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Scientists at The Scripps Research Institute Determine Role of Human Protein in HIV Infection

La Jolla, CA. December 1, 1999 -- Scientists at The Scripps Research Institute (TSRI), have determined how a human protein is helping the human immunodeficiency virus type-1 (HIV-1) to enter human cells. While the protein, cyclophilin A, has been known for some time to be required for HIV-1 infection, its precise role in the process had yet to be clearly defined. However, in an article published today in the journal, EMBO, Philippe Gallay, Ph.D., Assistant Professor, Department of Immunology, at the La Jolla institution, reports that HIV-1 in effect hijacks cyclophilin A from cells at the time it buds and then presents the protein on its surface. Gallay's laboratory found that this exposed human or "host" protein plays a crucial role in HIV-1 infection: it mediates attachment of the virus to the surface of target human cells.

The laboratory also identified a binding partner for cyclophilin A on human cells, a carbohydrate called heparan which abundantly decorates the surface of a wide variety of human cells. "The interaction between cyclophilin A and heparan appears to be the earliest step in HIV-1 infection" says Gallay. "To our knowledge, this is the first example of a retrovirus using a host protein in this way, although it is likely that other viruses may be found to employ similar mechanisms for the initial attachment to target cells". He continued, "Although we don't know yet the precise physiological role of cyclophilin A in normal human cells as opposed to the virus this finding may open a new avenue for the development of anti-HIV-1 therapies. We are concentrating our efforts to develop new agents that can block CypA-mediated HIV-1 attachment to human cells."

The article, "Host Cyclophilin A Mediates HIV-1 Attachment to Target Cells via Heparans, " was authored by Andrew C.S. Saphire, Michael D. Bobardt, and Philippe A Gallay.

According to Gallay, cyclophilin A is only the second protein on the surface of HIV-1 that has been shown to be required for HIV-1 infection since studies on the virus began 20 years ago. "To date, the only protein on the surface of HIV-1 known to mediate HIV-1 entry, the HIV-1 envelope protein (gp120/41), is derived from the viral genome" he says. "We are particularly excited about this finding because cyclophilin A is not encoded by the viral genome, and thus cannot directly mutate in response to anti-viral selective pressure, unlike the virus's own envelope protein (gp120/41). This may present a weakness that we can exploit, although doing so will not be straightforward" says Andrew Saphire, Ph.D., a postdoctoral researcher in the lab and first author of the report.

Indeed, Gallay points out that the use of a human protein by HIV-1 in such a crucial step of infection may represent another example of the clever means the virus employs to defeat the normal protective immune response. When this protein is assessed by the immune response, it may appear to be "self" rather than a foreign protein. Because of this, it is unlikely that the immune system mounts a strong reaction to this protein. "This may be another example of how HIV-1 has evolved to avoid the human immune response. It's a smart strategy - as cyclophilin A is a host protein, our immune system probably does not recognize it as a threat," he remarked.   

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