An AIDS vaccine that wasn't effective in a clinical study did influence the genetic makeup of the virus that slipped past. And researchers think these findings could suggest new ideas for developing HIV vaccines.
The multinational, 3,000-patient Phase IIb STEP trial tested a Merck HIV-1 subtype B vaccine known as MRKAd5. It was designed to make the body produce white blood cells that could recognize and target specific parts of HIV-1 known as Gag, Pol and Nef. Preliminary tests indicated the vaccine was encouraging the appearance of the desired virus-attacking cells. However, immunizations were halted after the first interim analysis indicated that the vaccine neither prevented HIV-1 infection nor reduced the load of virus in the body.
But now James Mullins, University of Washington professor of microbiology, and his a team have analyzed the genome sequences in HIV-1 isolated from 68 newly infected volunteers in the STEP trial. The research team tested for a "sieve effect," which, Mullins explains, occurs when a vaccine successfully blocks some strains of virus and not others.
The researchers identified potential T-cell targets in the protein-producing regions of the founder virus genetic sequences and compared these to the virus protein-targets of the vaccine--Gag, Pol and Nef. The researchers found that the distances for these viral genetic sequences were greater for the viruses taken from the vaccinated individuals, compared with those from the placebo recipients.
The most significant virus genetic site distinguishing vaccine from placebo recipients was in the region known as Gag-84, which was encompassed by several of the viral segments targeted by the vaccine. The researchers said the extended divergence between the viruses from the vaccinated and the placebo groups was confined only to the sequences for the proteins targeted by the vaccine components (Gag, Pol and Nef) and was not found in other HIV-1 protein sequences. The influence of the vaccine on the virus genotype was subtle, according to Mullins.
This is the first evidence that vaccine-induced cellular immune responses against HIV-1 infection exert selective pressure on the virus. "Selective pressure" refers to environmental demands that favor certain genetic traits over others. The researchers added that their findings suggest that new vaccines should be designed to put selective pressure on the virus in a controlled manner. The results were published Feb. 27 in Nature Medicine.
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