LONDON - People who have anything to do with HIV and AIDS know what sort of HIV vaccine they would like. It would eliminate the virus from the body, be given in a single shot and provide lifelong protection.

Sadly, recent insights into the ways in which certain viruses evade the immune response suggest that, if a vaccine for HIV is ever going to be possible, it will be of the type currently available against influenza: only partially effective and given in repeated shots.

And - the biggest problem of all - it requires constant surveillance of new strains emerging worldwide, with parallel updating of the vaccine components.

Rolf Zinkernagel, professor of immunology at the Institute for Experimental Immunology at University Hospital, in Zurich, Switzerland, told BioWorld International, “All the evidence suggests that it would not be possible to design a sterilizing vaccine to protect against HIV - one which would eliminate the virus from the body. But I think there are strategies that would allow us to devise a vaccine that helps to control the virus better, that could change an incubation period of 10 years on average to, say, 40 or 50 years. This would be very good, but it's not the type of vaccine that most people would dream about.“

HIV, like hepatitis B (HBV), is probably a noncytopathic or poorly cytopathic virus. Unlike cytopathic viruses, which kill the cells they infect, noncytopathic viruses do not. Instead, it is the immune response to infected cells that causes the damage associated with the disease.

Paul Klenerman, also of the Institute for Experimental Immunology, and Zinkernagel have been studying the immune response to the noncytopathic virus called lymphocytic choriomeningitis virus (LCMV), which infects mice.

Research Investigates Original Sin

Zinkernagel said, “The games such noncytopathic viruses can play with the immune system of the host are much more varied and flexible than the straightforward kill-or-survive situation that cytopathic viruses usually present.“

The initial immune response to cytopathic viruses usually involves soluble factors such as interleukins and neutralizing, protective antibodies. By contrast, the early immune response to noncytopathic viruses is mediated by cytotoxic T lymphocytes.

One of the ways such viruses can escape the attention of these cells is by mutating the T cell epitope: the part of the protein the virus presents to the T cell via the class I major histocompatibility complex (MHC). Some of these mutations still allow binding of the viral protein to the MHC molecule but are no longer recognized by the T cell antigen receptor.

Zinkernagel and Klenerman studied the significance of these mutations in LCMV. They report their findings in Nature, July 30, 1998, in a paper titled “Original antigenic sin impairs cytotoxic T lymphocyte responses to viruses bearing variant epitopes.“

Original sin is the theological concept that humankind must atone for the sin committed by Adam and Eve in the Garden of Eden. Forty years ago, scientists studying the antibody response to influenza virus appropriated the term to describe the phenomenon whereby people infected with influenza strain A and later challenged with a mutated version of strain A respond with an increased titre of antibodies to strain A but only a slow, primary response to the mutant strain. This was called “original antigenic sin“ because the body “remembers“ the original antigen.

Until now, there was no evidence to suggest a parallel phenomenon existed with the cellular immune response. However, Klenerman and Zinkernagel reported in Nature it does.

They worked with wild-type virus and with a variant virus, LCMV-8.7. Cells infected with this latter strain cannot be killed by cytotoxic T cells, because the virus has a mutation in the T cell epitope.

Zinkernagel told BioWorld International, “We found that if you take the virus with the original wild-type peptide and you take the virus with the mutated peptide, then the cytotoxic T cell response against the wild-type virus only kills cells infected with the wild-type virus, but cannot kill cells infected with the mutant virus. Whereas if you immunize mice with mutant virus, then you generate cytotoxic T cells that kill cells infected with mutant virus, but also kill cells infected with the wild-type virus. This means that cytotoxic T cells seem to obey similar rules to influenza antibody responses with respect to their specificity and cross-reactivity.“

There is, he added, a cross-reactivity in the evolutionary backwards direction, but no cross-reactivity in the evolutionary forwards direction.

In Nature, the two researchers also showed the host's immune response to the previously seen antigen or virus seems to slow down the efficiency of the response to the mutant virus.

“This gives the virus a slight advantage and could help the mutant to win against the wild-type viruses in the host,“ Zinkernagel said.

Mutating Viruses May Become Less Pathogenic

Commenting on the paper in the same issue of Nature, Andrew McMichael, of the Institute of Molecular Medicine, in Oxford, U.K., wrote, “Original antigenic sin in cytotoxic T lymphocyte responses could be very important - it could explain some of the complexity in cytotoxic T lymphocyte responses to HIV and its variants. If it were a common phenomenon, it would give viruses another means of escape from the immune system. That is, once a high-level cytotoxic T lymphocyte response has become fixed, immunogenic mutants might escape and become dominant in the swarm of viral quasispecies, failing to provoke an effective cytotoxic T lymphocyte response.“

Zinkernagel said it is interesting to speculate that if viruses such as HIV or HBV were to adapt in this way, over many rounds of infection through many individuals, they might end up less immunogenic and thus less pathogenic.

“This situation is the reverse of what commonly happens in viral infection,“ he said. “Usually, if a cytopathic virus escapes immune responses, it becomes more dangerous because it kills more cells. But if a virus is noncytopathic, like LCMV, HBV and, potentially, HIV, then by avoiding the immunopathological consequences of the infection and of the immune response, the virus persists for longer without causing problems.“

Next, Klenerman and Zinkernagel plan to collect viruses from mice naturally and persistently infected with LCMV, and look for attenuation of the virus in vivo. *

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