecular patterns, or PAMPs) that are quickly recognised by host innate immune defences. There are different types of germ-line encoded pattern recognition receptors (PRRs) such as those belonging to the Toll-like receptor (TLR) family found on the surface of cells, endosomes, and within the cytoplasm. These PRRs bind to a pathogen-associated ligand and activate a signalling cascade resulting in the expression of genes that induce inflammation as well as modulate the adaptive immune response. Innate immune recognition sensing by these receptors are not non-specific. For example, TLR-5 specifically recognises the molecular patterns of bacterial flagellin, TLR-4 responds to lipopolysaccharides found in Gram-negative bacteria, and the ligand of TLR-7 is single-stranded RNA. Double-stranded RNA that result from viral infections are specifically sensed by PRRs like TLR-3 and RIG-I with subsequent downstream effects that induce an antiviral state, such as the production of type I interferons (IFNs), followed by activation of antiviral restriction factors and natural killer cells. There is emerging research that shows how expressed ERVs may activate such immune signalling pathways, with consequences for many inflammatory diseases.

The immune system must be able to distinguish between foreign and self antigens in order to protect host tissue integrity. During development, immune cells that react too strongly to self antigens are deleted by apoptosis. Because ERVs are part of the host, ERVs are technically self antigens. However, immune cells that undergo loss of self-tolerance is characteristic of autoimmune disease, and the upregulation of ERVs in many cancers may contribute to its inflammatory pathological state.

Tara Hurst and Gkikas Magiorkinis have written a review in the Journal of General Virology discussing how ERVs activate innate immune sensing pathways and the potential implications for human disease.

 

Read the review paper here: Activation of the innate immune response by endogenous retroviruses

 

-- Audrey Lin

14. 11. 11
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Hepatitis C Virus (HCV) is a blood-borne virus that preferentially infects human hepatocytes (liver cells) and is intricately adapted to the environment of the liver. The virus is usually transmitted through contaminated needles during intravenous drug use, and medical procedures such as transplantation of infected organs or transfusion of infected blood. HCV screening of donated blood has significantly decreased the risk of iatrogenic transmission of the virus, but many developing countries do not have adequate blood screening policies in place. Currently, an estimated 130-150 million people worldwide are chronically infected with HCV. From that number, 15-45% of the infected will spontaneously clear the virus without any treatment, but the remaining 55-85% will develop chronic HCV infection, which carries an increased risk of developing cirrhosis of the liver and liver cancer. Many of those chronically infected with HCV do not know that they are infected because the virus is often asymptomatic for years, causing liver damage in silence. Liver disease and liver failure resulting from chronic HCV infection remains the leading cause of liver transplantation.

The usual course of HCV treatment is a combination of the antiviral drugs pegylated interferon, which induces the immune system to an antiviral state; and ribavirin, a synthetic guanosine analog that inhibits synthesis of viral RNA. Unfortunately, these drugs are sometimes unavailable in developing countries, and furthermore, are often poorly tolerated by the patients who take them. Many undergoing pegylated interferon/Ribavirin treatment experience a number of unpleasant side-effects, including flu-like symptoms such as headaches, muscle pain, and gastrointestinal problems. Recent advances in HCV therapies have led to new drugs that are better tolerated by the patient, such as the orally administered Daclatasvir, which targets the viral nonstructural protein NS5A and appears to interfere with viral replication. However, these drugs are prohibitively expensive, and are only available in wealthy, developed nations. The majority of people infected with HCV are in resource-poor countries that do not have access to these new drugs. In addition, many of these drugs available do not provide protection from re-infection, and there currently is no HCV vaccine. It is difficult to develop a vaccine that protects against a virus as genetically diverse as HCV is.

One HCV vaccine development strategy is to focus on the powerful T-cell responses seen in HCV-infected individuals who spontaneously clear the virus during primary infection. An interesting study by Klenerman's and Barnes's groups at University of Oxford published in Science Translational Medicine this month reports a new HCV vaccine that not only showed strong HCV-specific CD4+ and CD8+ T-cell response in 15 healthy human volunteers, but also appears to be safe and well-tolerated. The vaccine strategy has two parts. First, a replication-defective chimpanzee adenovirus vector (ChAd3) – that encodes the HCV polyprotein NS3-NS5B and a defective NS5B polymerase – delivers its genetic material to the patient’s genome. The patient’s cellular machinery synthesizes the delivered viral genes that the patient’s T-cells subsequently respond to. Secondly, the vaccine incorporates modified vaccinia Ankara (MVA), an attenuated (serially passaged hundreds of times through chicken embryo fibroblasts) vaccinia virus that is safe for the immunocompromised and also induces a strong immune response.  The MVA also contains the same HCV nonstructural genes that ChAd3 encodes for. As an HCV vaccine, this combination of ChAd3 priming the host immune system and MVA adding an immunogenic boost shows promise with its ability to create a potent T-cell response against HCV infection, similar to the spontaneous clearance of HCV infection seen in 15-45% of individuals infected.

Read the paper here: A human vaccine strategy based on chimpanzee adenoviral and MVA vectors that primes, boosts, and sustains functional HCV-specific T cell memory

 

 

-- Audrey Lin