HIV Is Evolving To Evade Human Immune Responses

HIV is evolving rapidly to escape the human immune system, an international study led by Oxford University has shown. The findings, published in Nature, demonstrate the challenge involved in developing a vaccine for HIV that keeps pace with the changing nature of the virus.The extent of the global HIV epidemic gives us a unique opportunity to examine in detail the evolutionary struggle being played out in front of us between an important virus and humans,’ says lead researcher Professor Philip Goulder of the Peter Medawar Building for Pathogen Research at Oxford University.

‘Even in the short time that HIV has been in the human population, it is doing an effective job of evading our best efforts at natural immune control of the virus. This is high-speed evolution that we’re seeing in the space of just a couple of decades.’

The study better describes HIV's ability to adapt by spelling out at least 14 different "escape mutations" that help keep the virus alive after it interacts genetically with immunity molecules that normally attack HIV.

"Key genetic regions of HIV introduced into individuals of different ancestry in different places have been evolving to a greater or lesser degree according to inherited factors controlling immune response," said Richard Kaslow, M.D., a professor in the UAB School of Public Health and a co-author of the study. "If HIV adapts differently in genetically distinct hosts, the challenge ahead in vaccine design is formidable," he said.

HIV has already killed 25 million people, and an estimated 33 million are currently infected. However, HIV does not kill all people at the same rate. On average, an adult with HIV will survive for ten years without anti-HIV drugs before developing AIDS. But some people will progress to AIDS within 12 months while others can make effective immune responses to the virus and survive without any anti-HIV therapy for over 20 years.

Genes encoding a key set of molecules in the human immune system called the human leucocyte antigens (HLA) are critically important. HLA determine the progress of many infectious diseases including HIV, and enable the recognition and killing of HIV-infected cells. Humans differ from each other in the exact HLA genes they have, and small differences can make the difference in how long it takes to progress to AIDS.

The research team set out to determine whether HIV is adapting to human immune responses. They looked at HIV genetic sequences in different countries around the world, including the UK, South Africa, Botswana, Australia, Canada, and Japan, wanting to see whether the HIV sequences could be related to the different HLA genes present in the different populations.

The collaboration between Oxford University, the Ragon Institute at Massachusetts General Hospital, Kumamoto University in Japan, the Royal Perth Hospital and Murdoch University in Australia and others analysed the genetic sequences of the HIV virus and human leucocyte antigen (HLA) genes in over 2,800 people.

Mutations that allow HIV to get round immune responses directed by a particular HLA gene were found more frequently in populations with a high prevalence of that HLA gene. This is strong evidence for HIV adaptation to the human immune system at the level of populations.

‘Where a favourable HLA gene is present at high levels in a given population, we see high levels of the mutations that enable HIV to resist this particular gene effect,’ says author Professor Rodney Phillips, co-director of the James Martin Institute for Emerging Infections at Oxford University. ‘The virus is outrunning human variation, you might say.’

‘The temptation is to see this as bad news, that these results mean the virus is winning the battle,’ says Professor Goulder. ‘That’s not necessarily the case. It could equally be that as the virus changes, different immune responses come into play and are actually more effective.’

The results are important because it is our most effective immune responses that vaccines against HIV would try and boost to a level that would protect against the virus.

‘The implication is that once we have found an effective vaccine, it would need to be changed on a frequent basis to catch up with the evolving virus, much like we do today with the flu vaccine,’ explains Professor Goulder.

‘In this anniversary year of Darwin’s birth, we are accustomed to think of evolution happening over thousands, tens of thousands and even millions of years,’ says Professor Goulder. ‘But we are seeing changes in HIV, and our immune response to the virus, in just a couple of decades.’

The work was funded by a number of organisations including the Wellcome Trust, the Medical Research Council, the US National Institutes of Health, and Oxford’s James Martin 21st Century School.

'Obesity Gene' Involved In Weight Gain Response To High-fat Diet Identified

Scientists have determined that a specific gene plays a role in the weight-gain response to a high-fat diet.The finding in an animal study suggests that blocking this gene could one day be a therapeutic strategy to reduce diet-related obesity and associated disorders, such as diabetes and liver damage, in humans.

The researchers found that a diet rich in fat induced production of this gene, called protein kinase C beta (PKC beta), in the fat cells of mice. These mice rapidly gained weight while eating a high-fat diet for 12 weeks.

On the other hand, mice genetically engineered to lack PKC beta gained relatively little weight and showed minimal health effects after eating the same high-fat diet.

In comparing the effects of the high-fat diet and a regular diet, the scientists found that mice fed the high-fat diet produced more PKC beta in their fat tissue than did mice eating a regular diet.

“So we now know this gene is induced by a high-fat diet in fat cells, and a deficiency of this gene leads to resistance to fat-induced obesity and related insulin resistance and liver damage,” said Kamal Mehta, senior author of the study and a professor of molecular and cellular biochemistry in Ohio State University’s College of Medicine.

“It could be that the high-fat diet is a signal to the body to store more fat. And when that gene is not there, then the fat storage cannot occur.”

Though the complete mechanism remains unknown, the research to date suggests that rather than storing fat, mice lacking the gene burn fat more rapidly than they would if the PKC beta were present, Mehta said.

The research is available online in the journal Hepatology and is scheduled for later print publication.

Mehta and colleagues previously had created the hybrid mouse model by cross-breeding mice deficient in PKC beta with the C57 black mouse, a common animal used in research for studying diabetes and obesity. Despite the propensity for obesity from their original genes, the new mice lost weight while eating up to 30 percent more food than other mice.

In the earlier study, the mice ate a regular diet. In this new study, the researchers fed PKC beta-deficient and normal mice either a diet in which 60 percent of calories were derived from fat – the high-fat diet – or a standard diet in which 15 percent of calories came from fat. In the typical American diet, about 40 percent of calories are derived from fat.

The normal mice on the high-fat diet showed weight gain within three weeks, a trend that continued throughout the 12-week study. The PKC beta-deficient mice on the same diet gained less weight even while appearing to be extra hungry and eating more calories than the normal mice – meaning their lower body weight was not the result of eating less.

Of animals eating the high-fat diet, the fat tissue and livers in the normal mice were larger than those in the PKC beta-deficient mice, as well. The livers of the normal mice were on average about 50 percent larger than the livers in mice lacking the gene. And the white fat tissue – the tissue in which PKC beta was expressed as a result of the high-fat diet – was almost three times as heavy in the normal mice as in the PKC beta-deficient mice.

The protein-deficient mice were able to clear insulin to regulate blood sugar more rapidly than normal mice after eating the high-fat diet, meaning avoiding obesity also allowed them to avoid development of insulin resistance associated with diabetes, said Mehta, also an investigator in Ohio State’s Davis Heart and Lung Research Institute.

“Obesity leads to liver damage and to diabetes. So if we can take care of obesity associated with a high-fat diet, we can also take care of most of the related disorders,” Mehta said.

A separate component of the current study further showed that mice engineered to be obese also had about 500 percent more of the gene in their fat cells than did normal mice. Mehta and colleagues have assembled a team that includes an endocrinologist, bariatric surgeon and molecular biologist to examine human fat tissue from obese and lean patients to see if levels of PKC beta are elevated in obese humans, as well.

“It is very likely that this gene may be involved in a predisposition to obesity,” he said.

Knowing the gene is responsive in the fat cells is important to figuring out how to suppress its action. Future research will involve deleting the gene from fat cells in mice to see if these new mice have the same lean body type as mice that are completely deficient of PKC beta throughout their entire genome.

“We are generating more mouse models to vary expression of this gene and study the consequences of that on obesity and related disorders,” Mehta said.

So far, mouse models lacking the protein have not shown any damaging side effects related to the suppression of the gene, Mehta said. He speculates that PKC beta could be a so-called “thrifty” gene left over from humans’ days as hunter-gatherers, when the body needed to retain fat for survival.

This work is supported by the National Institutes of Health.

Co-authors on the paper were Wei Huang and Rishipal Bansode of the Department of Molecular and Cellular Biochemistry, and Madhu Mehta of the Department of Internal Medicine, all at Ohio State.

Soybean Product Fights Abnormal Protein Involved In Alzheimer’s Disease

A vegan food renowned in Asia for its ability to protect against heart attacks also shows a powerful ability in lab experiments to prevent formation of the clumps of tangled protein involved in Alzheimer’s disease, scientists in Taiwan are reporting. Rita P. Y. Chen and colleagues point out that people in Asia have been eating natto — a fermented food made from boiled soybeans —for more than 1,000 years. Natto contains an enzyme, nattokinase, that has effects similar to clot-busting drugs used in heart disease.Nattokinase is sold a dietary supplement to improve the body’s circulatory system.

The scientists term this the first study on whether nattokinase also can dissolve amyloids. Those tangled proteins are involved in Alzheimer’s disease and several other health problems.

In the study, the nattokinase degraded several kinds of amyloid fibrils, suggesting its possible use in the treatment of amyloid-related diseases. “Moreover, since natto has been ingested by humans for a long time, it would be worthwhile to carry out an epidemiological study on the rate of occurrence of various amyloid-related diseases in a population regularly consuming natto,” the scientists say.