Important note: Information in this article was accurate in April 1999. The state of the art may have changed since the publication date.AIDSWEEKLY Plus; Monday, April 19, 1999
Daniel J. DeNoon, Senior Editor
Doherty and colleague Rolf M. Zinkernagel jointly won medicine's top honor for their discovery that CMI responses are triggered by the T-cell recognition of foreign antigens in the context of the "self" molecules now known as major histocompatibility complex (MHC) antigens. They published the key findings of this work in 1974 (Nature 1974 Apr 19;248(450):701-2 and Nature 1974 Oct 11;251(5475):547-8).
Now affiliated with St. Jude Children's Research Hospital, Memphis, Tennessee, Doherty is working with murine gamma-herpesvirus 68 (MHV-68). This virus establishes a lifelong latent infection in B lymphocytes. Recent studies - using a powerful new assay employing tetrameric MHC molecules loaded with viral peptides that bind and directly stain virus-specific effector and memory CD8(+) T cells - show that vaccination of MHV-68 infected mice with a vaccinia/MHV construct greatly enhances anti-MHV CMI responses. The advent of the tetrameric MHC assay recently revolutionized immunology by showing that the size of the specific CMI response to an invading virus is more than an order of magnitude greater than had previously been suspected (see Vaccine Weekly, April 4, 1998).
"In actual fact you can get a tremendous boosting effect in a chronic virus situation," Doherty said. "Now I find myself talking about post-exposure vaccines, which I never thought I would."
Doherty spoke in the keynote address to the Second Annual Conference on Vaccine Research, held March 28-30, 1999, in Bethesda, Maryland.
He noted that vaccine pioneer Jonas Salk had predicted this development, joking that "Back then I thought maybe he had gone around the bend." But the MHV experiments demonstrated that even in the context of a chronic infection, vaccination greatly boosts anti-MHV CMI.
"One might expect you would also see this happen in a tumor situation," Doherty said. However, he warned that HIV infection may not be as amenable to CMI vaccination alone because of the AIDS virus's extremely high rate of replication.
"In terms of HIV I think you want to be thinking in terms of all components of the immune system," he said.
Vaccines that elicit CD8(+) T-lymphocyte-mediated immune responses could also be employed as preventive vaccines. However, Doherty warned that the nature of secondary CMI responses predict that they will be better at preventing disease than at blocking infection.
"The CD8 secondary response may not be enough to prevent infection, but may be enough to prevent the lethal consequences of infection," he said. "This is the limitation of secondary CTL responses. Although they can get to the site of pathology more quickly, they have to be activated and they can only be activated in the lymph node - not at the site of pathology."
The Nobel laureate noted that vaccines have been made for all major pathogenic viruses susceptible to conventional approaches.
"What we are left with are the viruses that are doing something to the immune system," he said. "These are generally big viruses with lots of involvement with the host - not necessarily to kill but to proliferate."
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