AIDS used to be considered a male-specific health problem — but now, the majority of its victims are female.

Those numbers aside, some studies have shown that certain females take much longer than males to progress to AIDS after being infected with HIV. Now, researchers have now found a mechanism that might explain this difference.

A two-stage study by Siddiqui et al. identified a genetic variant on the X chromosome that may slow progression from HIV-1 to AIDS in women. The study analyzed both primates and humans, demonstrating that genetic association findings can successfully translate across species, even over an evolutionary distance of 25 million years.

The researchers first analyzed 136 rhesus monkeys infected with SIV (simian immunodeficiency virus). They found a common genetic marker on the X chromosome among those monkeys that progressed slowly to AIDS-related disease. Researchers then studied 303 HIV-infected humans and found an analogous marker on the X chromosome —the SNP rs5968255 — that may affect progression to AIDS in human females.

The results, published in the online version of The American Journal of Human Genetics, indicate that in humans, females with one copy of the C version of rs5968255 progressed to AIDS more slowly than either females with TT or males with a C or T. (Note that females have two X chromosomes, while males only have one.)

Females with one copy of the C version of the SNP took an average of eight years to progress from HIV infection to AIDS, nearly four times less than females with no copies or males. Women with two copies of C are so rare that none were found in the study.

Previous research has linked some degree of HIV resistance to a mutation in SNP i3003626, which is in a gene that encodes the CCR5 receptor.

(23andMe customers can check their data for rs5968255 using the Browse Raw Data feature. Information on i3003626 is available in the Resistance to HIV/AIDS Clinical Report.)

The CT genotype of rs5968255 is more frequent among Asians than Europeans or Africans, suggesting that future research may find that HIV-1 positive Asian females have a slower progression to AIDS. Future studies may also be able to use this X chromosomal variant as a clue toward new drug development for both genders.

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In a way, organ transplantation is the one branch of medicine that has already been personalized, because doctors must carefully match the immune systems of donor and recipient to prevent rejection.

Now transplant physicians in Germany have taken that procedure a step further by engineering not just a successful bone marrow transplant, but one that appears to have cured their patient’s HIV infection as well. The doctor who conceived the operation has suggested that in principle, the accomplishment could inspire a gene therapy for HIV. But it will take much more research, and a lot of luck, for that to happen.

This week Dr. Gero Huetter and his colleagues at the Charite Hospital in Berlin announced that they were treating a 42-year-old patient who required a bone marrow transplant for leukemia, but had also been HIV-positive for a decade.

The doctors knew of a gene, CCR5, that confers resistance to the most common form of HIV. People who have a particular mutation, known as Delta32, on both copies of CCR5 can be exposed repeatedly to HIV-1 without becoming infected.

23andMe customers can learn their CCR5 status by referring to the Resistance to HIV/AIDS report in our Health and Traits section.

The doctors reasoned that if they could find a donor who was not only immune compatible with their patient, but also had two copies of the Delta32 mutation in the CCR5 gene, perhaps they could simultaneously eradicate his leukemia and his HIV infection.

Remarkably, such a donor existed. And 600 days after his bone marrow transplant, the patient is both leukemia- and HIV-free.

Is this a cure for AIDS? Not a chance. Doctors do not consider the procedure a potential treatment for HIV, because bone marrow transplants are expensive and risky — about one patient in four does not survive the procedure. But the case does provide inspiration and hope for researchers who are working on ways to harness the resistance conferred by CCR5Delta32 to treat the infection.

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A gene variant found mainly in people with African ancestry increases the odds of HIV infection in African Americans exposed to the virus says a study published today. Once infection has set in, however, this same variant slows the progression of the disease, allowing people to live about two years longer.

The authors of the study, published today in Cell Host & Microbe, estimate that in Africa, this genetic variant may be responsible for 11% of the HIV burden.

In a cohort of close to 1,300 African Americans, He et al. found that those people who lacked a protein on their red blood cells called the Duffy antigen had 40% higher odds of being infected by HIV but were more likely to have a slower progression of their disease.

About 90% of sub-Saharan Africans, and close to 70% of African Americans, are “Duffy negative,” meaning they have two copies of a particular version of the Duffy antigen gene that prevents the protein from being made in red blood cells. Duffy negativity has previously been associated with resistance to one strain of malaria, Plasmodium vivax.

“After thousand of years of adaptation, this Duffy variant rose to high frequency because it helped protect against malaria,” said Matthew Dolan, one of the study’s authors. “Now, with another global pandemic on the scene, the same variant renders people more susceptible to HIV. It shows that complex interplay between historically important diseases and susceptibility in contemporary times.”

The slowing of disease progression seen in Duffy-negative HIV-positive individuals was comparable to that seen in Europeans who carry a genetic variant called “CCR5Delta32”. Two copies of CCR5Delta32 render people resistant to the most common strain of HIV, while having just one copy is associated slowed disease progression.

(23andMe customers can see their data for the Duffy antigen, CCR5Delta32, and other SNPs mentioned here at the end of this post.)

The authors of the current study speculate that the seemingly contradictory effect of the Duffy antigen on HIV – lacking the protein promotes infection but slows disease — are due to complex interactions between the Duffy antigen and chemicals called chemokines that bind to it and the HIV virus itself. They propose a model in which being Duffy-positive results in increased anti-HIV chemokines in the bloodstream, which helps fight off an HIV infection. But in the event the virus does get a foothold, the increased chemokines actually facilitate disease progression by increasing inflammation, and the Duffy antigen ends up being a liability by providing a binding site for the HIV virus.

“The parts of a car that get it into gear are separate from those that get it moving once in gear,” said Sunil Ahuja, senior author of the paper. “ A similar analogy applies to HIV; the factors that influence its transmission are not necessarily the same as those that influence disease progression.”

The results of the current study not only suggest that Duffy-negativity might be an important part of the picture when considering the global HIV pandemic; they also help explain previous studies, which showed genetic variants that increase the levels of two chemokines in particular – CCL2 and CCL5 – were associated with faster disease progression in European Americans.

The authors of the current study found that those other variants also accelerate disease progression among African Americans – but only among those who are Duffy positive. Among the majority of African Americans who are Duffy negative, the genes affecting CCL2 and CCL5 appear to make little difference. In their conclusion, the researchers point out that these results demonstrate the importance of understanding the interactions between genes that affect disease susceptibility.

If you are a 23andMe customer, you can use the links and tables below to check your data for each of the SNPs mentioned in this post.

Duffy Antigen

(this is the same SNP used in the 23andMe My Gene Journal (now called Health and Traits) article on Malaria Resistance)
rs2814778

CCR5Delta32
23andMe custom SNP i3003626

CCL2
rs1024611

CCL5
rs2107538

My Gene Journal (now called Health and Traits) also has articles about Duffy antigen and CCR5Delta 32 [Malaria Resistance (Duffy antigen) and HIV/AIDS Infection, respectively].

If you’re really interested, here are links to the original CCL2 and CCL5 studies that found that the SNPs detailed above increased the levels of these chemokines and the rate of disease progression in HIV infected European Americans.

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