Research Could Lead To New Drugs For HIV

The increased frequency of drug resistance in isolates of the AIDS virus, HIV, makes identification of new antiviral targets an urgent necessity. Host genes required to support the replication of HIV are a potential source of such novel targets, but relatively few appropriate target genes have been identified in animal cells thus far. A new study, conducted by Dr. Suzanne Sandmeyer and colleagues at the University of California, reports the discovery of over 100 host genes that affect the replication of a model retrovirus. Their results are reported in the May issue of Genome Research.

Many organisms harbor mobile genetic elements that are non-pathogenic molecular relatives of retroviruses. In budding yeast, these mobile elements (called Ty -- or transposable yeast -- elements) encode proteins that are homologs of retroviral proteins. The proteins encoded by Ty elements and the steps of the life cycle in yeast are similar to the proteins encoded by retroviruses and their life cycles in animal cells. Scientists believe that these simple elements in a single-celled organism are a good model for understanding how retroviruses such as HIV interact with their hosts. Yeast has previously been used as a model to help scientists understand how cancer cells replicate out of control.

The Sandmeyer laboratory, which has expertise in genetics and biochemistry, screened a collection of over 4457 mutant yeast strains representing most of the known genes in yeast. They then solicited the help of computer scientist Pierre Baldi, also at the University of California, to focus on gene functions likely to be particularly significant in the Ty3 lifecycle. Together, they developed an interactive program (GOnet) allowing them to search through large amounts of genetic and biochemical data to identify "clusters," or related groups of genes, that are most likely to affect key points in the Ty3 lifecycle. In total, they identified 130 genes that affect the replication of the retrovirus-like element Ty3.

Over half of the genes identified in this study have at least one clear relative or homolog in the human genome, thus providing a rich source of candidate retrovirus host genes. Sandmeyer and colleagues hope that this study, along with related studies of retrovirus-like elements in yeast, will ultimately lead to the development of a new generation of anti-retroviral therapeutics.

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