Posts Tagged ‘retrovirus’

Larger body size – less retroviruses?

Friday, July 18th, 2014

Retrovirus replication Retroviruses have been invading mammalian genomes for over 100 million years, leaving traces known as endogenous retroviruses (ERVs). Early genome sequencing studies revealed a marked difference in the activity of retroviruses among species, with humans largely containing inactive lineages of ERVs, while the mouse contains numerous lineages of active ERVs. A new paper explores the hypothesis that life history traits determine the activity of ERVs in mammalian genomes, and shows that larger mammals have fewer ERV copies over recent evolutionary time (the last 10 million years) compared to smaller mammals. This association is determined by body size independently of any confounding variables.

A mathematical model that shows that ERV abundance in genomes decreases with larger body size and increases with horizontal transmission. Retroviral integration can cause cancer, and our analysis suggests that larger bodied animals control ERV replication in order to postpone cancer until a post-reproductive age. This is in line with a long-standing observation that cancer rates do not fluctuate among mammals of different body size, a phenomenon known as Peto’s paradox, and opens up the possibility that larger animals have evolved mechanisms to limit ERV activity.

Larger animals exert greater control over ERV proliferation. This could be due to the evolution of mechanisms capable of limiting retroviral activity and consequently limiting the incorporation of ERVs in the genome. Such mechanisms could involve the enhancement of innate or adaptive responses to retroviruses, or perhaps epigenetic regulation is more potent in larger mammals. An intriguing alternative is that the effect is indirect via an improved immune surveillance – some genes involved in pattern recognition for defence against pathogens such as viruses are also involved in controlling cancers. Antiviral genes are the result of a continuous and ancient arms race between viruses and their hosts, and elucidating their roles in controlling cancer across animals of different body size could provide insights into cancer susceptibility.

 

Larger Mammalian Body Size Leads to Lower Retroviral Activity. (2014) PLoS Pathog 10(7): e1004214. doi:10.1371/journal.ppat.1004214
Retroviruses have been infecting mammals for at least 100 million years, leaving descendants in host genomes known as endogenous retroviruses (ERVs). The abundance of ERVs is partly determined by their mode of replication, but it has also been suggested that host life history traits could enhance or suppress their activity. We show that larger bodied species have lower levels of ERV activity by reconstructing the rate of ERV integration across 38 mammalian species. Body size explains 37% of the variance in ERV integration rate over the last 10 million years, controlling for the effect of confounding due to other life history traits. Furthermore, 68% of the variance in the mean age of ERVs per genome can also be explained by body size. These results indicate that body size limits the number of recently replicating ERVs due to their detrimental effects on their host. To comprehend the possible mechanistic links between body size and ERV integration we built a mathematical model, which shows that ERV abundance is favored by lower body size and higher horizontal transmission rates. We argue that because retroviral integration is tumorigenic, the negative correlation between body size and ERV numbers results from the necessity to reduce the risk of cancer, under the assumption that this risk scales positively with body size. Our model also fits the empirical observation that the lifetime risk of cancer is relatively invariant among mammals regardless of their body size, known as Peto’s paradox, and indicates that larger bodied mammals may have evolved mechanisms to limit ERV activity.

 

Retroviruses – NCBI Bookshelf

Thursday, January 16th, 2014

Retroviruses - NCBI Bookshelf Earlier today I needed to look something up. You know, in a real book, not Wikipedia. Except that the book was electronic, online and free.

Many people will have seen the NCBI Bookshelf, but it’s always a surprise to me that a resource of this quality has existed, for free, for so long. It’s also a reminder of how long I’ve been in this microbiology game and how much has changed.

Like many of the other NCBI resources, Retroviruses could be viewed as a bit long in the tooth these days. Certainly everything in it needs to be checked for currency by following citation trails to later knowledge (you do have the information skills that allow you to do that, don’t you?) but as an authorative resource it’s second to none.

I’ve had some good days and some bad days this week. The NCBI Bookshelf has certainly helped to make this one of the better ones.

 

We know what retroviruses were up to 407 million years million years ago

Wednesday, August 22nd, 2012

Coelacanth The deep history of retroviruses is still obscure. Retroviruses can leave integrated copies within their hosts’ genomes, providing a fossil record for studying their long-term evolution. Endogenous forms of foamy viruses, complex retroviruses known to infect only mammalian species, appear to be extremely rare, so far found only in sloths and the aye-aye.

This paper reports the discovery of endogenous foamy virus-like insertions within the genome of a so-called ‘living fossil’, the (Latimeria chalumnae). It provides evidence suggesting that foamy viruses and their hosts share a coevolutionary history of more than 407 million years, and that foamy viruses accompanied their vertebrate hosts on the evolutionary transition from water to land. These findings indicate that the retroviruses originated in the primeval ocean millions of years ago.

 

An Endogenous Foamy-like Viral Element in the Coelacanth Genome. (2012) PLoS Pathog 8(6): e1002790. doi:10.1371/journal.ppat.1002790
Little is known about the origin and long-term evolutionary mode of retroviruses. Retroviruses can integrate into their hosts’ genomes, providing a molecular fossil record for studying their deep history. Here we report the discovery of an endogenous foamy virus-like element, which we designate ‘coelacanth endogenous foamy-like virus’ (CoeEFV), within the genome of the coelacanth (Latimeria chalumnae). Phylogenetic analyses place CoeEFV basal to all known foamy viruses, strongly suggesting an ancient ocean origin of this major retroviral lineage, which had previously been known to infect only land mammals. The discovery of CoeEFV reveals the presence of foamy-like viruses in species outside the Mammalia. We show that foamy-like viruses have likely codiverged with their vertebrate hosts for more than 407 million years and underwent an evolutionary transition from water to land with their vertebrate hosts. These findings suggest an ancient marine origin of retroviruses and have important implications in understanding foamy virus biology.

Goats cause cancer. Yes they do. Really.

Monday, May 28th, 2012

Goat Although studies have so far failed to find an infectious agent, the evidence is now pretty clear that “professional exposure to goats” increases the risk of lung cancer.

 

Professional Exposure to Goats Increases the Risk of Pneumonic-Type Lung Adenocarcinoma: Results of the IFCT-0504-Epidemio Study. (2012) PLoS ONE 7(5): e37889. doi:10.1371/journal.pone.0037889
Pneumonic-type lung adenocarcinoma (P-ADC) represents a distinct subset of lung cancer with specific clinical, radiological, and pathological features. Given the weak association with tobacco-smoking and the striking similarities with jaagsiekte sheep retrovirus (JSRV)-induced ovine pulmonary adenocarcinoma, it has been suggested that a zoonotic viral agent infecting pulmonary cells may predispose to P-ADC in humans. Our objective was to explore whether exposure to domestic small ruminants may represent a risk factor for P-ADC. We performed a multicenter case-control study recruiting patients with P-ADC as cases and patients with non-P-ADC non-small cell lung cancer as controls. A dedicated 356-item questionnaire was built to evaluate exposure to livestock. A total of 44 cases and 132 controls were included. At multivariate analysis, P-ADC was significantly more associated with female gender (Odds-ratio (OR) = 3.23, 95% confidence interval (CI): 1.32–7.87, p = 0.010), never- smoker status (OR = 3.57, 95% CI: 1.27–10.00, p = 0.015), personal history of extra-thoracic cancer before P-ADC diagnosis (OR = 3.43, 95% CI: 1.10–10.72, p = 0.034), and professional exposure to goats (OR = 5.09, 95% CI: 1.05–24.69, p = 0.043), as compared to other subtypes of lung cancer. This case-control suggests a link between professional exposure to goats and P-ADC, and prompts for further epidemiological evaluation of potential environmental risk factors for P-ADC.

Novel Approaches to Inhibit HIV Entry

Monday, February 27th, 2012

CCR5 Human Immunodeficiency Virus (HIV) entry into target cells is a multi-step process involving binding of the viral glycoprotein, Env, to its receptor CD4 and a coreceptor – either CCR5 or CXCR4. Understanding the means by which HIV enters cells has led to the identification of genetic polymorphisms, such as the 32 base-pair deletion in the ccr5 gene (ccr5∆32) that confers resistance to infection in homozygous individuals, and has also resulted in the development of entry inhibitors – small molecule antagonists that block infection at the entry step. The recent demonstration of long-term control of HIV infection in a leukaemic patient following a hematopoietic stem cell transplant using cells from a ccr5∆32 homozygous donor highlights the important role of the HIV entry in maintaining an established infection and has led to a number of attempts to treat HIV infection by genetically modifying the ccr5 gene. This review describes the HIV entry process and provide an overview of the different classes of approved HIV entry inhibitors while highlighting novel genetic strategies aimed at blocking HIV infection at the level of entry.

 

Novel Approaches to Inhibit HIV Entry. Viruses 2012, 4(2), 309-324; doi:10.3390/v4020309

See: HIV and the CCR5 coreceptor

 

First RNA virus-encoded miRNAs

Tuesday, February 14th, 2012

miRNAs

Although the first miRNA was identified 18 years ago, it was only in 2001, with the development of technologies that allowed the efficient cDNA cloning and sequencing of small RNA species, that it became apparent that all multicellular eukaryotes encode numerous members of this class of small regulatory RNAs. Shortly after the identification of the first human miRNAs, the first virally encoded miRNAs were reported in the human herpesvirus Epstein–Barr virus (EBV). Although this initial discovery suggested that viruses in general might use miRNAs to down-regulate cellular factors that inhibit viral replication, the subsequent analysis of a wide range of RNA viruses failed to identify any viral miRNAs. However, virally encoded miRNAs are expressed by many members of the herpesvirus family of nuclear DNA viruses and are also found in a small number of other nuclear DNA viruses, particularly polymaviruses.

Although >250 viral microRNAs (miRNAs) are expressed by a range of nuclear DNA viruses, efforts to identify miRNAs expressed by RNA viruses have so far been in vain. In PNAS, Kincaid et al. report the identification of five miRNAs encoded by the delta retrovirus bovine leukemia virus (BLV) that are expressed in BLV-transformed B cells. It appears likely that these viral miRNAs play an important role in BLV pathogenesis:

MicroRNA expression by an oncogenic retrovirus. PNAS USA, 30 Jan 2012

RNA virus microRNA that mimics a B-cell oncomiR. PNAS USA, 30 Jan 2012; doi: 10.1073/pnas.1116107109

Be thankful for retroviruses

Monday, February 13th, 2012

Placenta Retroviruses have had a tremendous impact on animal genomes. At least eight percent of the human genome is comprised of retroviruses at various stages of “fossilization”. These elements represent retroviruses that have directly infected genomes of germline tissues such that their imprints can now be passed on with the rest of the genome. Most insertions into host genomes are likely to (i) be instantly so deleterious that they are never passed on, or alternatively (ii) have very little consequence to host biology and be expected to abrade away via the accumulation of mutations. Although the large fraction of retroviral imprints show expected signatures of mutational degeneration, some retroviral genes have been surprisingly preserved against mutational inactivation. These represent instances in which host genomes have usurped some retroviral genes for their own use. Particularly intriguing are host domestications of retroviral envelope (env) genes. The best-known classes of these genes are the syncytin genes, which have been coopted by the host to mediate nutrient transfer from the mother to the developing embryo in mammals.

 

Ancestral capture of syncytin-Car1, a fusogenic endogenous retroviral envelope gene involved in placentation and conserved in Carnivora. PNAS USA 17 January 2012 doi: 10.1073/pnas.1115346109
Syncytins are envelope protein genes of retroviral origin that have been captured for a function in placentation. Two such genes have already been identified in simians, two distinct, unrelated genes have been identified in Muridae, and a fifth gene has been identified in the rabbit. Here, we searched for similar genes in the Laurasiatheria clade, which diverged from Euarchontoglires—primates, rodents, and lagomorphs—shortly after mammalian radiation (100 Mya). In silico search for envelope protein genes with full-coding capacity within the dog and cat genomes identified several candidate genes, with one common to both species that displayed placenta-specific expression, which was revealed by RT-PCR analysis of a large panel of tissues. This gene belongs to a degenerate endogenous retroviral element, with precise proviral integration at a site common to dog and cat. Cloning of the gene for an ex vivo pseudotype assay showed fusogenicity on both dog and cat cells. In situ hybridization on placenta sections from both species showed specific expression at the level of the invasive fetal villi within the placental junctional zone, where trophoblast cells fuse into a syncytiotrophoblast layer to form the maternofetal interface. Finally, we show that the gene is conserved among a series of 26 Carnivora representatives, with evidence for purifying selection and conservation of fusogenic activity. The gene is not found in the Pholidota order and, therefore, it was captured before Carnivora radiation, between 60 and 85 Mya. This gene is the oldest syncytin gene identified to date, and it is the first in a new major clade of eutherian mammals.

See also: Retroviruses push the envelope for mammalian placentation

Thirty Years of HIV – 1981-2011

Sunday, June 5th, 2011

HIV On June 5 1981, MMWR published a report of Pneumocystis carinii pneumonia in five previously healthy young men in Los Angeles, California; two had died. This report later was acknowledged as the first published scientific account of what would become known as human immunodeficiency virus (HIV) and acquired immunodeficiency syndrome (AIDS). Thirty years after that first report, the most recent estimate is that 33.3 million persons were living with HIV infection worldwide at the end of 2009.

In 1981 I was working on my PhD (on poliovirus) when I first heard about AIDS. Someone from the department came back from a trip to San Francisco with lurid and scary tales. Over the next couple of years, my interest in retroviruses grew and when I finished my PhD in 1984, I went off to California to work on HTLV and HIV.

In the United States, CDC estimates that 1,178,350 persons were living with HIV at the end of 2008, with 594,496 having died from AIDS since 1981. At this 30-year mark, efforts are being accelerated under the National HIV/AIDS Strategy of the United States, with goals of reducing the number of persons who become infected with HIV, increasing access to care and optimizing health outcomes for persons living with HIV, and reducing HIV-related health disparities.

I worked on HIV for 10 years before moving on to other things. I still maintain a close interest in the topic. 30 years – it seems like yesterday.

MMWR 60(21): 689 June 3 2011

XMRV – the fight continues

Tuesday, March 29th, 2011

XMRV In October 2009 it was reported that 68 of 101 patients with chronic fatigue syndrome (CFS) in the USA were infected with a novel gamma retrovirus, xenotropic murine leukaemia virus-related virus (XMRV), a virus previously linked to prostate cancer. This finding, if confirmed, would have a profound effect on the understanding and treatment of an incapacitating disease affecting millions worldwide.

But does XMRV cause disease? It’s far from clear that it does.

No Evidence of XMRV or Related Retroviruses in a London HIV-1-Positive Patient Cohort. 2011 PLoS ONE 6(3): e18096. doi:10.1371/journal.pone.0018096
Background
Several studies have implicated a recently discovered gammaretrovirus, XMRV (Xenotropic murine leukaemia virus-related virus), in chronic fatigue syndrome and prostate cancer, though whether as causative agent or opportunistic infection is unclear. It has also been suggested that the virus can be found circulating amongst the general population. The discovery has been controversial, with conflicting results from attempts to reproduce the original studies.
Methodology/Principal Findings
We extracted peripheral blood DNA from a cohort of 540 HIV-1-positive patients (approximately 20% of whom have never been on anti-retroviral treatment) and determined the presence of XMRV and related viruses using TaqMan PCR. While we were able to amplify as few as 5 copies of positive control DNA, we did not find any positive samples in the patient cohort.
Conclusions/Significance
In view of these negative findings in this highly susceptible group, we conclude that it is unlikely that XMRV or related viruses are circulating at a significant level, if at all, in HIV-1-positive patients in London or in the general population.