Identification of Human Proteins may Provide New Target for HIV Drugs

by Jagadeswaran on  January 11, 2008 at 7:59 PM AIDS/HIV News   - G J E 4
Identification of Human Proteins may Provide New Target for HIV Drugs
Scientists from Harvard Medical School in Boston, Massachusetts have identified more than 250 human proteins that support the spread of HIV in the body.

Stephen Elledge, a geneticist, says that these proteins may lead to the development of reasonably effective HIV drugs.

The researcher says that HIV might be stopped in its tracks if drugs could deactivate these proteins, without having too drastic an impact on the patient.

"If you could inhibit a host protein that is necessary for HIV progression, HIV would have to develop a new ability. And in the number games, that doesn't happen. That's why host proteins could make tremendously good drug targets," Nature magazine quoted him as saying.

Scientists were aware of only a few human proteins that are exploited by HIV before this study.

With an eye on finding more of them, Elledge's team used RNA interference to block the expression of a single gene in each of some 21,000 pools of human cells, thereby creating 'knockout' cells for every gene in the human genome.

The researchers then treated the pools of cells with HIV. They also examined the pools for two signs of HIV progression — the presence of an HIV-protein called Gag on the surface of the human cells, and the ability of the cells to infect new, uninfected human cells.

It was found that 273 of the gene knockouts were lacking one or both of these signs of HIV progression, suggesting that the proteins encoded by such genes are important to HIV.

The researchers said that only 36 of such genes had previously been implicated in helping HIV.

"There are certainly lots of proteins that no one would have ever guessed are involved in HIV infection," Nature magazine quoted Elledge as reporting in the journal Science.

Martin Hirsch, another expert at Harvard Medical School, said that the new finding might eventually spur new therapeutic approaches against HIV, but pointed out that drugs that interact with human proteins could be toxic.

"Many previous investigators have gone this route over the past 20 years, with minimal success," he said.

Elledge said that minimizing toxicity of medicines could be achieved if they were programmed to interfere with several of the proteins, without knocking any of them out completely.

He says that this way the critical functions of the proteins could be preserved for the patient, while wiping out a critical function for HIV.

"The cell may not depend on these pathways for a single function, but the virus could," he said.

Elledge's team are now planning to study how these human proteins interact with HIV.

Source: ANI

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I was surprised to learn the Harvard study led by Professor Stephen Elledge was conducted in highly aneuploid “HeLa-derived TZM-bl cells”. I've worked the past 11 years studying the consequences of aneuploidy and feel I should pass along some of my concerns about the study’s experiments and the authors’ conclusions.

As I say, HeLa cells are massively aneuploid cervical cancer cells from the 1950s, containing typically 76–80 chromosomes and 22–25 abnormal chromosomes per cell instead of the normal complement of 46 (Macville M, Schrock E, Padilla-Nash H, Keck C, Ghadimi BM, Zimonjic D, Popescu N, Ried T: Comprehensive and definitive molecular cytogenetic characterization of HeLa cells by spectral karyotyping. Cancer Res 1999, 59:141-150).

No two HeLa cells are genetically alike, in fact no two use the same network of genes, gene products, transcription factors, receptors, etc. Furthermore, the HeLa cells are highly genomically unstable; they change with each cell division.

Thus, the claimed “273 proteins that the AIDS virus needs to survive in human cells” are probably an artifact of performing the experiments in the HeLa cells and actually have little or nothing to do with what goes on in people.

Ultimately, the multi-million dollar question is even if one can prevent HIV from replicating in HeLa cells by removing the susceptible human proteins, will the same thing happen in normal human cells in patients? The odds are strongly against it.

There is also the conceptual problem of administering drugs against human proteins since these drugs will be inherently toxic. I was in the drug design and development business for 20 years. The first principle in coming up with drugs against infectious agents was to target proteins specific to the pathogen and not human in order to minimize potential and actual toxic consequences.

Researchers should ponder these questions before going down the very expensive road suggested by the Harvard group.


David Rasnick, PhD

guest Sunday, January 13, 2008

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