University of Michigan scientists have identified a new reservoir for hidden HIV-infected cells that can serve as a factory for new infections. The findings, which appear online March 7 in Nature Medicine, indicate a new target for curing the disease so those infected with the virus may someday no longer rely on AIDS drugs for a lifetime.

“Antiviral drugs have been effective at keeping the virus at bay. However once the drug therapy is stopped, the virus comes back,” says senior author of the study Kathleen L. Collins, M.D., Ph.D., associate professor of both internal medicine and microbiology and immunology at the U-M Medical School.

In people infected with HIV (human immunodeficiency virus), the virus that causes AIDS, there’s an unsolved problem with current anti-viral drugs. Though life-saving, they cannot root the virus out of the body. Infected cells are able to live on, undetected by the immune system, and provide the machinery for the virus to reproduce and spread.

Important new research by U-M has discovered that bone marrow, previously thought to be resistant to the virus, can contain latent forms of the infection.

“This finding is important because it helps explain why it’s hard to cure the disease,” Collins says. “Ultimately to cure this disease, we’re going to have to develop specific strategies aimed at targeting these latently infected cells.”

“Currently people have to take anti-viral drugs for their entire life to control the infection,” she says. “It would be easier to treat this disease in countries that don’t have the same resources as we do with a course of therapy for a few months, or even years. But based on what we know now people have to stay on drugs for their entire life.”

Using tissue samples, U-M researchers detected HIV genomes in bone marrow isolated from people effectively treated with antiviral drugs for more than six months.

While further studies are needed to demonstrate that stem cells can harbor the HIV virus, the study results confirm that HIV targets some long-lived progenitor cells, young cells that have not fully developed but mature into cells with special immune functions. When active infection occurs the toxic effects of the virus kill the cell even as the newly made viral particles spread the infection to new target cells.

“Our finding that HIV infects these cells has clear ramifications for HIV disease because some of these cells may be long-lived and could carry latent HIV for extended periods of time,” she says. “These HIV cell reservoirs can be induced to generate new infections.”

The new research gives a broader view of how HIV overwhelms the body’s immune system and devastates its ability to regenerate itself.

Globally more than 30 million people are infected with HIV, including millions of children. Improvements have been made since the 1990s in the way the disease is treated that has led to an 85 percent to 90 percent reduction in mortality.

“Drugs now available are effective at treating the virus, making HIV more of a chronic disease than a death sentence,” Collins says. “This has made a huge impact in quality of life, however only 40 percent of people worldwide are receiving anti-viral drugs and unfortunately that means that not everybody is benefiting.”

Intensive home-based nursing in HIV/AIDS patients significantly improves self-reported knowledge of HIV, awareness of medications, and self-reported adherence to medication programmes, according to a new Cochrane Systematic Review. One home-based care trial included in the review also significantly impacted on HIV stigma, worry, and physical functioning. It did not, however, help improve depressive symptoms, mood, general health, and overall functioning.

These conclusions are interesting, but more research is needed to understand the impact of home-based care in developing countries and on important disease outcomes, say the researchers. The study represents the first systematic review of the impact of home care in HIV/AIDS.

As a disease that affects 33 million people, HIV/AIDS puts a huge strain on health systems, particularly in developing countries. Therefore, in countries where health services are overstretched, home-based care is offered to HIV patients as an alternative to hospital care. Home-based care can include counselling, medical management, exercise, and spiritual support to try to improve patients’ quality of life in familiar surroundings, while reducing costs and pressure on hospital beds.

Researchers examined data from 13 studies, two of which were ongoing. The researchers report that home-based care has positive impacts on some aspects of patient wellbeing but little effect on others. Patients said that home care improved their knowledge of the disease, and of HIV medications, and helped them adhere to medication programmes. It also reduced worry and improved physical functions of patients, but had little effect on depression, general health, or indicators of disease progression such as CD4 counts.

Importantly, few studies considered the effects of home-based care in developing countries or on important disease outcomes. “Further large studies are needed to evaluate the effects of home-based care in developing countries, where HIV and AIDS take the biggest toll,” said Young. “And there should be a greater focus on how home-based care impacts on progression to full blown AIDS and death from the disease.”

“This study is a useful addition to the literature because of the wide range of home care options considered. However, there is no doubt that the evidence base for home-based care in HIV needs further development.”

Hormone Helps to Regulate Energy Homeostasis, Neuroendocrine Function, and Metabolism

Leptin is a hormone that plays a central role in fat metabolism. Patients with genetic leptin deficiency are obese, and treatment with leptin leads to dramatic weight loss through decreased food intake and possible increased energy expenditure. However, most obese people who produce leptin normally are resistant to the weight-loss effects of the hormone. Leptin deficiency is a clinical syndrome associated with distinct conditions such as recent weight loss, diet- or exercise-induced hypothalamic amenorrhea, and lipoatrophy.

Recombinant human leptin is an emerging potential therapy for these leptin-deficient conditions because in replacement doses, it normalizes energy homeostasis, neuroendocrine function, and metabolism.

Replacement of leptin in physiologic doses may help people who have recently lost weight because relative leptin deficiency may drive them to eat more, expend less energy, and regain weight. Leptin also restores ovulatory menstruation in women with hypothalalmic amenorrhea and improves metabolic dysfunction in patients with lipoatrophy, including lipoatrophy associated with HIV or highly active antiretroviral therapy.

A new study from Zambia suggests that halting breastfeeding early causes more harm than good for children not infected with HIV who are born to HIV-positive mothers. Stopping breastfeeding before 18 months was associated with significant increases in mortality among these children, according to the study’s findings, described in the Feb. 1, 2010 issue of Clinical Infectious Diseases, and available online now.

The researchers’ initial hypothesis, which proved to be incorrect, suggested that by 4 months of age, children would have passed the critical developmental point when breastfeeding is essential to their survival. However, stopping breastfeeding at 4 months, compared to usual breastfeeding as the child reaches 6 months to 24 months or older, did not decrease mortality or play a significant role in protecting the child from HIV transmission.

These findings were consistent with those for mothers not infected with HIV; longer breastfeeding is necessary to protect children against potentially fatal infectious diseases, especially those prevalent in low-resource settings. To prevent postnatal HIV transmission, however, mothers with HIV should be on antiretroviral drugs.

“Our results help support the recent change in the World Health Organization (WHO) guidelines for prevention of mother-to-child HIV transmission,” said study author Louise Kuhn, PhD, of Columbia University in New York City. “The new guidelines encourage postnatal use of antiretrovirals through the duration of breastfeeding to prevent vertical [mother-to-child] transmission.”

Retroviruses such as HIV and HTLV-1 don’t hit-and-run, they hit-and-hide. They slip into host cells and insert their own DNA into the cell’s DNA, and from this refuge they establish an infection that lasts a lifetime.

But that infection might be much less troublesome and much more manageable if the immune system could mount a strong response to the virus during its first few days in the body, according to a new study by cancer researchers at the Ohio State University Comprehensive Cancer Center-Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC-James).

The animal study, published online in the journal Blood, examined the human T-lymphotropic virus type 1 (HTLV-1), which causes adult T-cell leukemia and several inflammatory diseases in some people.

“Our findings indicate that if the immune system could respond strongly to HTLV-1 and kill infected target cells early, it may inhibit the virus’s ability to establish reservoirs of infected cells and make the infection more manageable later,” says principal investigator Michael Lairmore, a professor and chair of veterinary biosciences and a cancer researcher at OSUCCC-James.

“This study tells us that the more we know about the earliest events of infection, the more it will help us develop vaccines and might block those events.”

Lairmore and his colleagues examined HTLV-I infection in rabbits that were treated with the drug cyclosporin A, which is commonly used to suppress the immune system in people following organ transplantation. The researchers compared animals treated with this drug prior to viral infection with those given the drug one week after infection.

This study builds on earlier work by Lairmore and his colleagues showing that HTLV-I produces proteins that activate infected immune cells and causes them to divide, thereby increasing the number of infected cells in the body. The researchers found that cyclosporin A blocked that activation.

In this new study, the researchers used cyclosporin A to learn whether modifying the immune response – by providing fewer immune cells for the virus to attack – at a critical time, after the first week of infection when the virus needs to spread, would influence the extent of the infection weeks later.

In animals given the immune-suppressing drug first, the virus flourished. The number of virus copies jumped to 200 per 10,000 immune cells (lymphocytes), compared with 40 per 10,000 immune cells in control animals (these were infected with the virus but not given the drug). After a week or two, the number of virus copies fell, ranging from 113 to 160 for remainder of the 10-week experiment.

In the animals that were given the virus first and then the immune-suppressing drug a week later, on the other hand, the virus languished. The number of virus copies in these animals was lower than the controls, and it remained that way throughout the 10-week experiment. At week four after infection, for example, the immune-suppressed animals had on average nine virus copies per 10,000 immune cells, compared with 40 copies in control samples. At week 10, they had 10 virus copies compared with 30 in controls.

“The first experiment told us that if the immune system is suppressed, the viral load goes up – and we expected that,” says Lairmore. “The second group was the surprise. Their viral load was low from the start, and it stayed that way. We didn’t expect that. We thought the virus would recover and come back up.

“Collectively, our findings indicate that the immune system plays a key role in controlling HTLV-1 spread during early infection, which has important implications for a vaccine against this virus and for therapy for HTLV-1-associated diseases,” says Lairmore.

Two new studies showing that protein bits produced by unusual “reading” of the HIV genome can induce immune responses appeared online in the Journal of Experimental Medicine on Jan. 11.

Small, compact RNA viruses like HIV make the most of their limited genomes by stuffing genes that direct protein production into several different reading frames and orientations. When teams – led by Berger et al. at the Ragon Institute of MGH, MIT, and Harvard; and Bansal et al. at the University of Alabama – examined viral genomes in groups of HIV-infected individuals, they found an accumulation of genetic variations specifically in unusual reading frames and orientations. This finding suggested that mutations in these reading frames may have been caused by pressure from the hosts’ immune systems.

The notion was supported by their finding that HIV-infected individuals exhibited killer immune cell responses specific for protein fragments generated by unconventional reading of the HIV genome. In some cases, mutations in these reading frames allowed HIV-infected cells to escape immune cell killing.

The information provided by these findings may prove useful during future HIV vaccine design efforts.

Imagine this future of personalized healthcare: you have been diagnosed with a disease for which there are five different treatments, your doctor feeds your genetic details into a computer, and the virtual human in the machine suggests which of the five is likely to be most effective and have fewer side effects for you personally.

Or what about this: you are standing in front of 12 choices of painkiller in your local drugstore, you pull out your smartphone or other personal internet device, log onto a personalized healthcare site that is already loaded with your personal genetic information, feed in your symptoms and the choices in front of you, and the virtual human tells you which product is most likely to get rid of your headache without side effects.

To many of us, such scenarios might seem like fantastic science fiction ranking alongside “beam me up Scotty”, but not to Professor Peter Coveney, a chemist at University College London in the UK, who is leading their Virtual Physiological Human (VPH) project funded under the EU Framework Programme 7 Initiative and supported by the Engineering and Physical Sciences Research Council (EPSRC).

Coveney and colleagues are creating a virtual human in “cyberspace” that they and many others hope will revolutionize medical treatment.

The VPH will use a global network of computers to simulate the entire human body from neural signals in the brain to the flow of blood in the toes.

Currently, most medical treatments are determined by what works for the “average” patient or clinical trial participant, but what would be ideal for each and every one of us would be to know what works for the individual “me”, characterized by a unique and distinct genetic blueprint. The average person doesn’t really exist, it is a statistical compromise and in reality, each of us deviates from that central point, some more than others.

“Deviations from average can be very substantial,” said Coveney in an article about the VPH that appeared recently in Pioneer, a quarterly magazine published by the EPSRC.

While choosing which product to take to alleviate a nagging headache may seem a trivial reason for investing a lot of money and time creating a virtual human, for more serious conditions like cancer and HIV, where choosing the right medication can be a life and death decision, it makes a lot of sense.

The goal of the VPH project is to revolutionize healthcare by tailoring it to the unique genotype of individual patients. On their website, the EU-wide VPH network of excellence (NOE), describes its aim as to:

“Foster, harmonise and integrate pan-European research in the field of i) patient-specific computer models for personalised and predictive healthcare and ii) ICT-based tools for modelling and simulation of human physiology and disease-related processes”.

“This is the Holy Grail for medical treatment and an incredible ambition for us,” said Coveney, from the Department of Chemistry at UCL, and leader of the UK’s EPSRC-supported team.

An example of how the VPH might work is in the treatment of HIV patients, where medication choice is a critical decision. There are currently 9 drugs that inhibit the protein that the virus uses to replicate itself: HIV-1 protease. The drugs latch onto the protein and disable it.

However, the protein mutates efficiently, rapidly changing the sequence and arrangement of its constituent amino acids, as Coveney explained:

“HIV-1 protease is made up from 20 different amino acids, and so the number of possible variants is astronomically large.”

Just switching two amino acids can make the protein unrecognizable to the drug, allowing the virus to start replicating again.

At the moment there is no way of knowing which of the 9 available treatments is the best match to the particular HIV-1 protease mutation in an HIV patient, except by trial and error.

Coveney and his colleagues are trying to find a solution to this problem: they are testing “virtual drugs” on “virtual cells” in “virtual patients”. While their computer simulations are specific to the HIV virus and the 9 drugs, they show the potential of the VPH concept, they said.

For this example they collected genotypic assays from HIV patients, in other words exact maps of how each patient’s mutated HIV-1 protease protein had arranged its amino acids, and then simulated how each drug might bind to each variant.

“We were able to rank the efficacy of the nine drugs for each individual patient,” said Coveney.

Coveney and his team say it is still early days in the project and there are lots of issues to overcome, not just on the clinical side such as validating and verifying results before using the simulations with real patients, but also on the legal and ethical front.

“Currently the Medical Research Council in the UK has no policy on using this kind of computer model,” said Coveney in the Pioneer article.

In the meantime, the team is working on a simplified version of VPH, and they are developing another prototype simulation, looking at how tumors evolve in patients with lung cancer.

They see no limits to the potential of VPH. For example as Coveney explained:

“It could be used to help surgeons plan brain surgery, improve our understanding of diseases and disease processes (osteoporosis, for example) and design and test new medical devices.”

Another potential use for the VPH might be in drug testing where it could reduce clinical trial timescales and the number of animals used.

However, the cost of personalized medical care could be its major stumbling block: Coveney estimates a cost of around 7,000 pounds (over 10,000 US dollars) to do an HIV-1 protease simulation for a single patient. But as with all new technology, he is confident that costs will tumble once economies of scale kick in.

While it may be a long time before VPH is in your doctor’s surgery, and even longer before you are standing in the drugstore with your personal VPH just a few keystrokes away on your handheld, for people with serious life threatening conditions, a simple form of VPH could be just a few years away.

More than half of HIV patients experience memory problems and other cognitive impairments as they age, and doctors know little about the underlying causes. New research from Washington University School of Medicine in St. Louis suggests HIV-related cognitive deficits share a common link with Alzheimer’s-related dementia: low levels of the protein amyloid beta in the spinal fluid.

However, by analyzing biomarkers in the fluid surrounding the brain and spinal cord, the researchers report Dec. 8 in the journal Neurology, they could distinguish patients with HIV-related cognitive impairments from patients with mild Alzheimer’s disease. This is important because as patients with HIV age, some will develop cognitive deficits related to HIV and others to Alzheimer’s. New treatments in the pipeline to improve memory and thinking may not work for both conditions.

“HIV patients with cognitive dysfunction don’t have early Alzheimer’s – although some of the symptoms may be similar,” says lead author David Clifford, M.D., an authority on the neurological complications of HIV and director of Washington University’s AIDS Clinical Trials Unit. “The underlying biology of both conditions may be related to amyloid, and we think this clue can help us find the cause of cognitive impairment in HIV patients.

Cognitive dysfunction is a major problem among the estimated 1 million Americans living with HIV. The impairments are often mild but can affect a person’s daily life, relationships and ability to hold a job. They include difficulties with memory, processing complex information and making decisions. These problems are expected to worsen as HIV patients live longer, due to potent drug cocktails that keep the virus in check.

In the new research, the scientists looked at the spinal fluid of 49 HIV patients with cognitive impairments, 21 HIV patients with normal cognitive function, 68 patients with mild Alzheimer’s and 50 normal, healthy “controls.” The Alzheimer’s patients were older (average age 74) than the controls (average age 50), impaired HIV patients (average age 48) and cognitively normal HIV patients (average age 43).

They tested the spinal fluid for the presence of amyloid beta – the protein that folds and accumulates in the brains of Alzheimer’s patients and is thought to play a key role in driving the brain damage that characterizes the disease. They also looked at other biomarkers associated with Alzheimer’s, including tau, a protein found in tangled nerve fibers in Alzheimer’s patients.

When amyloid beta accumulates in the brains of Alzheimer’s patients, levels decrease in the spinal fluid, and Clifford and his colleagues expected to find low levels of the protein in samples of the Alzheimer’s patients they studied.

But they were surprised to find the same low levels in the spinal fluid of HIV patients with cognitive dysfunction. Both groups of patients had significantly lower amyloid beta levels than HIV patients without cognitive impairments and the normal controls. The lower levels are an indicator that amyloid beta in the brain alters the normal turnover of the protein in the body.

Although Australian and European researchers had uncovered a link between HIV-related cognitive deficits and amyloid beta in 2005 in a smaller study, Clifford thought that finding was an artifact and embarked on the current study largely to disprove it.

“I really did not expect the biology of HIV cognitive dysfunction to be related to Alzheimer’s,” Clifford says. “If you look at the brains of HIV patients with cognitive impairments, they don’t look like Alzheimer’s brains – they don’t have the same atrophy or a plethora of plaques and tangles characteristic of Alzheimer’s.”

But low amyloid beta is where the similarity to Alzheimer’s disease ends. The researchers found that patients with mild Alzheimer’s had significantly higher levels of tau than either group of HIV patients or normal controls – a finding that strongly suggests Alzheimer’s and HIV cognitive dysfunction are not one and the same, Clifford says.

He suspects the HIV-related cognitive impairment may be due to low levels of the virus that hide out in the brain, beyond the reach of drugs that can’t easily cross the blood-brain barrier. Another cause may be low-grade inflammation in the brain that is driven by the virus.

Almost all HIV patients in the study were taking anti-retroviral therapy. “I am almost certain the dementia in AIDS patients is linked to HIV and not to anti-retroviral drugs – we see it even in patients who haven’t received HIV therapy,” Clifford says. “However, the more subtle impairment may be in some way associated with a change in the way the body processes amyloid beta. This will certainly be an important area of future research.”

Researchers conducting clinical trials in Rwanda have concluded that the risk of postnatal transmission is minimal in HIV-positive mothers undergoing highly active antiretroviral therapy (HAART) while breastfeeding. The results of the trials have been published in the current issue of AIDS, the leading journal in the field of HIV and AIDS research. The journal is published by Lippincott Williams & Wilkins, a part of Wolters Kluwer Health, a leading provider of information and business intelligence for students, professionals, and institutions in medicine, nursing, allied health, and pharmacy.

Although formula feeding has been the recommended strategy for preventing postnatal HIV transmission in developed countries for many years, researchers have recognized that this intervention is not feasible for many women in resource-limited settings. Despite this, there had until now been no single study conducted which formally compared maternal breastfeeding with HAART with formula feeding within the same cohort in resource-limited countries.

Dr. Cécile Alexandra Peltier, together with her colleagues, conducted their study with the aim of assessing the 9-month HIV-free survival of children with two strategies to prevent HIV mother-to-child transmission. Women participating in the cohort study could choose the mode of feeding for their infant: breastfeeding with maternal HAART for six months, or formula feeding. All received HAART from 28 weeks of gestation.

Of the 227 infants who were breastfed during the trial, only one became infected with HIV, corresponding to a 9-month cumulative risk of postnatal infection of 0.5% in the breastfeeding group. Moreover, the overall mortality rate of the infants involved in the study was significantly higher in the formula-fed group (5.6%) than in the breastfed group (3.3%).

The results of the study have lead researchers to conclude that maternal HAART while breastfeeding could be a promising alternative strategy in resource-limited settings. A key implication of this study is that women can be offered a choice in infant-feeding options, both of which could be safe and effective, given regular postnatal follow-up and counseling.

A rare parasitic disease, which normally only is transmitted by contaminated water, has been shown to be transmitted by gay sex between hiv-positive men. In the industrial world the disease is virtually absent, but from now on that could change. For this observation, Taiwanese researcher Chieng-Ching Hung received a doctorate from the University of Antwerp and the Institute of Tropical Medicine Antwerp.

Amebiasis, an infection with the single-celled amoeba Entamoebia histolytica, normally is very rare. You only catch it in a few developing countries where the amoeba is endemic, and where hygiene is somewhat substandard, leading to contact with contaminated water. It only becomes dangerous when the amoeba invades your intestinal lining and causes a bloody diarrhoea, or when it enters the bloodstream, where it, among other things, causes liver abscesses. All in all amebiasis takes some 70 000 lives a year, worldwide.

For some time now, physicians suspected the disease to be a bit overrepresented among HIV-positive male homosexuals. But it was difficult to come to conclusions from small numbers, and in addition the classical diagnostic test (putting the stool under the microscope) was not really dependable. Hung used modern molecular techniques, pinpointing the amoeba more precisely and, what’s more, showing which amoebas were closely related. In other words: who had got the infection from whom.

In Taiwan, seropositive (hiv-infected) gay men showed to be infected much more often with the amoeba than the healthy population, and also than seropositive heterosexuals. On top of that, Hung found men from different regions nevertheless to be infected by closely related amoebas. The only sensible explanation is that the infection happened through homosexual (oral-anal) contact.

In today’s mobile world this means that those people in turn can transmit the infection to regions where it normally is absent.

In other words: physicians in industrial countries from now on better know who Entamoebia histolytica is, and what it brings about.

Not only amebiasis marches in the wake of hiv; Hung also confirmed in his Taiwanese cohort what is seen elsewhere: tuberculosis and hepatitis B and C are more virulent in combination with hiv, and more often present.