Closer to Vanquishing the Virus

The field of human genomics is at long last enabling us to focus medical thinking on the infected host.

By SHARE

Soldiering through the winter months, we carry our hand sanitizers and shrink from others' sneezes and coughs in hopes we won't be overtaken by the common cold or a bad case of the flu. And regular reports from the World Health Organization keep alive the fear that the deadly H5N1 bird influenza incubating in Asia could wipe out a big hunk of the world's population if the virus takes a wrong genetic turn. But a virus, however powerful, is not all there is to it. As doctors will tell you, even the most aggressive of viruses do not infect everyone, and some people who are infected breeze through with barely a sniffle. What researchers are beginning to realize by studying the differences in individual genetic makeup is that those differences influence the course of disease, whether it's influenza, SARS, hepatitis B, or HIV. The virus itself has drawn the most research attention, particularly when it comes to vaccine and drug development. Now, the field of human genomics is at long last enabling us to focus medical thinking on the infected host.

HIV, surely the most heavily researched virus on the planet, is teaching us a good deal about host diversity. Just two weeks ago, Stephen Elledge and colleagues from Harvard reported what has been hailed as one of the leading discoveries in the field of AIDS research in the past decade: that HIV exploits an astonishingly high number of host genes during the course of infection. In a scan of the entire genome of cultured human cells newly exposed to HIV, more than 200 genes showed up as being critical to viral growth and survival. Since individual genes can vary widely among individuals, so can host sensitivity to pathogen invasion.

Viruses are tiny packets of disease-causing genetic material in search of survival. They seek out the cell type that gives them entry based on their own genetic makeup. For HIV, the welcoming cell is the immune system's lymphocyte. Other viruses are designed to target cells such as those in the respiratory tract, the liver or gut, the heart, or the brain. Once inside the host cell, the virus takes over and churns out thousands upon thousands of viral copies, which are then spewed out into surrounding tissue and fluid. The process goes on and on until the host's immune system controls or destroys the virus—or the host dies.

But outcome is very much a function of the host, and teasing out innate human variation has already helped explain why as many as 4 percent of people (the so-called long-term nonprogressors) can coexist 10 or more years with HIV without showing clinical illness. Some people escape HIV infection entirely, despite extensive exposure to the virus from contaminated needles or unprotected sex. Gene variants have been shown to confer bulletproof vests of sorts on lymphocytes that block HIV entry into the cell. Differences in the many immune chemicals that bathe infected cells can make the host more resistant or susceptible to disease. Gene-coded proteins inside the host cell can affect viral reproduction or release, while others roaming about the body fight off bacterial and fungal infections as well as viruses. The colorfully named defensins, small molecules that act as a kind of inborn antiviral drug and vary in type and strength, are also secreted in breast milk and influence transmission of viral illness from mother to child.

New drug. Unlike viruses, which are forever mutating their tiny genomes to thwart host defenses, humans have a relatively stable genome over generations. This stability has enabled genomic studies of large populations that also offer clues to the riddle of varied host susceptibility. A nonworking version of a protein called CCR5 that blocks viral entry into the cell is believed to be a throwback to a time when bubonic plague and smallpox swept northern Europe. The gene involved is present in about 10 to 15 percent of people of European descent. A recently approved drug for HIV targets this protein.

History tells us that viruses will always be in our midst. But personal genomics that reveal the many dimensions of human defense, acquired over the ages and in different parts of the world, point to new targets for antiviral drug and vaccine design. And we must take advantage of this information to tailor therapy to the distinctive genetic traits of the individual patient. Who knows? This approach might even take us on a path to cure the common cold.