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NIAID Grants $3M for Proteomics Study of HIV Resistance

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NEW YORK (GenomeWeb) – A new grant from the National Institutes of Health will fund a collaboration using mass spectrometry to try to find proteins and post translational modifications that can inhibit HIV latency in T cells.

Led by Mathias Lichterfeld of the Ragon Institute and Rushdy Ahmad of the Broad Institute, the collaboration will investigate a population of patients with HIV who naturally can control viral replication without the help of medications. For these "elite controllers," which make up less than 1 percent of the HIV patient population, a viral load test will come back negative, even if the patient isn't on drugs, Lichterfeld told GenomeWeb.

"There's a natural mechanism that controls HIV replication. We found in previous work that phosphorylation of certain proteins is regulated differently in these patients," he said. While earlier studies focused on a single molecule, the new project will look proteome-wide, between 10,000 and 15,000 proteins and their phosphorylations.

The National Institute of Allergy and Infectious Diseases has granted $652,471 to the project researchers this year and has allocated approximately $3 million over five years.

The Ragon Institute of Massachusetts General Hospital, the Massachusetts Institute of Technology, and Harvard, has cultivated a cohort of elite controllers, which Lichterfeld has been studying dating back to 2008. While not easy to find, they provide "living evidence that immune defense against HIV can work," Lichterfeld said.

CD4 T cells from these patients are less susceptible to HIV infection, even when taken out of the body, suggesting cell-specific attributes. When looking at the possible underlying mechanisms for this, Lichterfeld's team noticed that host cyclin-dependent kinase (CDK) 2 involved in protein phosphorylation was important to HIV's reverse transcriptase enzyme and that a CDK inhibitor was upregulated in CD4 cells from elite controllers.

Lichterfeld said that there's evidence that many viruses depend on host kinases for phosphorylation. While some viruses are big enough to encode for their own, HIV is small and relies on hijacking the host kinase machinery, he said.

One component of the grant is to identify which parts of HIV the human kinases phosphorylate, which would suggest areas of great host-dependence and, therefore, vulnerability.

"Phosphorylation at different sites might change how effectively it can replicate," Lichterfeld said. "The entire life cycle probably depends on host kinases that modify different parts of HIV."

The second component of the grant is to identify which proteomic signatures exist in latently infected cells.

For this part, especially, Lichterfeld needed to engage with high-throughput proteomics, bringing him to collaborate with Ahmad. While gene expression profiling is still useful for this kind of research, Lichterfeld said it doesn't provide as much detailed information as the proteomic approach.

If all goes well, the research could suggest druggable targets that would disrupt the ability of HIV to become latent, eliminating the reservoir of virus.

There also have been studies to suggest that phosphorylations aren't the only post-translational modification that could be studied using a high-throughput approach.

Acetylation can regulate HIV viral integration, according to a 2005 paper published in the EMBO Journal by researchers at the International Centre for Genetic Engineering and Biotechnology in Trieste, Italy.

For now, the collaboration will stick to phosphorylation. Lichterfeld said he expects to submit the first manuscript with data funded by the grant in the first half of this year.