The balance of bacterial strains living in the vagina can influence how effective a medicated gel is at protecting against HIV. The finding may explain why women need to take PrEP treatments more regularly than men to be protected against contracting the virus.

The drug tenofovir is a mainstay of HIV treatment and prevention. When taken orally, it protects well against HIV infection, but researchers have wondered why it doesn’t work as well when applied as a microbicidal gel in the vagina. Some have suggested this is because the women taking part in tests of the gel didn’t use it reliably, but now it looks like vaginal microbes might bear part of the blame.

The vaginas of healthy women are known to be dominated by Lactobacillus bacteria. Having a more diverse collection of bacteria has been linked to an increased likelihood of urinary tract infections, while the presence of particular species, such as Gardnerella vaginalis, is linked to bacterial vaginosis, a poorly understood condition that causes abnormal discharge and odour.

Now at the University of Washington, Seattle, and her colleagues have found that the types of microorganisms living in the vagina are linked to how effective tenofovir gel is at protecting against HIV infection.

“It’s a really serious effect,” says Klatt, whose team made this discovery by analysing samples taken during a clinical trial. “We went from 60 per cent protection if you have good Lactobacillus to 18 per cent – really no protection at all – if you have bad bacteria.”

Less protected

G. vaginalis seems to be the main culprit. The team found that this species takes up tenofovir and chemically processes it at high rates, stopping the drug from entering the cells it is intended to protect. Other types of bacteria can do this too, but they aren’t as efficient so don’t pose the same danger.

“This is an interesting and exciting finding,” says at the University of Pittsburgh. “To me, it means that tenofovir dosing is less forgiving of a missed dose if you have bacterial vaginosis.”

The finding raises the question of whether the microbiome may help explain the different protective effects of oral PrEP, a preventative HIV procedure, in men and women. Men can skip the pill for a day or two, but to be protected, women are less likely to get away with missing a day’s pill.

It was thought that this difference may be due to differences in the tissues involved in vaginal and anal sex, but now it seems that may not be the whole story. There are a lot of reasons to think bacterial vaginosis could be affecting vaginal protection from oral PrEP, says Klatt.

Balancing bacteria

, at the  Ragon Institute in Boston, believes Klatt’s findings may be important when protective measures are only partially effective. “By targeting the microbiome, you may be able to make it more efficacious,” he says. While oral PrEP already works very well, the microbiome may be more of a problem when using protective gels.

Bacterial vaginosis is the most common infection in women between the ages of 15 and 44. While antibiotics can be used to treat bacterial vaginosis, it recurs within a year in around 60 per cent of cases in the US, and at even higher rates in developing nations where HIV is most common.

Nevertheless, Klatt is hopeful that antibiotics can be used to knock out bad players in the vaginal microbiome. Other researchers are developing a product that may be able to re-establish and maintain a healthy Lactobacillus-based microbiome, to boost protection against HIV and other sexually transmitted infections.

Read more: Unprotected sex may disrupt the microbiome in vagina

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T cells, such as this one, can be destroyed by an invading HIV army (red dots) that is transferred directly into the cell (Image: NIBSC/SPL)

It’s the world’s most studied virus, but HIV can still take us by surprise. It turns out that the virus can infect and kill immune cells by being pumped directly from one cell into another, during brief connections made between the two.

Until recently, we thought that HIV particles circulating in the blood were largely to blame for infecting and destroying crucial immune cells called CD4 T cells. According to this classic model, after a single virus has infected a T cell, it hijacks the cell’s machinery to build hundreds of copies of itself, which bud off into the blood and eventually wear out and kill the host cell.

This thinking was based on research using blood, a relatively easy way to study the virus. But work with newer tools suggests that this is only part of the story. Using tissue-culture methods, a team led by at the Gladstone Institutes in San Francisco, has shown that in fact large numbers of virus particles are often pumped directly from one CD4 T cell into another. And it seems that this process may kill the vast majority of CD4 cells – not infection by single viruses.

Blocking transmission

HIV armies storm neighbouring T cells by hijacking yet another cell system, the immunologic synapses. These are short-term connections between immune cells that allow them to send chemical messages between themselves, which HIV uses to flow from an infected CD4 cell to an uninfected one.

Evidence suggests that this process is hundreds, possibly thousands, of times more efficient than the traditional mode of external infection. Greene says that 95 per cent of the CD4 cells they studied died by this process, rather than from infection by free-floating particles.

This new understanding could open up ways to target the virus, as well as influencing what drugs we choose to treat the disease. has been studying cell-to-cell HIV transmission at Yale University, and he says that although most antiretroviral drugs work against both forms of infection, the much higher efficiency of pumping viruses directly into a cell can overwhelm some of these drugs, making them less effective.

But the finding may open the way for new treatments. The monkey version of HIV can also be transmitted directly from cell to cell, but monkeys may be able to tolerate this process.

Unlike their human equivalents, monkey CD4 cells manage to survive being inundated with virus particles, and Greene thinks that they have evolved a way to avoid self-destructing. He hopes that anti-inflammatory drugs could be used to mimic this effect in human CD4 cells. One potential drug candidate, VX-765, looks promising in the lab.

Hunt for a vaccine

A better understanding of how the virus spreads directly between cells is probably an important part of the HIV puzzle, says at the Fenway Institute in Boston. He suggests that neglecting to take this mode of transmission into account may at least partly explain the failure of recent vaccine research.

HIV vaccines would work by generating antibodies to fight the virus. But that different types of antibodies would be needed to kill viruses that are inside cells and viruses that are free-floating in the body. Viruses hiding out inside cells may be more likely to escape destruction, and could perhaps find it easier to evolve resistance to antibodies.

of the US National Institute of Allergy and Infectious Diseases in Bethesda, Maryland, says that to better understand how to protect against cell infection, we need better vaccine candidates. “Is cell-to-cell transmission going to torpedo a vaccine? We don’t know the answer to this because we don’t have a safe, effective and durable HIV vaccine to understand the exact mechanisms,” he says.

Journal reference: Cell Reports, DOI:

The good news is that a more friendly alternative is in the pipeline. Researchers developing the approach believe a single day of specially prepared foods, with the necessary laxatives and electrolytes incorporated into the preparation, can do the cleansing job just as well as the traditional, gruelling approach.

Initial results in a pilot study were so promising that it met its objectives after only 10 of the anticipated 30 patients had tested the method, according to results presented by of the Dartmouth-Hitchcock Medical Center in Lebanon, New Hampshire, at the held this week in Washington DC.

All patients were subsequently assessed as good or better on the global assessment for a squeaky-clean colon. This rating is needed for optimal spotting of troubling polyps and lesions that could become cancerous.

Bigger menu

That outcome prompted the researchers to team up with food scientists and culinary experts in Rhode Island to design an expanded menu.

It was a challenge, says , a lead investigator on the project who is also at Dartmouth-Hitchcock. “Adding polyethylene glycol [the laxative component] to many substances just doesn’t work. It either makes it fall apart or taste funny, or it doesn’t hold a form. That is where the food scientists came in.”

They created menu options – designed to reduce the frequency and volume of stools – including cereal, pasta, an energy-bar-like treat and smoothies, for the phase 2 follow-up study that is now under way. The food is not only tasty, but also easy to manufacture and distribute, says Siegel.

Levy takes particular comfort from the fact that people who ate the original, simpler and more limited food products in the pilot study responded favourably to them and said they would eat them again. “It is not going to work if patients don’t enjoy taking it,” he says.

Need for screening

Numerous technical improvements such as miniaturisation and digitised imagery have significantly improved the ability of colonoscopy to identify and treat polyps and lesions before they become cancerous, says Levy.

But even with those advances, the procedure only works if the bowel has been sufficiently cleaned to allow doctors to spot problems – so if people are reluctant to go through uncomfortable regimes to do this, they won’t be able to take advantage of the potential health benefits of colonoscopy.

“Everybody should have colon-cancer screening starting at age 50,” says Donald Campbell, chair of the department of internal medicine at Saint Luke’s Hospital in Kansas City, Missouri. “But everybody hates the prep.”

The National Colorectal Cancer Roundtable has a goal of increasing US screening rates from 58 per cent to 80 per cent of those aged between 50 and 75 by 2018. The new food-prep option might help achieve this, potentially becoming available by 2017 if further studies are successful.

Enhanced screening would detect more cancers at an early stage in their development, and so would end up saving lives over the long term.

“Colonoscopy is the gold standard method for detecting cancers in the colon,” says Campbell. “The nice thing about it is that if you find a polyp, you can take it out then and the patient does not have to have a second procedure.”

The malaria parasite, Plasmodium falciparum, reproduces in the human liver before jumping to mosquitoes when the insects feed on human blood. It completes its life cycle in the insect gut, where it reproduces again.

Given that a mosquito’s gut bacteria are known to affect Plasmodium development, at Imperial College London and her colleagues wondered whether interfering with the gut bacteria would have an impact on Plasmodium infection in the insects.

They allowed mosquitoes to feed on blood carrying penicillin and streptomycin, and found that 24 hours later, the number of bacteria in the insects’ gut had dropped by 70 per cent, while bacterial diversity had plummeted. What’s more, the antibiotics left the mosquitoes 21 per cent more likely to develop a malaria infection.

No one is quite sure how to explain what is going in the mosquito gut, says Gendrin. It could be that the parasites and gut bacteria compete for the same nutrients, so knocking out the bacteria leaves more food for the parasites. Or perhaps the antibiotics dampen the mosquitoes’ immune response, so the parasites can multiply more easily. It may even be that the few gut bacteria species that do thrive when the mosquitoes ingest antibiotics produce a metabolite that benefits the parasite. Or a combination of two or more of these factors may be at work.

Whatever the mechanism, Gendrin says the new findings reinforce the view that people taking antibiotics – particularly if they carry malaria – should take steps to break the malaria cycle. For instance, they should sleep under netting to lower their risk of being bitten by mosquitoes.

Gendrin and her colleagues are planning further experiments to explore whether narrow spectrum antibiotics – as opposed to broad spectrum antibiotics like penicillin and streptomycin – have a less drastic effect on the bacteria living in the mosquito gut. With luck, she says, the researchers may identify antibiotics that are less likely to destroy the gut bacteria and so will not encourage malaria to proliferate in mosquitoes. People living in the malaria zone of the tropics might then be better off taking those antibiotics to treat infections, says Gendrin.

Journal reference:

Children with autism spectrum disorder (ASD) normally start receiving treatment at about 2 years old or older. This is an improvement on 10 years ago, when children with ASD were unlikely to receive treatment until they were 4 years old or more. But and at the University of California, Davis, have sought to intervene even earlier, in infants as young as 6 months old.

In a pilot study, Rogers and Ozonoff taught the parents of seven infants with symptoms of ASD, aged between 6 and 15 months old, how to overcome developmental delays through interactions during play, bathing and diaper-changing.

Two researchers independently used multiple tests and evaluations to distinguish between infants with symptoms of ASD and those who might just be developing more slowly than average. “These were very symptomatic infants,” says Rogers. “In general these babies did not use their bodies, faces or voices to send and receive messages from their caregivers on what they liked or didn’t like, or wanted more or less of.”

The programme adapted positive-reinforcement strategies known to reduce symptoms in older children.

Plastic brains

Six of the infants began to show accelerated development by 18 months of age, and by the time they were 3 years old, their development was in the normal range, says Rogers. In contrast, four infants who qualified for the study but whose parents chose not to participate continued to show a worsening of ASD symptoms.

Rogers speculates that the reason for such a dramatic change is that the programme intervenes when infants’ brains are most plastic, when babies are establishing social skills. She cautions that a large, randomised trial is needed to prove that the intervention works.

, director of autism research at the University of Alberta in Canada, calls it “a significant study because it demonstrates the ability both to detect symptomatic infants and provide a meaningful intervention prior to 12 months of age.”

He says parents and doctors should feel encouraged by this approach as it is specific to autism, rather than a generic treatment drawn from experience with infants with developmental delay.

Parents spend much more time with their baby than a professional therapist can, and so are likely to have a greater impact on their development, says Paul Wang, head of medical research at the advocacy group , which also supported the study. Because parents can be trained to deliver these interventions, they should be cheaper and more widely available.

Journal reference: Journal of Autism and Developmental Disorders, DOI: 10.1007/s10803-014-2202-y

How does your skin smell? Pretty well, as it turns out, thanks to receptors dotted all over you. What’s more, they could help you heal.

There are more than 350 types of olfactory receptors in the nose, tuned to different scents. About 150 are also found in internal tissues such as those of the heart, liver and gut, but they are hard to study.

lab at Ruhr University Bochum in Germany focused on skin, which is easier to study, and tested the response to scents of receptors in keratinocytes, the main skin cell type.

They found that Sandalore – a synthetic sandalwood oil used in aromatherapy, perfumes and skin care products – bound to an olfactory receptor in skin called OR2AT4. Rather than sending a message to the brain, as nose receptors do, the receptor triggered cells to divide and migrate, important processes in repairing damaged skin.

Healing boost

Cell proliferation increased by 32 per cent and cell migration by nearly half when keratinocytes in a test tube and in culture were mixed for five days with Sandalore. Natural sandalwood oil and 10 different synthetic versions were tested, but only three had a beneficial effect.

“There is a big trend towards odour receptors being found elsewhere in the body doing other jobs,” says Joel Mainland of the in Philadelphia. So it is not unexpected to find receptors in skin, but it is a surprise to learn that they are involved in wound healing.

The concentrations of Sandalore used were a thousand times higher than those needed to activate a receptor in the nose. So a skin cream rather than aromatherapy would probably be needed to promote a healing effect, says Mainland.

Not for everyone?

Hatt and Mainland both caution that these olfactory receptors are very finely tuned, as is demonstrated by their distinguishing between various synthetic versions of sandalwood oil. And there is genetic variability in human receptors, so your receptor might be a bit different from your neighbour’s.

It leaves open the question of whether receptors might differ so much between individuals that the synthetic sandalwood that benefits one person might be neutral or even toxic to another.

Hatt says the 150-200 olfactory receptors identified in tissue outside the nose represent a new family of targets for experiments and new opportunities to treat disease.

Treatments that heal wounds and repair the effects of ageing in the skin with topical products are likely to be the easiest to develop, he says. Understanding receptors on internal organs and creating beneficial drugs is likely to take longer.

Journal reference: Journal of Investigative Dermatology, .

Victor Darley-Usmar measures how well cells make energy under stress – and says his system could be as useful to doctors as a blood pressure meter

You stress the importance of bioenergetics. What is it?
It’s a broad term in biology that refers to how energy is produced and used. We focus on the cellular level, primarily with mitochondria, which produce the energy used by the cell.

How can it measure how healthy we are?
We are developing a measure called the Bioenergetics Health Index (BHI) that we believe can be used to predict the response to stressors such as diabetes or infection. The plan is to have an index, similar to blood pressure, so we know that if the BHI is below a certain range point, the body is more susceptible to disease.

To calculate BHI, we measure oxygen used by a cell at rest and then under a defined metabolic stress – and then look at the difference between the two. We can use oxygen consumption as a marker of how much energy mitochondria are able to generate. The cell needs a certain level of energy to carry out basic functions and even more to deal with stressors like disease.

So BHI could serve as a warning system?
There are different patterns of BHI, perhaps a different one for each disease. For example, excessive fat causes inflammation involving white blood cells. Part of the BHI calculation is based on circulating-white-blood-cell count, and we believe this component could be the canary in the coal mine for susceptibility to diseases such as diabetes and cardiovascular disease.

We have promising initial data from three ongoing pilot studies in patients with kidney disease, alcohol-related disease and HIV that shows differences in BHI between the patient populations. Of course this is just a snapshot in time of different people. But hopefully that will give us a platform to get to much more comprehensive long-term studies to better understand cause and effect.

Could BHI change our understanding of how diseases progress?
Yes. Another example is obesity. Some obese people remain healthy while others quickly develop metabolic diseases such as increased blood pressure and decreased kidney function. How sensitive you are to these diseases and how fast you progress may depend upon how well your body can make energy to combat that stress. That’s what BHI adds to the picture.

Are changes in bioenergetics the cause of disease or the result?
It is likely an interplay of both, depending upon the disease. But we don’t know that yet for sure, which is why we need to do long-term studies.

How will BHI change medical care?
Two people can have the same symptoms for a disease but their mechanisms can be quite different. Your blood pressure could be high for one reason and mine high for another. We hope that BHI will provide another tool for doctors to drill down to the underlying molecular mechanisms of the individual patient’s disease, and then choose the appropriate intervention.

This article appeared in print under the headline “Cells speak volumes”