A new study looking at unprotected intercourse within gay couples when each partner has established HIV-infection found a correlation between anti-HIV immune response and sexual activity.

Study results showed that individuals who had regular unprotected receptive anal intercourse with partners with significant levels of HIV in their blood showed a stronger anti-HIV immune response. In addition, the magnitude of anti-HIV specific immune response correlated with their exposure to HIV through sex.

Published in the October 24th, 2008 issue of PLoS Pathogens, the study paper is authored by a research team from UCSF and the Gladstone Institute for Virology and Immunology.

The researchers found no evidence of systemic superinfection (re-infection with another strain of HIV) in the receptive partners, whose virus had been successfully suppressed through antiretroviral therapy for at least five months. In a comparison group of HIV-infected couples in which both partners’ viruses had been suppressed by therapy, researchers did not find the same strength of immune responses correlations or the same correlations with sexual exposure.

“We found HIV-specific immune responses in the treatment-suppressed partners that correlated with the level and route of exposure. The individuals with no detectable virus who were on antiretroviral therapy and who were exposed to HIV through receptive intercourse with a partner with detectable virus, had the stronger anti-HIV immune responses in comparison to individuals exposed to partners whose virus was also suppressed by antiretroviral therapy, where no effect was seen,” said study lead author, Christian B. Willberg, PhD, post-doctoral fellow in the UCSF Division of Experimental Medicine.

Notwithstanding the intriguing HIV specific findings, the findings also reveal an important general mechanism occurring in infectious diseases.

“We found that immune responses to chronic viral infections are influenced not only by the chronic infection existing in an individual or host, but also by exposures to exogenous virus from outside the individual or host,” said study co-senior author, Douglas F. Nixon, MD, PhD, professor of medicine in the UCSF Division of Experimental Medicine.

The investigators were unable to determine from these findings whether there is any benefit from this type of repeated exposure to HIV—i.e., a type of therapeutic vaccination for HIV-infected patients with suppressed virus. Some HIV patients on antiretroviral regimens lose many of their HIV-specific immune responses over time due to the successful suppression of viral replication by therapy.

“Indeed, our hypothesis had been that in the context of these waning anti-HIV responses among the suppressed partners and the expected level of exposure from repeated unprotected receptive intercourse, we would find evidence of superinfection. While we did not find systemic super-infection, we cannot exclude limited or localized superinfections in the gut. And, antiretroviral therapy may have been the factor that prevented superinfection in these patients,” said study co-senior author Robert M. Grant, MD, MPH, senior investigator at the Gladstone Institute of Virology and Immunology and associate professor of medicine at UCSF.

The study involved 49 HIV-infected gay men from the San Francisco Positive Partners Program study—a cohort of couples in which both partners are HIV-positive that began enrolling participants in 2000. Viral suppression in this study meant viral loads less than 50 copies. Among those participants whose virus had not been suppressed, the lowest viral load was 9,420 copies.

The team that designed this study benefited from its unique multidisciplinary composition. Immunologists working with social researchers were able to design a study that managed to distinguish between different levels of viral suppression and different patterns of sexual contacts and correlate the immunological aspects with the behavioral variables.

“We call the interaction between these two scientific communities together: ’social immunology’. It may be true that patterns of social activities shape immune responses generally, as we observed for people with HIV having contact with other HIV infected persons. Obviously more study is needed and we would like to see whether social immunology will continue to offer important insights,” said Grant.

“While we have not found a case of superinfection in our cohort of chronically infected HIV couples, a handful of cases of superinfection verified by linkage to a known partner’s virus have been reported in chronically infected HIV patients. It is also important to stress, these findings do not address the negative consequences of acquiring other sexually transmitted diseases through engaging in unprotected sex or the potentially positive consequences that unprotected sex may have in partnerships where both individuals are HIV-positive,” said study co-author, J. Jeff McConnell, MA, director of the Positive Partners study at the Gladstone Institute for Virology and Immunology.

As the first globally co-ordinated plan for the planet’s gravest health threats is hatched by government ministers from around the world this weekend, a new report sets out a 10-point plan for this new, globalised approach to infectious diseases such as avian flu.

Ministers of health and agriculture will formulate a global plan to prepare for, and respond to, the threat of avian flu and other emerging infectious diseases at the International Ministerial Conference on Avian and Pandemic Influenza in Sharm el Sheikh, Egypt (October 24-26). The plan - called the One World, One Health initiative - aims for an unprecedented integration of animal, human and ecosystem health issues to fight the threat of the avian flu virus, H5N1.

A new report by Professor Ian Scoones and Paul Forster of the ESRC STEPS Centre at the UK’s Institute of Development Studies lays out 10 key recommendations for One World, One Health, based on analysis of lessons learned from the massive $2bn international response to the avian flu over the past five years, during which time 245 people have died.

According to the report - The International Response to Highly Pathogenic Avian Influenza: Science, Policy and Politics - ministers need to rethink current ideas in order to achieve an effective, equitable and resilient international plan of response to emerging diseases.

The recommendations include rethinking disease surveillance, redefining health security, new responses to uncertainty and ignorance, emphasising access and equity as well as questions of organisational architecture and governance.

“The One World, One Health initiative is a radical departure from the conventional sectoral approaches to health. It is essential, but presents many challenges. We have identified 10 challenges for the way ahead, and urge ministers to rethink rather than repackage their measures. One World One Health needs to be more than ‘old wine in new bottles’,” said Professor Ian Scoones, IDS Fellow and co-director of the ESRC STEPS Centre.

Over the last decade, the avian flu virus, H5N1, has spread across most of Asia and Europe and parts of Africa. In some countries – including Indonesia, China, Vietnam, Bangladesh, Nigeria and Egypt – the disease has become endemic. Although 245 deaths have been reported since 2003 there has, as yet, been no human pandemic. But somewhere, some time, a new emerging infectious disease will have major impacts, given changing disease ecologies and patterns of urbanisation and climate change.

A major international response, backed by over $2bn of public money, has affected the livelihoods and businesses of millions. Markets have been restructured, surveillance and poultry vaccination campaigns implemented, and over two billion birds have died or been culled. Simultaneously substantial investment has been made in human and animal health systems and developing drugs and vaccines.

In many countries pandemic contingency and preparedness plans have been devised. Yet coordination at country level has been found wanting; rivalries between professions and organisations persist; and funding and capacities for an effective and equitable global responses to a pandemic remain weak.

The themes addressed in this report are being explored as part of a project on avian influenza policy responses in Cambodia, Indonesia, Thailand and Vietnam, in collaboration with the UN Food and Agriculture Organisation. They are central to the ESRC STEPS Centre’s research programme on ecology, politics, policy and pathways to sustainability.

Among many global health challenges, infectious diseases remain among the most problematic, accounting for about one quarter of all deaths globally, and nearly two-thirds of deaths in sub-Saharan Africa. Dr. Fauci will discuss progress–and remaining challenges–in the fight against major infectious causes of death and disability such as HIV/AIDS, malaria, tuberculosis and drug-resistant microbes. He also will discuss how conceptual and technological progress in fields such as genomics and nanotechnology has invigorated infectious disease research. These advances also are contributing to exciting studies on the ecology of human disease, including the Human Microbiome Project, which is exploring how the billions of bacteria that inhabit our bodies contribute to health and illness.

Other NIAID scientists are scheduled to present findings during the four-day meeting as well. The range of topics covered reflects the broad scope of NIAID’s research efforts aimed at better understanding, treating and preventing infectious and immune-mediated diseases.

• Noroviruses, the highly contagious viruses that cause the episodes of acute gastroenteritis also known as winter vomiting disease (Kim Green, Ph.D.)
• The role of gut-dwelling commensal bacteria in producing the symptoms of Crohn’s disease, a chronic inflammatory disease of the intestines (Warren Strober, M.D.)
• Antibiotic-resistant bacterial infections caused by Staphylococcus epidermidis (Michael Otto, Ph.D.) and Staphylococcus aureus (Frank DeLeo, Ph.D.)
• Finding ways to treat primary immunodeficiencies, inherited conditions in which immune function is impaired (Steve Holland, M.D.)
• Containing Ebola virus, for which there is currently no vaccine or specific treatment (Gary Nabel, M.D., Ph.D.)

An international study led by University of Leicester researchers has determined that vaccination will be the best way to protect people in the event of the next influenza pandemic – but that each person would need two doses.

In an article in the New England Journal of Medicine published on October 9, researchers from the University of Leicester and University Hospitals of Leicester report on a study carried out at the Leicester Royal Infirmary.

Dr Iain Stephenson, Consultant in Infectious Diseases at the Infirmary and a Clinical Senior Lecturer at the University of Leicester carried out the research with Professor Karl Nicholson, Professor of Infectious Diseases at the University of Leicester and Consultant Physician at the Leicester Royal Infirmary.

The research was carried out in collaboration with Katja Hoschler, and Maria C. Zambon of the Health Protection Agency, Kathy Hancock, Joshua DeVos, Jacqueline M. Katz, from the Centers for Disease Control and Prevention, Atlanta, Michaela Praus and Angelika Banzhoff, from Novartis Vaccine, Germany. It is published in a letter to the NEJM.

An influenza pandemic occurs when a new influenza strain emerges (one to which humans have no immunity), mutates and spreads globally as a virus. Although it is not possible to predict the actual pandemic influenza strain, global health authorities have identified H5N1 avian influenza as a strain with the greatest pandemic potential in humans. H5N1 is currently circulating in birds and has caused serious illness in more than 380 people worldwide with a mortality rate, among people known to have been infected, of greater than 60 percent.

Dr Stephenson said: “In the event of the next influenza pandemic, vaccination will be the best way to protect people. Because of manufacturing capacity constraints, vaccines ideally need to be as a low dose as possible so that limited antigen material can be optimally used.

“In addition, it generally takes two doses of vaccine to give a good response, so if a pandemic occurred it would take some time to produce vaccine and then administer 2 doses to protect people. Therefore stockpiling of vaccines has been suggested to overcome some of these difficulties. However, subjects will still require 2 doses to generate protection and if the pandemic spreads rapidly this could be challenging to deliver.”

The Leicester study looks at boosting those people who were vaccinated up to 7 years ago in the first H5 vaccine trials conducted in Leicester with a new updated H5 vaccine, in comparison to vaccinating subjects for the first time.

“We have found that a single low dose booster vaccine, given 7 years later, generated a very rapid response and within 1 week of vaccination, over 80% subjects had an excellent response to all strains of the H5 virus. In comparison, the unprimed subjects who were vaccinated for the first time needed two doses of vaccine and achieved protective levels of antibody after 6 weeks as expected.

The results indicate that regardless of which avian strain individuals are originally primed with, they are quickly protected against a broad range of avian strains following their booster vaccine, even strains they were not initially inoculated against. These results potentially provide a rationale to prevent pandemic influenza by proactively immunizing the public with stockpiled pre-pandemic vaccines.

“Therefore the importance of this study is to help policy makers decide how to use the stockpiled vaccine. We find that proactively priming subjects (such as key personnel and first responders) to generate long lived memory immune responses that could be boosted rapidly many years later could be used as a potential vaccination strategy.”

Flaviviruses such as tick-borne encephalitis virus (TBEV), yellow fever, and dengue are dangerous human pathogens.  These membrane-encircled viruses enter cells by being gobbled up into endosomes and fusing their membrane with that of the endosome.

Fusion is triggered by the endosome’s acidic environment.  Low pH prompts the aptly named fusion protein, on the virus’s outer membrane, to change shape and grab hold of the endosome membrane, bringing the two membranes together.  In their search for possible pH sensors, researchers have focused on five highly conserved histidine residues in the flavivirus fusion protein.  The chemical properties of histidines make them prime candidates—they switch from uncharged to having a double positive charge upon acidification of their environment, such as that in endosomes.

Fritz et al.  Replaced each of the five histidines of the TBEV fusion protein with alternative residues and observed the virus’s fusion ability.  Given the conservation of the five histidines, the team was surprised, that mutation of one of the histidines, His323, was sufficient to completely abolish fusion.  Individual mutation of three of the others had no effect on fusion whatsoever, and mutation of the fourth led to an untestable ill-formed fusion protein.

The team went on to show that mutation of the crucial His323 interfered with the pH-induced shape change of the fusion protein.

In research aimed at addressing a global epidemic, a team of scientists from around the world has cracked the genetic code for the parasite that is responsible for up to 40 percent of the 515 million annual malaria infections worldwide, Nature reveals in its October 9 cover story.

Led by a parasitologist from NYU Langone Medical Center, Jane Carlton, PhD, some 40 researchers sequenced the genome of Plasmodium vivax (P.  Vivax), one of four malaria parasites that routinely affect humans.  P. vivax, which is increasingly resistant to some antimalarial drugs, is the species most common outside Africa, particularly in Asia and the Americas, including the United States, the site of periodic outbreaks.

Vivax malaria, as it is known, is believed more robust and resilient than its cousin, the more deadly malaria species, P. falciparum – and is thus more difficult to eradicate.  Distinctively, vivax malaria can be transmitted by mosquitoes in cooler temperatures.  It also has a dormant stage that enables it to re-emerge as climates warm, causing “relapses” of the disease months and even years after a first attack.

Symptoms for the two strains of malaria are similar – flu-like, featuring fever and abdominal pain, often leading to severe anemia – and, in children, lifelong learning disabilities.  Malaria is a disease of poorer populations, and overall is estimated annually to kill more than a million people worldwide.

Researchers also identified several pathways in the P. vivax parasite that could eventually be targets for drug treatment.  Both P. vivax and P. falciparum vivax are also being studied to identify potential vaccine targets.

The research is regarded as all the more significant in that P. vivax has long remained little-researched, little-known and little-understood.  Such neglect is mainly due to the focus on the more deadly malaria species, P. falciparum -P.  Vivax is seldom lethal -and also because the parasite cannot be grown in a lab setting.  Further, the growing burden of vivax malaria will complicate efforts to control P. falciparum in areas where the two coincide.

Indeed, the project that led to the landmark genetic decoding was in the works for a total of six years, involving researchers from England, Spain, Australia and Brazil as well as the United States.  After two years, remaining funds from the P. falciparum genome project were exhausted, and funding from the Burroughs Wellcome Fund and the National Institutes of Health allowed its completion.

P. vivax is the second species of human malaria parasite to be sequenced.  Researchers found the genome for P. vivax dramatically different from the genomes of three other sequenced malaria parasites – different in content, structure and complexity.  They used whole genome shotgun methods to produce high-quality sequences that will enable malaria researchers worldwide to undertake further research on the parasite.  The next step is to sequence six other P. vivax genomes – from Brazil, Mauritania, India, North Korea and Indonesia -to identify novel vaccine candidates and generate an evolutionary map of the species.

“This project is a tribute to the collegiality and tenacity of the vivax malaria community,” says Jane M. Carlton, associate professor at NYU School of Medicine’s Department of Medical Parasitology, who led a team of investigators from around the world.  “They have persevered despite financial tribulations and lack of interest to generate an invaluable resource.  These findings will be used by all malariologists for years to come to advance scientific investigation into this neglected species.”

“The availability of genome sequence data has great potential to accelerate the identification and development of novel vaccines and therapeutics against this major human pathogen,” says Claire Fraser-Liggett, PhD, director of the Institute of Genomic Sciences at University of Maryland School of Medicine and formerly president of The Institute for Genomic Research, Rockville Maryland where the project began.  “Dr.  Carlton is to be congratulated for her leadership role in bringing this project to completion.”

“Unveiling the full genome sequence of Plasmodium vivax is a tremendous advance – a huge step forward in parasite biology and the fight against malaria,” says Nick White, MD, professor of tropical medicine, Oxford University, England and Mahidol University, Thailand.

Researchers at the University of Toronto have shown that the EBNA1 protein of Epstein-Barr virus (EBV) disrupts structures in the nucleus of nasopharyngeal carcinoma (NPC) cells, thereby interfering with cellular processes that normally prevent cancer development.  The study, published October 3rd in the open-access journal PloS Pathogens, describes a novel mechanism by which viral proteins contribute to carcinogenesis.

EBV is a common herpesvirus whose latent infection is strongly associated with several types of cancer including NPC, a tumor that is endemic in several parts of the world.  With NPC only a few EBV proteins are expressed, including EBNA1.  EBNA1 is required for the persistence of the EBV genomes, however, whether or not EBNA1 directly contributes to the development of tumors has not been clear, until now.

In this study Frappier and her team examined PML nuclear bodies and proteins in EBV-positive and EBV-negative NPC cells.  Manipulation of EBNA1 levels in each cell type clearly showed that EBNA1 expression induces the loss of PML proteins and PML nuclear bodies through an association of EBNA1 with the PML bodies.  PML nuclear bodies are known to have tumor-suppressive effects due to their roles in regulating DNA repair and programmed cell death, and accordingly, EBNA1 was shown to interfere with these processes.

The researchers conclude that there is “an important role for EBNA1 in the development of NPC, in which EBNA1-mediated disruption of PML nuclear bodies promotes the survival of cells with DNA damage.”  Since EBNA1 is expressed in all EBV-associated tumors, including B-cell lymphomas and gastric carcinoma, these findings raise the possibility that EBNA1 could play a similar role in the development of these cancers.  The cellular effects of EBNA1 in other EBV-induced cancers will require further investigation.

A surprising interaction may enable development of new HIV treatment strategies by exploiting infection with multiple pathogens.  The research, published by Cell Press in the September 11th issue of the journal Cell Host and Microbe, demonstrates that a drug commonly used to treat herpes directly suppresses HIV in coinfected tissues and thus may be beneficial for patients infected with both viruses.

Commonly, individuals infected with HIV are infected also with other microbes.  Infection with human herpesvirus (HHV), especially with herpes simplex virus-2 (HSV-2), is often associated with HIV.  These HHV infections may be either active or dormant, but HIV infection makes HHV reactivation more likely.

For many years, acyclovir (ACV), a well-studied drug, has been used safely to treat HHV in humans.  “HHV has a unique ability to phosphorylate ACV to activate it, making the drug quite specific for HHV and, for the same reason, relatively non-active against other viruses, including HIV,” offers senior study author Dr. Leonid Margolis from the National Institute of Health.  Nevertheless, some patients coinfected with HIV and HSV-2 exhibit lower HIV levels after ACV treatment.

“We decided to investigate this phenomenon experimentally using small blocks of human tissues” says Dr. Margolis.  “Drs.  Andrea Lisco and Christophe Vanpouille who performed this work in my laboratory found that although ACV doesn’t inhibit HIV in ’sterile’ cell lines, it does, surprisingly, suppress HIV in tissues that carry no HSV-2 but various other HHVs.”  In collaboration with a prominent AIDS researcher Dr. Raymond Schinazi from Emory University and Dr. Matthias Gotte from McGill University, the researchers found that phosphorylated ACV that is formed in HHV-infected cells directly inhibits the HIV-1 reverse transcriptase (RT), thus preventing HIV from copying itself.

These results not only help to explain the response to ACV seen in patients coinfected with HSV-2 and HIV, but also suggest that ACV may be used against HIV in patients infected with various other HHVs, including the low-pathogenic and ubiquitous HHV-6 and HHV-7.  Moreover, in collaboration with Drs.  Balzarini from Catholic University of Leuven and McGuigan from Cardiff University, Dr. Margolis and his team demonstrated that new strategies for development of novel HIV inhibitors based on ACV structure can now be developed.  “We provide definitive experimental evidence of inhibition of HIV-1 RT activity by phosphorylated ACV and demonstrate that ACV phosphorylation occurring in human tissues infected by various HHVs transforms this widely-used inexpensive anti-herpes drug into a direct HIV inhibitor,” concludes Dr. Margolis.

Yeast fungus cells that kill thousands of AIDS patients every year escape detection by our bodies’ defences by hiding inside our own defence cells, and hitch a ride through our systems before attacking and spreading, scientists heard today (Tuesday 9 September 2008) at the Society for General Microbiology’s Autumn meeting being held this week at Trinity College, Dublin.

Cells of the Cryptococcus yeast responsible for one of the three most life-threatening infections that commonly attack HIV infected patients, causing cryptococcal meningitis, are using a previously unknown way to avoid detection, according to scientists from the University of Birmingham, UK.

“We have shown that these airborne yeast cells can hide inside our bodies’ own white blood cells, called macrophages, and then use them as vehicles to travel around inside our bodies, using them just like a bus,” said Miss Hansong Ma of the University of Birmingham.  “The yeast cells then escape from inside the macrophages when they arrive at the right destination – but importantly, they do this without killing the macrophage, which would trigger alarm bells.”

When a host’s cells are invaded by bacteria, fungi or viruses the invaders usually use the opportunity to multiply inside the cells and escape by bursting out, killing the host and releasing thousands of copies of the pathogen to attack other cells.  The death of the host cell releases debris and by-products which usually triggers our bodies into mounting an immune response, causing inflammation.

“This new method of remaining inside the host cells means that the pathogen can spread more efficiently round our bodies and is protected from the natural defences in our bloodstream that would normally kill the yeast or other invader,” said Hansong Ma.  “Yeast cells avoid killing or damaging the macrophages.  They leave by a method that we call ‘vomocytosis’; the yeast cells are acting like spies rather than terrorists, and go unnoticed, giving them more time to establish an infection.”

Although the use of antiretroviral drugs is cutting the number of AIDS patients with Cryptococcus infections there is still a major epidemic in Southeast Asia and Africa.  Up to 30% of AIDS patients there are infected, and up to 44% will die from the disease within 8 weeks.  Even in the USA or European countries like France where antiretroviral drug treatments are readily available, one in ten infected patients will die.

“We badly need to better understand the interaction between hosts, viruses and attacking pathogens like the yeast fungus to help us find new drug targets and so design new ways to treat these patients,” said Hansong Ma.

“We used time-lapse microscope photography to identify this new escape mechanism, and watched the yeast cells escaping into the fluid surrounding cells or, remarkably, directly into other host cells through cell-to-cell transmission, continuing to avoid detection by using this extremely rapid vomocytosis,” said Hansong Ma.  “Worryingly, this enables the cryptococci to avoid antifungal drugs and other treatments as well as our normal immune system, and may allow the yeast to become latent, achieving a long-term infectious state which could then be spread even further, to other individuals, without anyone realising.”

Researchers are describing progress toward developing a new generation of chemotherapy agents that target and block uncontrolled DNA replication — a hallmark of cancer, viral infections, and other diseases — more effectively than current drugs in ways that may produce fewer side effects.  Their article is scheduled for the Aug. 27 issue of ACS’ Biochemistry, a weekly journal.

In the article, Anthony J. Berdis updates and reviews worldwide research efforts to develop drugs that target DNA polymerases, the enzymes responsible for assembling DNA from its component parts.  Several promising strategies are already in use that inhibit uncontrolled DNA replication, particularly in anticancer therapy, but most produce severe side effects and are hampered by drug resistance, the researcher notes.

Berdis says that one of the more promising strategies to date involves the use of so-called nucleoside analogues, artificial pieces of DNA that inhibit replication by substituting for natural segments.  Most nucleoside analogues directly target the active site of the polymerase enzyme, a non-specific approach that can also harm healthy cells which contain the enzyme.  Berdis describes an alternative approach in which the drugs directly target damaged DNA while avoiding healthy DNA, side-stepping the polymerase enzymes of normal cells.  The development, which shows promise in preliminary lab studies, could lead to improved nucleoside analogues with fewer side effects, he says.

Providing preventive treatment for malaria, given once per term, dramatically reduces rates of malaria infection and anaemia among schoolchildren, and significantly improves their cognitive ability, according to new research published today in the Lancet.

Malaria is a major cause of morbidity and mortality in early childhood, but its consequences during the school-age years are less widely acknowledged.  By the time an African child enters school they have generally been repeatedly infected with malaria and have acquired immunity to the parasite making them less likely to die.  However, malaria still accounts for up to 20% of deaths among schoolchildren, is an important cause of school absenteeism, and may hinder educational achievement.  Additionally, many schoolchildren continue to harbour malaria parasites without displaying any symptoms of disease.  These asymptomatic infections frequently go unrecognised and untreated, leading to anaemia and, as demonstrated for the first time in this study, impaired performance in school.

School-based health programs have been shown to work well in combating other diseases, such as worm infections, but less is known about their role in tackling malaria.  Yet more children are now attending school than ever before and governments are increasingly recognising the importance of child health for educational achievement.

A multi-disciplinary team of Kenyan and British researchers investigated the impact of IPT, a new method of tackling malaria which involves the mass administration of a full course of an anti-malarial drug irrespective of whether children are infected.  They assessed whether IPT could reduce the prevalence of anaemia, and improve classroom attention and educational achievement in schoolchildren.  They carried out a randomised, placebo-controlled trial of IPT in 30 primary schools in a rural area of high malaria transmission in western Kenya.  In total, 4916 children, aged 5-18 years, received three treatments (sulfadoxine-pyrimethamine combined with amodiaquine, or a dual placebo) at four-monthly intervals, once each school term.  The impact of treatment was assessed through cross-sectional surveys 12 months later.

IPT dramatically reduced the occurrence of malaria infection in schoolchildren.  The risk of anaemia was halved among those receiving IPT compared with the controls, and significant improvements were also seen in class-based tests of sustained attention among those receiving IPT.  No impact was observed for educational achievement.

Dr. Matthew Jukes, Assistant Professor of International Education at the Harvard Graduate School of Education, worked on the study and comments: ‘Although it has long been suspected that malaria impairs school performance, this is the first study to provide evidence of a direct link between malaria and reduced attention in class.  These results indicate that malaria infection may hinder learning and its prevention could be important to enhance the educational potential of schoolchildren.’

Dr. Siân Clarke, a Lecturer in Malaria Research and Control at the London School of Hygiene & Tropical Medicine, comments: ‘Our findings highlight the neglected burden of malaria in older children, and reveal that malaria infection in schoolchildren may have more profound consequences than previously appreciated.  Preventing malaria could have important health and cognitive benefits for African schoolchildren and deserves more attention.  These results show us that intermittent preventive treatment in schools is a novel and effective means to address this problem.’

The findings of the study have particular relevance for the global ‘Education for All’ initiative which aims to achieve universal school enrolment and enhance schooling.

The intervention could prove a valuable and affordable addition to realising ‘Education for All’ goals through school health and nutrition programmes which already provide treatments against worm infections.  School-age children represent 26% of Africa’s population where 94% of children go to school.  Numerically, this represents up to191 million children who could benefit from a systematic approach to school-based malaria control, which could include IPT.

Dr. Simon Brooker, a Reader in Tropical Epidemiology at the London School of Hygiene & Tropical Medicine adds: ‘For a small financial investment the potential gains from the approach of IPT are extremely attractive.  An important next step will be to work with government and development partners in Africa to investigate further the feasibility and costeffectiveness of scaling up an IPT package within the context of school health programmes’.

A study published July 11th in the open-access journal PloS Pathogens suggests that herpesviruses use multiple strategies to manipulate important components of the host cell nuclear environment during infection.  The study, conducted by researchers at the University of Toronto in collaboration with Affinium Pharmaceuticals Inc., provides novel insights into the potential functions of over 120 previously uncharacterized viral proteins.

Most people are infected with the three human herpesviruses that were the subject of this study; namely herpes simplex virus (type 1), Epstein-Barr virus, and cytomegalovirus.  Herpesviruses have complex life cycles due to their adept manipulation of the host cell environment.  Although often asymptomatic, herpesviruses can cause life-threatening diseases.  In order to provide a more complete understanding of how these viruses alter host cells, the researchers developed a system to examine each viral protein individually in human cells.

The researchers investigated over 230 individual proteins from the three herpesviruses.  They focused on 93 identified viral proteins that localized to the cell nucleus and altered key cellular components that regulate gene expression, cell growth and death, and antiviral responses.

Cells depend on nuclear structures called PML bodies to control cell proliferation and survival, to ensure damaged DNA is repaired, and to inhibit virus replication.  24 of the nuclear viral proteins, several of which had no previously assigned function, were found to disrupt or reorganize PML bodies, suggesting that herpesviruses employ multiple strategies for manipulating this key regulator of essential cellular processes.

Further studies will be needed to determine how the identified viral proteins function in the context of viral infection, but this research provides a starting point for investigating how these proteins affect important processes of the cell nucleus.

Individuals inhale measles virus particles in aerosols and it is currently thought that these particles infect the cells that line the airways (respiratory epithelial cells) before being passed to immune cells that carry the virus particles to other parts of the body and then back to the airways, which again become infected and shed virus into exhaled aerosols.  In the study, a measles virus unable to bind to and infect epithelial cells was found to cause symptoms of measles virus infection in monkeys even though it did not infect respiratory epithelial cells and was not being shed into exhaled aerosols.  These data suggest that, in fact, inhaled measles virus particles first infect lymphocytes and are only passed to respiratory epithelial cells from the lymphocytes in the tissues.  Further, they indicate that the protein that measles virus particles bind to on respiratory epithelial cells, which has yet to be identified, is likely to be found on the surface of the cells that faces the tissues rather than the surface that faces the airways, as previously assumed.  As discussed in an accompanying commentary by Makoto Takeda, at Kyushu University, Japan, the results of this study should help researchers identify this protein.

Coronaviruses, a group including the well-known SARS virus, are the causative agents of many respiratory and enteric infections in humans and animals. As with all viruses, virtually every step of their infection cycle depends on host cellular factors. As the first, most crucial step after their penetration into cells, coronaviruses assemble huge RNA replication “factory” complexes in association with characteristic, newly induced double membrane vesicles. The cellular pathways hijacked by these plus-strand RNA viruses to create these “factories” have thus far not been elucidated.

The researchers, led by Cornelis A. M. de Haan, showed that RNA replication of mouse hepatitis coronavirus (MHV) was inhibited by a drug — brefeldin A — that disrupts the central station in the cell’s secretory pathway, the Golgi complex. Consistently, depletion of both the cellular target of brefeldin A, a factor called GBF1, and its downstream target, ARF1, was also shown to negatively affect coronavirus infection.

The researchers conclude that “an intimate association exists between the early secretory pathway and MHV replication.” They speculate that, while GBF1 and ARF1 are not involved in the formation of the viral replication structures, they probably play a key role in their maturation or functioning. As this work was limited to the mouse hepatitis coronavirus, an interesting next step would be to study the importance of GBF1 and ARF1 in the replication of other coronaviruses.

Viruses are true experts at importing genetic material into the cells of an infected organism. This trait is now being exploited for gene therapy, in which genes are brought into the cells of a patient to treat genetic diseases or genetic defects. Korean researchers have now made an artificial virus. As described in the journal Angewandte Chemie, they have been able to use it to transport both genes and drugs into the interior of cancer cells.

Natural viruses are extremely effective at transporting genes into cells for gene therapy; their disadvantage is that they can initiate an immune response or cause cancer. Artificial viruses do not have these side effects, but are not especially effective because their size and shape are very difficult to control—but crucial to their effectiveness. A research team headed by Myongsoo Lee has now developed a new strategy that allows the artificial viruses to maintain a defined form and size.

The researchers started with a ribbonlike protein structure (β-sheet) as their template. The protein ribbons organized themselves into a defined threadlike double layer that sets the shape and size. Coupled to the outside are “protein arms” that bind short RNA helices and embed them. If this RNA is made complementary to a specific gene sequence, it can very specifically block the reading of this gene. Known as small interfering RNAs (siRNA), these sequences represent a promising approach to gene therapy.

Glucose building blocks on the surfaces of the artificial viruses should improve binding of the artificial virus to the glucose transporters on the surfaces of the target cells. These transporters are present in nearly all mammalian cells. Tumor cells have an especially large number of these transporters.

Trials with a line of human cancer cells demonstrated that the artificial viruses very effectively transport an siRNA and block the target gene.

In addition, the researchers were able to attach hydrophobic (water repellant) molecules—for demonstration purposes a dye—to the artificial viruses. The dye was transported into the nuclei of tumor cells. This result is particularly interesting because the nucleus is the target for many important antitumor agents.