MicrobiologyBytes

I spent 10 years working on Human T Lymphotropic Virus (HTLV), so it’s dear to me, although it’s fallen out of fashion recently, which is why it’s good to see this excellent review paper from my former UCLA colleague Pat Green:

Human T Lymphotropic Virus Type 1 (HTLV-1): Molecular Biology and Oncogenesis. (2010) Viruses 2(9): 2037-2077. doi:10.3390/v2092037
Human T lymphotropic viruses (HTLVs) are complex deltaretroviruses that do not contain a proto-oncogene in their genome, yet are capable of transforming primary T lymphocytes both in vitro and in vivo. There are four known strains of HTLV including HTLV type 1 (HTLV-1), HTLV-2, HTLV-3 and HTLV-4. HTLV-1 is primarily associated with adult T cell leukemia (ATL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). HTLV-2 is rarely pathogenic and is sporadically associated with neurological disorders. There have been no diseases associated with HTLV-3 or HTLV-4 to date. Due to the difference in the disease manifestation between HTLV-1 and HTLV-2, a clear understanding of their individual pathobiologies and the role of various viral proteins in transformation should provide insights into better prognosis and prevention strategies. In this review, we aim to summarize the data accumulated so far in the transformation and pathogenesis of HTLV-1, focusing on the viral Tax and HBZ and citing appropriate comparisons to HTLV-2.

Related:

• Viruses and Human Cancer
• Viruses and Lymphomas

Mouse mammary tumor virus (MMTV), which was discovered as a milk‑transmitted, infectious cancer-inducing agent in the 1930s, has been used since that time as an animal model for the study of human breast cancer. Like other complex retroviruses, MMTV encodes a number of accessory proteins that both facilitate infection and affect host immune response. In vivo, the virus predominantly infects lymphocytes and mammary epithelial cells. High level infection of mammary epithelial cells ensures efficient passage of virus to the next generation. It also results in mammary tumor induction, since the MMTV provirus integrates into the mammary epithelial cell genome during viral replication and activates cellular oncogene expression. Thus, mammary tumor induction is a by-product of the infection cycle. A number of important oncogenes have been discovered by carrying out MMTV integration site analysis, some of which may play a role in human breast cancer.

Because MMTV has existed as an infectious virus in mice for millions of years, it has evolved to take advantage of its host’s biology, using host genes from transcription factors to immune regulatory molecules, to establish infection. Although it causes mammary tumors, this does not occur until relatively late in life and thus the virus has persisted, since infected mothers are able to transmit virus to offspring. The lack of acute MMTV-induced pathogenesis is most likely due to different host means of limiting virus infection, including factors that operate at the cellular level like intrinsic restriction factors and immune response genes. As additional host-antiviral genes are discovered, MMTV will continue to serve as an important model for testing the ability of these factors to function in vivo. In addition to serving as an important means for studying virus infection, MMTV has provided a number of critical models for understanding human breast cancer. Finally, the use of the MMTV LTR to direct oncogene expression to murine epithelial cells has resulted in the creation of numerous transgenic mouse strains that serve as critical models for understanding human breast cancer. It is likely that such transgenic mice will continue to be a critical tool as additional human breast cancer genes are identified through large-scale human genetic studies.

Mouse Mammary Tumor Virus Molecular Biology and Oncogenesis. (2010) Viruses 2010 2(9): 2000-2012 doi:10.3390/v2092000

Related:

• No HMTV in human breast cancer samples?
• Vaccines To Prevent Infections by Oncoviruses
• The search for infectious causes of human cancers

The recent identification of retrovirus XMRV and a second retrovirus of a different subtype in chronic fatigue syndrome has aroused much interest, not least among sufferers. However, it remains highly controversial whether the detection of these viruses represents true infection or laboratory artifacts. In this paper, Professor Robin Weiss, the UK’s leading authority on retroviruses, gives his critical appraisal of this confusing data and concludes:

A cautionary tale of virus and disease. BMC Biology 2010, 8: 124 doi:10.1186/1741-7007-8-124

Related:

• XRMV does not cause CFS in the UK
• Viruses and Cancer: XMRV and Prostate Cancer
• Viruses and Human Cancer

Retroviruses undergo several critical steps to complete a replication cycle. These include the complex processes of virus entry, assembly, and budding that often take place at the plasma membrane of the host cell. Both virus entry and release involve membrane fusion/fission reactions between the viral envelopes and host cell membranes. Accumulating evidence indicates important roles for lipids and lipid microdomains in virus entry and egress. This review outlines the current understanding of the role of lipids and membrane microdomains in retrovirus replication.

The Role of Lipids in Retrovirus Replication. Viruses 2010, 2(5), 1146-1180. doi:10.3390/v2051146

Within the past century, a number of “emerging viruses” with pathogenic properties, such as HIV-1, SARS-CoV, and several novel reassortments of influenza A, have entered the human population on a large scale. However, novel pathogenic viral infections of humans are not unique to modern history. “Paleovirology” is the study of ancient extinct viruses (called “paleoviruses”) and the effects that these agents have had on the evolution of their hosts. Thus far, the study of these viruses has mostly been limited to endogenous retroviruses that can be directly identified from their remnants in host genomes. However, one can infer the existence of other paleoviruses from their evolutionary pressures on host genes. This paper suggests that selection to survive the pathogenic effects of these viruses has shaped our repertoire of antiviral defenses in ways that impact our resistance or susceptibility to modern-day emerging viruses.

Paleovirology – Modern Consequences of Ancient Viruses. 2010 PLoS Biol 8(2): e1000301 doi:10.1371/journal.pbio.1000301

Related:

• Phoenix from the ashes: The 5 million year old virus
• The Island of Fossil Viruses

As obligate intracellular parasites, viruses have evolved diverse mechanisms to enter and exit from host cells. A requirement that is shared by all animal viruses is the use of cellular receptors for entry into cells to initiate viral infection. Receptors can function in virus attachment to the cell surface and can also mediate virus internalization and penetration of the cell membrane. Receptors are often grouped into “primary receptors” and “secondary receptors” or “co-receptors” depending either on their function in the virus entry process or historical precedence.

Viruses can be classified into two broad groups: enveloped and non-enveloped. Direct cell-to-cell spread has only been described for enveloped viruses. Viruses that spread directly from infected to uninfected cells can avoid the obstacles to infection which occur for for infection via free virus particles (biophysical and immunological). Once the initial infection has occurred, the cell-to-cell mode of virus spread enables direct infection of target cells by adjacent infected cells – a very efficient process.

Direct cell-to-cell spread requires intimate contact between cells and can occur at tight junctions between cells or neurological synapses. Immune cells contain machinery that allows them to polarize their secretory apparatus towards a second cell that is involved in an immunological synapse. This machinery can be subverted by retroviruses such as HTLV-1 and HIV-1 to form a virological synapse. Virions bud from the infected cell into the synapse, from where they fuse with the target-cell plasma membrane. Certain viruses have therefore engineered novel structures in infected cells to promote more efficient spread within the host.

Avoiding the void: cell-to-cell spread of human viruses. 2008 Nature Reviews Microbiology 6: 815-826. doi:10.1038/nrmicro1972
The initial stages of animal virus infection are generally described as the binding of free virions to permissive target cells followed by entry and replication. Although this route of infection is undoubtedly important, many viruses that are pathogenic for humans, including HIV-1, herpes simplex virus and measles, can also move between cells without diffusing through the extracellular environment. Cell-to-cell spread not only facilitates rapid viral dissemination, but may also promote immune evasion and influence disease. This review discusses the various mechanisms by which viruses move directly between cells and the implications of this for viral dissemination and pathogenesis.

Related:

• Biofilm-like extracellular viral assemblies mediate HTLV-1 cell-to-cell transmission at virological synapses. Nature Med. 2009 16, 83-89. doi:10.1038/nm.2065
• Saturday Cinema: HIV spreading from cell to cell

The stable insertion of a copy of their genome into the host cell genome is an essential step of the life cycle of retroviruses. The site of viral DNA integration, mediated by the viral-encoded integrase enzyme, has important consequences for both the virus and the host cell. The analysis of retroviral integration site distribution was facilitated by the availability of the human genome sequence, revealing the non-random feature of integration site selection and identifying different favored and disfavored genomic locations for individual retroviruses. This new review summarizes the current knowledge about retrovirus differences in their integration site preferences as well as the mechanisms involved in this process.

Retroviral Integration Site Selection. Viruses 2010, 2(1) 111-130. doi:10.3390/v2010111

Related:

• Current and Novel Inhibitors of HIV Protease
• Mutation Rates and Intrinsic Fidelity of Retroviral Reverse Transcriptases
• HIV-1 Protease: Structural Perspectives on Drug Resistance
• Reverse Transcriptase and Cellular Factors: Regulators of HIV-1 Reverse Transcription
• HIV-1 Integrase-DNA Recognition Mechanisms
• Revisiting Plus-Strand DNA Synthesis in Retroviruses and Long Terminal Repeat Retrotransposons

PLoS Pathogens is two years old, and to celebrate, they’ve just published a list of the top ten papers downloaded from September 2005 to July 2007, so if you need to catch up on your reading:

1. Carrageenan Is a Potent Inhibitor of Papillomavirus Infection
   Sexually transmitted human papillomavirus (HPV) infections are very common. Although most HPV infections don’t cause noticeable symptoms, persistent infection with some genital HPV types can lead to cervical cancer or other anal/genital cancers. Another subset of HPV types can cause genital warts. Recent studies have suggested that condoms are not highly effective in preventing HPV infection. Although HPV vaccines will soon become available, they probably will not protect against all genital HPV types and will be too expensive for use in the developing world. Inexpensive HPV-inhibitory compounds (known as topical microbicides) might be useful for blocking the spread of HPV. Using a newly developed cell culture–based HPV inhibition test, we have discovered that an inexpensive gelling agent called carrageenan is an unexpectedly potent HPV infection inhibitor. Carrageenan is also under investigation as a topical microbicide targeting HIV and herpes viruses, but it is a thousand times more effective against HPV in cell culture tests. Interestingly, carrageenan is used as a thickener in some commercially available sexual lubricants and lubricated condoms. Several of these commercial lubricant products are potent HPV inhibitors in our cell culture–infection system. Clinical trials are needed to determine the effectiveness of carrageenan as a topical microbicide against HPV.
2. Modulation of Tumor Necrosis Factor by Microbial Pathogens
   In response to invasion by microbial pathogens, host defense mechanisms get activated by both the innate and adaptive arms of the immune responses. TNF (tumor necrosis factor) is a potent proinflammatory cytokine expressed by activated macrophages and lymphocytes that induces diverse cellular responses that can vary from apoptosis to the expression of genes involved in both early inflammatory and acquired immune responses. A wide spectrum of microbes has acquired elegant mechanisms to overcome or deflect the host responses mediated by TNF. For example, modulatory proteins encoded by multiple families of viruses can block TNF and TNF-mediated responses at multiple levels, such as the inhibition of the TNF ligand or its receptors, or by modulating key transduction molecules of the TNF signaling pathway. Bacteria, on the other hand, tend to modify TNF-mediated responses specifically by regulating components of the TNF signaling pathway. Investigation of these diverse strategies employed by viral and bacterial pathogens has significantly advanced our understanding of both host TNF responses and microbial pathogenesis. This review summarizes the diverse microbial strategies to regulate TNF and how such insights into TNF modulation could benefit the treatment of inflammatory or autoimmune diseases.
3. Identification of a Novel Gammaretrovirus in Prostate Tumors of Patients Homozygous for R462Q RNASEL Variant
   Prostate cancer is the most frequent cancer and the second leading cause of cancer deaths in US men over the age of 50. Several genetic factors have been proposed as potential risk factors for the development of prostate cancer, including a viral defense gene called RNASEL. A common genetic variant in this gene, R462Q, was recently implicated in up to 13% of prostate cancer cases. Given the antiviral role of RNASEL, the authors sought to examine if a virus might be present in prostate cancers associated with the R462Q variant. Using a DNA microarray designed to detect all known viral families, the authors identified a novel virus, named XMRV, in a subset of prostate tumor samples. Polymerase chain reaction testing of 86 prostate tumors for the presence of XMRV revealed a strong association between the presence of the virus and being homozygous for the R462Q variant. Cloning and sequencing of the virus showed that XMRV is a close relative of several known xenotropic murine leukemia viruses. This report presents the first documented cases of human infection with a xenotropic retrovirus. Future work will address the potential connection between XMRV infection and the increased prostate cancer risk in patients with the R462Q RNASEL variant.
4. Human Neutrophils Kill Bacillus anthracis
   Bacillus anthracis is the bacterium that causes anthrax, a disease that can occur through natural infections and also through intentional release. B. anthracis makes spores, which are in a dormant state, similar to seeds of a plant, and are extremely resistant to the environment. B. anthracis spores can infect through the skin or the lung. Lung infections disseminate through the body and are lethal. In contrast, skin infections often remain localized, and patients survive even without treatment. It is not well understood why these bacteria cause a localized infection through the skin and a lethal disease through the lung. Little is known about how B. anthracis is controlled. Neutrophils are the first white blood cells recruited to a site of infection and are specialized in killing microbes. Previous studies show that neutrophils are abundant in the skin form, but not in the lung form of anthrax. The researchers report that human neutrophils can take up B. anthracis spores. Once inside, the spores germinate to form vegetative bacteria. The vegetative bacteria are extremely susceptible to neutrophil-killing mechanisms. The B. anthracis virulence factors (molecules that make bacteria cause diseases) manipulate other human cells but do not deter neutrophils. B. anthracis is indeed exquisitely sensitive to the neutrophil protein α-defensin. These data support a new model where B. anthracis skin, but not lung, infections are controlled by the antimicrobial activity of neutrophils.
5. A Novel Bacterium Associated with Lymphadenitis in a Patient with Chronic Granulomatous Disease
   As new bacteria continue to be discovered every year, it is inevitable that some of them will be found to cause human disease. The authors describe the isolation and characterization of a new bacterium, grown from a patient with chronic granulomatous disease (CGD). In this genetic disease, one of the main lines of defense against infection, the neutrophil, has a discrete defect in the generation of superoxide, leading to recurrent infections with a narrow spectrum of bacteria and fungi. This new organism was cultured from lymph nodes that had been inflamed for several months. To prove that this new bacterium was indeed a pathogen, Greenberg and colleagues measured specific antibody response in the patient: they inoculated CGD mice with this organism and reproduced the appearance of the human infection; they recovered the organism in pure growth from infected mouse spleens. This new bacterium belongs to the family Acetobacteraceae, bacteria that are found widely in the environment. They have a variety of industrial uses, such as the production of vinegar, but have never been reported to cause invasive human disease. Disease-causing organisms remain to be discovered. The researchers outline some of the steps that can be taken to verify the pathogenicity of novel organisms.
6. Gene-Specific Countermeasures against Ebola Virus Based on Antisense Phosphorodiamidate Morpholino Oligomers
   Ebola virus (EBOV) causes a highly lethal hemorrhagic fever that results in up to 50%–90% mortality in humans. There are currently no available vaccines or therapeutics to treat EBOV infection. To date, multiple pre- and post-exposure therapeutic strategies, primarily focused on bolstering the host immune response or inhibiting viral replication, have been undertaken with limited success. Here, Bavari and colleagues report the development of a successful therapeutic regimen for EBOV infection based on antisense phosphorodiamidate morpholino oligomers (PMOs). PMOs are a subclass of chemically modified antisense oligonucleotides that interfere with the translation of viral mRNA, thus inhibiting viral amplification. Using a cell-free translation system, a cell-based assay, and survival studies in rodents, we identified several efficacious EBOV-specific PMOs. Further, prophylactic administration of a combination of three EBOV-specific PMOs specifically targeting VP24, VP35, and the viral polymerase L protected rhesus macaques from lethal EBOV infection. This is the first successful antiviral intervention against filoviruses in nonhuman primates. These findings may serve as the basis for a new strategy to quickly develop virus-specific therapies in defense against known, emerging, and genetically engineered bioterrorism threats.
7. The Role of Innate Immune Responses in the Outcome of Interspecies Competition for Colonization of Mucosal Surfaces
   Bacterial infection commonly begins with organisms that colonize and proliferate on mucosal surfaces. These microenvironments may be occupied by multiple microbial species, suggesting that successful colonizers are distinguished by their capacity to prevail over their competitors. This study examines interactions between two bacterial species that both colonize and infect the human upper respiratory tract. In a mouse model, strains of both Haemophilus influenzae and Streptococcus pneumoniae efficiently colonize the nasal mucosa when tested individually. In contrast, following co-inoculation, H. influenzae rapidly and completely outcompetes S. pneumoniae. This competitive effect is dependent on the local responses from the host in the form of a specific type of white blood cell (neutrophil) that acts to engulf and kill microorganisms that have been labeled by proteins that bind to microbial surfaces (complement). The results of this study show that recognition of microbial products from one species may activate inflammatory responses that promote the clearance of another competing species. This study also demonstrates how manipulations such as antibiotics or vaccines, which are meant to diminish the presence of a single pathogen, may inadvertently alter the competitive interactions of complex microbial communities.
8. Prions Adhere to Soil Minerals and Remain Infectious
   Transmissible spongiform encephalopathies (TSEs) are a group of incurable diseases likely caused by a misfolded form of the prion protein (PrP^Sc). TSEs include scrapie in sheep, bovine spongiform encephalopathy (“mad cow” disease) in cattle, chronic wasting disease (CWD) in deer and elk, and Creutzfeldt-Jakob disease in humans. Scrapie and CWD are unique among TSEs because they can be transmitted between animals, and the disease agents appear to persist in environments previously inhabited by infected animals. Soil has been hypothesized to act as a reservoir of infectivity, because PrP^Sc likely enters soil environments through urinary or alimentary shedding and decomposition of infected animals. In this manuscript, the authors test the potential for soil to serve as a reservoir for PrP^Sc and TSE infectivity. They demonstrate that PrP^Sc binds to a variety of soil minerals and to whole soils. They also quantitate the levels of protein binding to three common soil minerals and show that the interaction of PrP^Sc with montmorillonite, a common clay mineral, is remarkably strong. PrP^Sc bound to Mte remained infectious to laboratory animals, suggesting that soil can serve as a reservoir of TSE infectivity.
9. The Expanding Universe of Prion Diseases
   Prions cause fatal and transmissible neurodegenerative disease. These etiological infectious agents are formed in greater part from a misfolded cell-surface protein called PrP^C. Several mammalian species are affected by the diseases, and in the case of “mad cow disease” (BSE) the agent has a tropism for humans, with negative consequences for agribusiness and public health. Unfortunately, the known universe of prion diseases is expanding. At least four novel prion diseases—including human diseases variant Creutzfeldt-Jakob disease (vCJD) and sporadic fatal insomnia (sFI), bovine amyloidotic spongiform encephalopathy (BASE), and Nor98 of sheep—have been identified in the last ten years, and chronic wasting disease (CWD) of North American deer (Odocoileus Specis) and Rocky Mountain elk (Cervus elaphus nelsoni) is undergoing a dramatic spread across North America. While amplification (BSE) and dissemination (CWD, commercial sourcing of cervids from the wild and movement of farmed elk) can be attributed to human activity, the origins of emergent prion diseases cannot always be laid at the door of humankind. Instead, the continued appearance of new outbreaks in the form of “sporadic” disease may be an inevitable outcome in a situation where the replicating pathogen is host-encoded.
10. Crossing the Line: Selection and Evolution of Virulence Traits
    The evolution of pathogens presents a paradox. Pathogenic species are often absolutely dependent on their host species for their propagation through evolutionary time, yet the pathogenic lifestyle requires that the host be damaged during this dependence. It is clear that pathogenic strategies are successful in evolutionary terms because a diverse array of pathogens exists in nature. Pathogens also evolve using a broad range of molecular mechanisms to acquire and modulate existing virulence traits in order to achieve this success. Detailing the benefit of enhanced selection derived through virulence and understanding the mechanisms through which virulence evolves are important to understanding the natural world and both have implications for human health.

Nice work. Open access publishing has come of age.