Will Hemophiliacs Provide A Clue?

Three years ago, the Center for HIV/AIDS Vaccine Immunology (CHAVI) began looking at a small cohort of hemophiliacs who had been exposed to HIV but remained uninfected despite receiving Factor VIII concentrates derived from large pools of blood plasma collected from donors, some of whom were infected with HIV (see Individual Armor Against HIV, IAVI Report, July-Aug. 2008).

The study, known as CHAVI 014, set out to identify any key genetic determinants that might have explained the apparent resistance of these exposed seronegatives (ESNs) to HIV. During a session this morning about host genetics, David Goldstein, a Duke University immunologist heading up this CHAVI project, said whole genome sequencing failed to find any common genetic variants associated with HIV resistance among the 393 HIV-uninfected cases when compared to 823 HIV-infected controls. “Whatever is protective here, it’s pretty unlikely to be a common one,” said Goldstein, adding that he wasn’t completely surprised by the results.

Golstein said his lab is now in the hunt for much rarer genetic variants that may explain their apparent resistance to HIV infection. For the past 2.5 years, capitalizing on evolving sequencing technology that makes the process faster and more precise, Goldstein’s lab has identified close to 1,000 rare variants of interest, whittled down from a list of 43,000 variants, which might have contributed to protection against HIV acquisition in certain hemophiliacs. To get to this point, Goldstein’s lab sequenced the whole genomes of 41 HIV-uninfected hemophiliacs of European ancestry who were highly exposed to HIV and do not carry the CCR5(delta)32 mutation that is associated with protection against HIV. They compared these sequences to the genomes of 47 low-risk population controls, and any variant that was at equal or greater frequency in the controls was not considered.

Goldstein acknowledges that this approach is a “needle-in-a-haystack” exploration, but said he does not believe the fact that some hemophiliacs did not become HIV-infected after being exposed to contaminated blood products was merely a matter of luck.