More than 30 million people worldwide are living with HIV, and about three million more are infected each year. Although people infected with the virus are living longer and healthier lives thanks to intense research, there is still no cure.

One way to identify new strategies for fighting HIV is to look to those people whose bodies are naturally able to keep the virus as bay, at least for a time.  In 2007 researchers identified a variation near the HLA-C gene that was shown to affect the amount of virus present in the body after acute infection but before onset of AIDS symptoms.  This so-called “viral set point” correlates with rate of disease progression, infectiousness and response to treatment.

Now another set of researchers has yet again shown that this variant affects viral set point.   Their results, published online this week in the journal Nature Genetics, further show that this variant influences the time it takes to progress to AIDS.

Rasmi Thomas and colleagues analyzed the DNA from 828 people infected with HIV, all of European ancestry.  Patients were divided into groups with low, medium and high viral loads (<2,000 copies of viral RNA per milliliter of blood, 2,000-10,000 copies, and >10,000 copies). About 62% of people with two Cs at rs9264942 had a viral load below 2,000, while only about 15% of people with two Ts controlled the HIV virus to this extent.  About 33% of people with CT at rs9264942 fell into the “controller” group.  These results agree with what was found by previous researchers.

(23andMe Complete Edition customers can check their data using the Browse Raw Data feature or the link above.)

In a separate group of 763 people infected with HIV (also all of European descent), the researchers found that the C version of rs9264942 was somewhat protective against progression from HIV infection to extremely low CD4 cell count, a measure of immune system strength.  The C version of this SNP also conferred some protection against progression to an AIDS-defining complications and death.

As noted above, low viral set point is known to correlate with slower progression to AIDS, but the analysis by Thomas et al. indicates that the effects of rs9264942 on viral set point and progression are at least somewhat independent.

The researchers examined blood from 50 health donors to investigate the function of rs9264942.   They found that the C version was associated with increased HLA-C protein on the surface of immune cells.  They conclude that this increased protein expression must be what helps the body fight off HIV, although the details of how increased HLA-C is beneficial are still unknown.  Further research will be needed in order to translate these findings into new strategies for treatment or prevention of HIV infection.

• When rs9264942 was initially identified as a variant that could affect HIV viral set point, researchers suggested that vaccines designed to elicit an immune response mediated by HLA-C might be a good idea.  Perhaps this new research, which further solidifies the importance of HLA-C variation in virus control, will rekindle that idea, especially in light of recent HIV vaccine disappointments (more here and here).

• Several genetic variations to HIV infection and treatment have been identified and are detailed in the following 23andMe reports:
  • HIV Progression
  • Resistance to HIV/AIDS
  • Abacavir Hypersensitivity

• Related Spittoon posts:
  • SNPwatch: Genetic Variation in X Chromosome May Slow Progression of AIDS
  • Very Personalized Medicine: Genetically Customized Bone Marrow Transplant May Have Eradicated Patient’s HIV
  • SNPwatch: Genetic Variant Common in African Americans May Influence Susceptibility to HIV

SNPwatch gives you the latest news about research linking various traits and conditions to individual genetic variations. These studies are exciting because they offer a glimpse into how genetics may affect our bodies and health; but in most cases, more work is needed before this research can provide information of value to individuals. For that reason it is important to remember that like all information we provide, the studies we describe in SNPwatch are for research and educational purposes only. SNPwatch is not intended to be a substitute for professional medical advice; you should always seek the advice of your physician or other appropriate healthcare professional with any questions you may have regarding diagnosis, cure, treatment or prevention of any disease or other medical condition.

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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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