Important note: Information in this article was accurate in March 1999. The state of the art may have changed since the publication date.AIDSWEEKLY Plus; Monday, March 1, 1999
Daniel J. DeNoon, Senior Editor
Yes, according to monkey studies conducted at the U.S. National Cancer Institute (NCI).
Three of four animals that received the prototype vaccine remain AIDS free four to five years after challenge with pathogenic simian immunodeficiency virus (SIV).
"We created a particle that can't package its RNA," said Larry O. Arthur, director of the AIDS Vaccine Program at the NCI-Frederick Cancer Research and Development Center (NCI-FCRDC), Frederick, Maryland.
Arthur spoke in a poster discussion session at the 6th Conference on Retroviruses and Opportunistic Infections, held January 31-February 4, 1999, in Chicago, Illinois.
The vaccine concept follows in the footsteps of NCI-FCRDC researchers who are developing new drugs that target the HIV nucleocapsid (NC) protein. The tiny protein not only is needed for encapsidation of the viral genome, but also plays critical roles in virus maturation and in the earliest stages of host-cell infection.
NC function depends upon a domain called a zinc finger (or sometimes, because it is rather stubby, a zinc knuckle), with a CCHC peptide motif. This motif is so basic to retroviral function that all retroviruses have at least one; HIV has two. The CCHC motif tightly binds zinc; when it is forced to release its grip it no longer works.
Arthur and colleagues have constructed a DNA plasmid that encodes SIV with a mutant zinc-finger domain.
"With the advent of techniques that allow in vivo expression of a DNA construct, it is theoretically possible to duplicate the steps of viral replication, in effect imitating an attenuated virus vaccine, without a replicating agent," he explained.
When transfected into cells, the DNA is expressed as a viral particle carrying all viral proteins but no genomic RNA. It is able to bind and fuse to susceptible cells but, as intended, is totally unable to replicate.
All this is very well to describe in laboratory cultures, but can it work in real life?
To find out, Arthur and colleagues immunized four macaque monkeys with DNA encoding zinc-finger-mutant SIV. Only two of the animals developed detectable anti-SIV antibodies at very low levels.
The researchers then challenged the animals (and a control animal) with pathogenic SIV. The control monkey soon had a high viral load.
The vaccinated animals all had low or undetectable viral load after challenge," Arthur said. "One got AIDS, the others are okay four to five years post-challenge with good CD4 counts."
Because the DNA particles were expressed only at low levels, Arthur and colleagues hope to improve expression with a new version of the plasmid that replaces the SIV LTR promoter sequence with the more powerful cytomegalovirus (CMV) promoter sequence.
Monkeys already have been immunized with this vaccine. Arthur said that in March 1999 they are scheduled to be intravenously or mucosally challenged with pathogenic SIV. This larger study will also examine the animals' intracellular-cytokine and cytotoxic-lymphocyte (CTL) responses to the vaccine.
Another NCI research team is exploring a different approach to creating a NC-disabled AIDS vaccine, please see the accompanying story.
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