► Immune To Hiv?, "Genetic HIV Resistance Deciphered"

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Genetic HIV Resistance Deciphered - Randy Dotinga

Throughout the history of the AIDS epidemic, a few lucky people have avoided infection despite being exposed again and again. Now, researchers are traveling back in evolutionary time to understand why some people are resistant -- and in some cases virtually immune -- to the AIDS virus.

Studies released this week and last year suggest that the roots of AIDS immunity extend back for centuries, long before the disease even existed. Our ethnic backgrounds and the illnesses suffered by our distant ancestors appear to play a crucial role in determining whether our genes will allow HIV to take hold in our bodies.

For now, the findings seem likely to inspire more raised eyebrows than cutting-edge drugs. But over time, the research into why some people don't get HIV may help doctors treat those who do. By understanding which genes help people fight off infection, "we might move to a time where we can make more refined decisions about timing or intensity of therapy. Now, it's like a glove where one size fits all," said Dr. Matthew Dolan, an AIDS specialist in the U.S. Air Force and co-author of a new AIDS genetics study in an online edition of the journal Science.

Genetic resistance to AIDS works in different ways and appears in different ethnic groups. The most powerful form of resistance, caused by a genetic defect, is limited to people with European or Central Asian heritage. An estimated 1 percent of people descended from Northern Europeans are virtually immune to AIDS infection, with Swedes the most likely to be protected. One theory suggests that the mutation developed in Scandinavia and moved southward with Viking raiders.

All those with the highest level of HIV immunity share a pair of mutated genes -- one in each chromosome -- that prevent their immune cells from developing a "receptor" that lets the AIDS virus break in. If the so-called CCR5 receptor -- which scientists say is akin to a lock -- isn't there, the virus can't break into the cell and take it over.

To be protected, people must inherit the genes from both parents; those who inherit a mutated gene from just one parent will end up with greater resistance against HIV than other people, but they won't be immune. An estimated 10 percent to 15 percent of those descended from Northern Europeans have the lesser protection.

Using formulas that estimate how long genetic mutations have been around, researchers have discovered that the mutation dates to the Middle Ages. (Similar research in mitochondrial DNA -- passed along by women -- has suggested that Europeans are all descended from seven Ice Age matriarchs.)

Why would the mutation stick around so long instead of giving up the ghost? Researchers initially thought the mutation provided protection against the bubonic plague that caused the Black Death in Europe. Those with the mutation would have lived longer and had more children while many of their neighbors died off. The fact that the genetic mutation also provided protection against HIV centuries later would just be a coincidence.

The plague scenario has been largely discarded in favor of another deadly scourge. "A disease like smallpox that has been continuous since that time ... is more likely," said Yale University professor of epidemiology Alison Galvani, who co-wrote a study about the possible smallpox link in 2003.

According to Galvani, while the plague came and went, smallpox stuck around well into the 20th century, providing even more incentive for a protective gene to live on: It would keep people alive generation after generation, instead of just during one brief epidemic.

There are other cases of genetic mutations affecting two diseases: People who inherit one of the two mutations necessary to develop sickle-cell anemia end up with extra resistance to malaria, said Dr. Donald Mosier, professor of immunology at The Scripps Research Institute in La Jolla, California.

Last February, Mosier co-wrote a report in the journal Nature that debunked the plague theory after researchers found that mice bred with the AIDS-protective gene mutation still got sick with the plague. Mosier's not quite sure smallpox deserves credit for extending the mutation's life either, however, and suspects that a less high-profile disease -- diarrhea-causing dysentery -- may be why the mutation has lived on.

Besides the Northern Europeans and Central Asians with the CCR5 receptor gene mutation, new research shows that members of several ethnic groups have another, less-powerful kind of AIDS resistance. In the Science study released this week, a large team of investigators report that people who have more copies of a specific gene end up with greater resistance to AIDS, in some cases significantly changing how they handle getting infected.

The researchers examined the number of copies of a gene known as CCL3L1 in 4,300 people -- some HIV-positive, some HIV-negative. Those with the most copies of the gene -- but only as compared with others in their ethnic group -- had the most immunity to HIV. The HIV-positive people with the fewest gene copies got sick as much as 2.6 times faster than others who were infected.

More copies of the CCL3L1 gene appear to translate into more proteins known as cytokines, which guide immune cells by latching onto receptors -- those cellular locks. The cytokines "tell inflammatory cells it's time to move and go somewhere," Mosier said. With more cytokines floating around gumming up the cellular keyholes, there are fewer locks for the AIDS virus to pick.

Compared with the almost-absolute protection afforded by the gene defects in Europeans, "the effect is not as complete, but the prevalence is much higher," said study co-author Dr. Sunil K. Ahuja, professor of medicine at the University of Texas and director of the Veterans Administration Center for HIV and AIDS in San Antonio.

What can scientists and doctors do with all this information? Doctors could potentially test AIDS patients to see if their genes make them especially vulnerable to progression of the disease, Ahuja said. "This hasn't happened yet, and we aren't there yet. But that would be some practical downstream value of the work we are doing."

Then there's the prospect that people will use genetic testing as a ticket to a carefree sex life. If you're naturally resistant to AIDS, why not dump the condoms and add a few notches to your bedpost?

The Scripps Research Institute's Mosier has gotten calls from curious citizens wondering about their genes. But don't go running to your nearest genetic laboratory just yet. For one thing, researchers aren't sure whether the protective genes both giveth and taketh away: Perhaps they make people more resistant to AIDS but also make them more vulnerable to other germs.

Then there's the pesky matter of the few people who have gotten infected with HIV even though they're supposed to be immune. "It's extremely rare," Mosier said, "but you don't want to tell people they'll be protected and then have them change their risk behavior and get exposed."

http://www.wired.com/medtech/health/news/2...currentPage=all

[Rish]

by Spasemunki

It's possible that around 14% of the population of Europe and the United States have at least a resistance, if not total immunity to HIV.

Why?

Apparently, because their ancestors survived the Black Plague.

A mutation that affects the protein structure of the cell membrane of immune cells, referred to as Delta 32, has been found to be present in significant numbers among both direct descendents of bubonic plague survivors, and among some gay men who received heavy exposure to the virus in the 1970's through unprotected sex with infected men who later died of AIDS, and yet failed to become infected themselves.

Tests in which the blood of these individuals is exposed to levels of HIV thousands of times higher than a typically infective dose have revealed that no matter what dosage of HIV they are exposed to, their cells are not penetrated by the virus. Apparently, this is due to the absence of a surface protein that bonded to by the protein coat of the HIV virus.

An individual may have either one or two copies of this mutation. It is suspected that individuals with one copy are the source of stories dating to the time of the Black Death that recall an individual being exposed to infection, acquiring symptoms of the disease, and then recovering. Their recovery was often attributed to external factors (one woman is said to have recovered because she drank bacon grease), but some scientists now suspect that genetic defense was the real answer.

Others, who are presumed to have had two copies of the mutation, failed to develop symptoms, despite constant exposure to the disease. Two anecdotes from a small village in England where studies where first carried out refer to a widow whose husband and six children all succumbed, but who never developed symptoms herself, and to a village grave digger who handled virtually every infectious corpse in the village without ever falling ill.

Back in the 20th Century, individuals with a single copy of the mutation have been observed to experience a longer delay in the onset of infection than those without it. Individuals with two copies of the mutation are those who seem to be totally immune to the infection.

Before you go out and go crazy barebacking the night away, sharing needles, and transfusing mysterious blood you find on the street, recall that global studies show that in the areas where the Black Death raged (and among their descendents), around 14% of the population has at least one copy of the mutation. In Asia and Africa, and among native North Americans (American Indians, silly, not you), the percentage is effectively zero, as the ancestors of the inhabitants of these areas didn't pass through the Bubonic Plague bottleneck. The percentage of this mutation is calculated to have been at its highest around the time of the Black Plague, and since then has been diluted.

Ultimately, it may be possible that this mutation may be exploited to 'inoculate' the uninfected, or even to treat the infected, through some form of gene therapy. Unfortunately, the therapeutic use of genetics remains in its infancy, and the mutation needs to be studied in greater depth. Strangely, while attention to AIDS in the media and the medical community has been intense (though arguably, particularly in the case of the crisis in Africa not as intense as you'd hope), there were almost no studies of why certain at-risk individuals weren't becoming infected- most clinical trials and studies right up until today have been on infected individuals.

The first studies of an apparently immune individual- a gay man named Steve Crohn- were carried out in the late 90's/early 00's by doctors in New York City. Crohn had been active in the gay scene in San Francisco right before HIV and AIDS were recognized. His lover was among the first individuals in the U.S to be recognized as having died of AIDS. In the decade following the discovery of AIDS, Crohn claims to have lost between 70 and 90 close friends and former lovers- all of whom engaged in the same practices as Crohn himself. Crohn was not infected, and volunteered for testing that showed that his blood seemed to be basically impervious to HIV. Testing has indicated that Crohn has two copies of the relevant mutation.

So some of us are immune to HIV. And the Bubonic Plague. And hopefully, we'll eventually know more. And in the meantime, don't take any stupid chances.

[Rish]

by Codex

Genetic Resistance to the Human Immunodeficiency Virus

The mutation that apparently confers significantly increased resistance to HIV occurs in the gene that codes for CCR5, a chemokine receptor found in the plasma membrane of certain cell types.

In order to infect a cell, HIV uses its envelope glycoprotein to bind the CD4 receptor found on several cell lineages of the immune system. This then changes the conformation of the envelope, allowing the virus to bind a coreceptor -- the main ones being CCR5 or CXCR4. Coreceptor binding induces the process of fusion, allowing viral RNA to enter and infect a cell. This mutation in the CCR5-coding gene alters the conformation of the final protein product, affecting its ability to bind chemokines.The import of the CCR5 mutation is that initial stages of infection with HIV, including infection via mother to child transmission, have been observed to involve cells that express CCR5. (With HIV-1 subtype B, which is common in the United States and Europe, for example, coreceptor switching to CXCR4 occurs later in the course of disease progression.) Apparently, the HIV virion is also unable to recognize this mutated CCR5, thus preventing the first stage of infection.

The association with the Black Death and bubonic plague is not yet solid. There are, however, reasons why it was singled out:

1. The extraordinarily high frequency of the mutation in European populations and those of European descent in the United States is quite striking. CCR5 normally functions by acting as a receptor for chemokines, signalling intracellularly to modulate the state and activity of the cell. With such a crucial role in the maintainence of normal immune function, it would require a very strong selective pressure to make the mutation provide enhanced fitness, thereby ensuring the continued presence of the mutation in a given population.

2. Population-level genetic analyses indicated that this mutation and its spread may be relatively recent. Certainly, it occurred after the separation of Asiatic, African and European races, as this mutation is not generally found in non-Europeans (this does not mean to say that the mutation may not have arisen spontaneously on various occasions, only to die out due to the decreased fitness that it confers).

3. Aside from the high selective pressure, the frequency indicates that there may have been a bottle-neck in the recent past. Genetic analyses suggested that the most recent impact of this pressure occurred around 700 years ago. This estimate coincides with the Black Death which rampaged through Europe in the mid 14th century. This disease, which resulted in the death of about a third of Europe's population, is hypothesized to have exerted powerful selective pressure on the relatively rare number of people carrying the mutation, subsequently allowing for the increased transmission of this mutated gene to the next generation.

HIV-1 Versus HIV-2

There are two types of HIV, denoted as 1 and 2. HIV-1 is the most widespread and most extensively studied. HIV-2 is more closely related to the simian immunodeficiency virus, or SIV, and is quite rare, being more or less confined to West Africa. Studies done on a cohort of female sex workers have suggested significantly slower progression to AIDS. It is also possible that prior infection with the less pathogenic HIV-2 maybe prevent superinfection with a HIV-1 strain.