Lying in Wait

The elusive HIV

HIV, the virus that causes AIDS, kills with deadly efficiency by disabling the human immune response, leaving people vulnerable to infection and other diseases. Since 1983, when researchers discovered the virus, at least 25 million people have died from AIDS or AIDS-related diseases and millions more have become infected with HIV.

One reason for HIV’s success is that the virus has several ways of eluding the immune system’s attempts to kill it. First, it targets and destroys CD4+ T cells — the cells that trigger the immune system to attack invading pathogens. Then, it mutates rapidly to stay one step ahead of a targeted immune response.

Recently, scientists have learned the virus has another trick up its sleeve. It can make itself invisible to the immune system by going into a latent state where its viral genes are inactive and no new virus is produced.

Researchers at Johns Hopkins Medical School found the first reservoir for latent HIV within resting CD4+ T cells. Now, U-M scientists have discovered a second hiding place for the virus in immature human bone marrow cells. Latent viral genes can lurk undetected within the DNA of these cells for long periods of time — waiting until conditions are right for a comeback.

HIV’s ability to go dormant and hide inside infected cells explains why powerful anti-HIV drugs cannot completely remove the virus from the body, says Kathleen Collins, M.D., Ph.D., associate professor of internal medicine and of microbiology and immunology, who led the U-M study.

“Current drug therapies prevent active virus from spreading to other cells, but the drugs have no effect on latently infected cells. Once drug therapy stops, the virus comes back,” says Collins. “To cure the disease, we have to find all the reservoirs and eradicate them.”

Christoph Carter, a student in the Medical School’s M.D./Ph.D. program, was a member of the research team that studied bone marrow samples from Health System patients who were taking anti-HIV drugs. He created a gene promoter that caused green fluorescent protein to glow in a small number of bone marrow cells infected with latent HIV. The glowing cells were hematopoietic progenitor cells — primitive bone marrow cells that give rise to red blood cells, white blood cells and immune system cells.

Postdoctoral fellow Adewunmi Onafuwa-Nuga (Ph.D. 2007) and graduate student Lucy McNamara analyzed the bone marrow samples to determine the number of cells that contained the virus. Some samples had as few as one out of 10,000 cells with latent HIV.

“In people on drug therapy, this very small number of latently infected cells may be the only virus that’s left in the body,” says Collins. “Unfortunately, it doesn’t take many latent cells to rekindle active infection.”

In future research, Collins hopes to find drugs capable of eliminating HIV from latently infected cells. She says her ultimate goal is to develop a “short-course therapy to cure the disease. That would have a global impact.” — SALLY POBOJEWSKI

 

David Canter to Lead NCRC

David Canter, M.D., the physician-scientist who formerly led Pfizer’s pharmaceutical research and development facility in Ann Arbor, is the first executive director of the U-M North Campus Research Complex (NCRC). Canter will develop and implement a university-wide strategy for use of the 30 buildings and 174 acres of land that make up the former Pfizer facility. U-M became the property’s new owner on June 16, 2009.

“I’m honored to be chosen as the first executive leader of the NCRC team,” says Canter. “It was a bold move by the U-M to purchase the Pfizer site and using it to its fullest potential will bring many challenges and opportunities.”

Canter has 25 years of experience in the pharmaceutical industry. He came to Michigan in 1986 as a vice president for Warner-Lambert/Parke-Davis, which was purchased in 2000 by Pfizer. Canter served for eight years as a senior vice president for Pfizer Global Research and Development until the company closed its Ann Arbor research operation in 2008&emdash;ending 50 years of pharmaceutical research and development on the site.

Canter began his appointment at the NCRC on July 19. He reports to Ora Hirsch Pescovitz, M.D., U-M’s executive vice president for medical affairs and CEO of the U-M Health System. — SP

An expanded version of the story
The North Campus Research Complex (NCRC)

 

Targeting the Trigger

In 2005, a team of scientists led by Arul Chinnaiyan (M.D. and Ph.D. 1999), the S.P. Hicks Endowed Professor of Pathology, discovered what triggers at least half of all prostate cancers. It was the abnormal fusion of two genes, one active only in prostate cells and the second an oncogene — a gene that causes cancer. Unfortunately, there was no way to target this gene fusion with existing pharmaceutical drugs.

Now, Chinnaiyan’s team has found a new gene fusion that is present in about 2 percent of prostate cancers. The oncogenes involved in this fusion are RAF1 and BRAF — members of a signaling pathway known to be involved in aggressive forms of melanoma and gastric cancer. Until this study, no one knew the RAF pathway was involved in prostate cancer, also.

The good news is that four “anti-RAF” drugs have been developed and are being tested now in clinical trials in patients with advanced melanoma. The U-M discovery suggests the same RAF-inhibiting drugs could be an effective treatment for the 2 percent of men whose aggressive prostate cancer is caused by RAF-pathway gene fusions. About 192,000 American men are diagnosed with prostate cancer every year. Researchers estimate that 3,600 of these tumors could be RAF-driven.

Chinnaiyan suspects RAF gene fusions could play a role in other types of cancer. If this is true, it means more people with aggressive cancers might benefit from treatment with RAF-inhibiting drugs.

“Rather than treating these cancers as just a ‘prostate tumor’ or a ‘gastric tumor,’ we need to think of it as a ‘RAF-mutant tumor,’ ” says Chinnaiyan. “We need to think more about the driving molecular basis for each patient’s tumor and what oncologists can do about it.” — SP

An expanded version of the story
Patient information on prostate cancer