|
||||||||
|
MICROBIOLOGY Herpesvirus Tames Natural Killer CellsWhat's the difference between true love and a herpes infection? Only one is guaranteed to last for life. A dark joke, but Jae Jung uses it as an apt description of how a herpesvirus can dodge an otherwise vigilant immune system and persist for the lifetime of its host. Jung, HMS associate professor of microbiology and molecular genetics, has been studying the most recently discovered member of the herpes clan, Kaposi's sarcoma-associated herpesvirus (KSHV), a tumor-causing virus that is much more specific in its targets than other herpesviruses.
Jae Jung, Satoshi Ishido (l to r), and their colleagues have discovered that Kaposi's sarcoma-associated herpesvirus defends against front-line immunity by preventing its host from activating natural killer cells. Photo by Pam Murray Kaposi's sarcoma, the cancer caused by KSHV, is one of the leading cancers in Africa and is especially common in HIV patients and immunosuppressed organ transplant patients; in fact, it was the high incidence of the cancer in gay men in the 1980s that heralded the emergence of AIDS in the U.S. Yet the virus that causes Kaposi's sarcoma was only discovered in 1994, and little is known about why it is so often linked with HIV and targets such specific populations. Jung and his team, led by research fellow Satoshi Ishido, have discovered some new strategies the virus uses, part of an intricate bag of tricks that enable it to evade the immune response of its host and linger for life. Their most recent findings, published in the Sept. 22 Immunity, explain the virus's strategy for avoiding one of the body's first lines of defense, natural killer (NK) cells. By uncovering the virus's secrets, Jung's team hopes to identify targets for a counterattack and perhaps explain KSHV's equally unusual epidemiology. In June, Jung and his colleagues published findings on two viral gene products, K3 and K5, that help KSHV avoid detection by killer T cells. When the team first discovered K3 and K5, the two proteins seemed so similar they might have been the product of a gene duplication. Together their function is strikingly similar to the HIV envelope protein Nef, an important target for experimental HIV vaccines. Like Nef, K3 and K5 interfere with an infected cell's ability to warn killer T cells of a foreign presence. Hide and SeekNormally a cell delivers MHC Class I molecules to the membrane that present viral peptides as beacons for roaming T cells. K3 and K5 put a damper on the ability of these molecular alarms to stay at the membrane, leaving the killer T cells clueless to the intruder's presence. The ability to manipulate the MHC Class I molecules of its host is a trademark strategy for herpesviruses, allowing them to remain undetected even within an otherwise active immune system.But the immune system has some more immediate defenses that a virus also needs to elude. While B and T cells can take days to respond to an infection, NK cells need only hours. These cells are part of the body's innate immunity, licensed to kill without an order from the normal T cell chain of command. They identify foreign invaders by looking for cells not carrying the signature MHC molecules that identify each cell in the body as self. What puzzled Jung and his team was finding that K3 downregulates some of these self-identifying molecules as well as those that warn T cells of a foreign presence. So while muffling the signals that might muster killer T cells, K3 was also potentially undermining the herpes invasion by disabling signals that disguise it from NK scouts. Shrewd MoveThe team suspected that K5 must somehow be working to counteract the unwanted effects of K3, but it was unclear how K5's effects on MHC Class I molecules could cancel out K3's. It turned out that K5 was not as similar to K3 as it seemed. While K5 does not have as strong a dampening effect on MHC Class I molecules as does K3, it has the added function of turning off two molecules, ICAM-1 and B7-2, that are part of the NK cell activation pathway. "K5 is weaker than K3, but it's smarter," Jung said. So although K3 threatens to block the NK cells' off switch, K5 moves in to inactivate its on switch. It is a novel mechanism for a virus to use."The immune strategy is very different from other viruses," said Jung. These two genes may serve as potential targets for therapies, similar to Nef for HIV, and the similarity in strategies of the two viruses may also help explain why they often strike concurrently. —Courtney Humphries |
