AIDSWEEKLY Plus; Monday, April 6, 1998
Daniel J. DeNoon, Senior Editor

Comparison of the immune responses of various mammals and humans to lentivirus infection reveals that the maturation of antibody responses is a common theme in protection against disease. Immature antibody responses are associated with disease progression.

The findings come with a promise and a warning. The promise is that there may be a way to elicit mature anti-HIV immunity. The warning is that suboptimal HIV vaccines may actually do harm.

"A vaccine may not just fail to protect, but may also make disease worse when a person is infected with HIV," warned Ronald C. Montelaro of the University of Pittsburgh, Pennsylvania.

Montelaro discussed maturation of antibody responses to persistent lentivirus infection in an invited address to the 1998 Palm Springs Symposium on HIV/AIDS, "Towards an HIV Vaccine: Immunopathogenesis of HIV Infection," held March 5-8, 1998, in Palm Springs, California.

Montelaro et al. began by studying antibody responses in monkeys protected against challenge by live, attenuated vaccines. They investigated the conformational dependence of antibodies, antibody avidity (as opposed to affinity), and virus neutralization. These responses had several distinct characteristics:

* Antibody avidity increased slowly over time.

* There was a six- to eight-month period of immature immunity wherein dynamic, complex antibody properties evolved and changed over time.

* Final mature immunity was stable and characterized by increased antibody titer, decreased neutralizing activity against the vaccine strain, increased breadth of neutralization activity, and a decreased conformation ratio.

The study of antibody maturation in successfully immunized monkeys yielded a number of findings with applications for vaccine development:

* Only minimal levels of SIV expression were needed to drive antibody responses.

* Severely attenuated SIV vaccine strains failed to produce mature antibody responses.

* Env sequence variation is not required for maturation of antibody responses.

"The serologic parameters identified in the study are necessary but not sufficient correlates of protection," Montelaro said. "The study raised more questions than it answered."

To answer these questions, Montelaro and colleagues performed a series of serological analyses - "serology ad nauseam," the researcher joked - to explore the development of envelope-specific antibody responses in several lentivirus/host systems.

The researchers examined monkeys infected with pathogenic strains of SIV or chimeric simian/human SHIV, humans infected with HIV, and horses infected with equine infectious anemia virus (EIAV).

These studies provided some answers:

* Is the maturation of antibody responses in vaccinated monkeys applicable to disease progression? Montelaro and colleagues showed that monkeys that do not progress to disease have similar antibody- maturation parameters to vaccine-protected animals.

* Is this maturation process unique to SIV envelope proteins? Monkeys infected with pathogenic SHIV - which bears the HIV envelope - showed the same type of antibody responses as SIV infected animals, except that maturation of antibody avidity took longer to mature in SHIV infection.

* Does antibody maturation occur in people with HIV? Human antibody responses to HIV Env evolved differently than those in the monkeys in terms of conformational requirements, but the avidity data was generally comparable. "This means that these parameters are not necessarily linked to one another," Montelaro said.

* Does antibody maturation occur in other lentivirus hosts? The horse/EIAV model yielded data comparable to that seen in the monkey/SIV model.

"I think this slow maturation of immunity is one more trick of lentiviruses," Montelaro said. "These viruses have evolved to be immune slippery."

He concluded that lentivirus infection is associated with a common maturation of antibody responses, and although there may be some interspecies differences in the nature of this maturation the process takes six to eight months.

"It appears that the development of immune responses to lentivirus infections involve a complex and lengthy maturation of antibody responses to viral antigens," he said. "This initial negotiation between virus and host may be critical for determining viral set points and disease progression."

Protection can only occur after the maturation process is complete. Completion of the process apparently required prolonged presentation of small amounts of antigen.

"The design of attenuated vaccines must minimize safety problems but maximize the ability to elicit mature protective immunity," Montelaro said. "This may not be as hard as many think."

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