AIDSWEEKLY Plus, Monday, 7 July 1997
Daniel J. DeNoon, Senior Editor
A novel approach to intracellular immunization against HIV would give cells three different weapons against the virus.
The experimental treatment, still on the drawing board, calls for hematopoietic stem cells to be provided with three different genetic mechanisms for resisting HIV infection. The cells would then be grown ex vivo and infused into the patient.
"Proposed studies will examine the HIV-1 protective effects of ribozymes targeted to CCR5 in combination with anti-HIV-1 ribozymes and in vitro evolved Rev binding element decoys," suggested John J. Rossi of the Beckman Research Institute of the City of Hope Medical Center, Duarte, California.
Rossi spoke in an address to "New Opportunities for HIV Therapy - From Discovery to Clinical Proof-of-Concept," the 2nd Joint Conference of the National Institute of Allergy and Infectious Diseases (NIAID) Strategic Program for Innovative Research on AIDS Treatment (SPIRAT) and the National Cooperative Drug Discovery Groups for the Treatment of HIV Infection (NCDDG-HIV), held June 22-26, 1997, in Vienna, Virginia.
Ribozymes are specialized RNA molecules with enzymatic activity. These molecules can be specifically targeted to retroviral RNA sequences and can interfere with multiple stages of viral replication.
Rossi noted that people with a homozygous 32-base-pair deletion in the gene for the CCR5 chemokine receptor are resistant to HIV infection but otherwise appear to have normal immune function. He suggested that expressing an anti-CCR5 ribozyme gene in stem cells would provide this same protection to T cells derived from the engineered stem cells.
"Hematopoietic progenitor cells can be targeted with retroviral constructs expressing anti-CCR5 ribozymes for use in autogenic or heterogenic stem-cell therapies," he said.
Rossi said that he and co-workers have developed Moloney murine retrovirus (MMRV) vectors that will permit either the cytoplasmic or nuclear localization of gene constructs.
In addition to the anti-CCR5 ribozyme, Rossi proposed the combinatorial use of additional anti-HIV genes:
* Genes expressing decoy molecules, called aptamers, that would block the binding site for the HIV Rev protein and interrupt reverse transcription. "A number of Rev aptamers have been evolved; all are effective," Rossi said.
* Gene expressing ribozymes targeted to the HIV-1 tat and rev genes.
* Genes expressing a chimeric ribozyme, dubbed tRNA(LYS3), that is co-packaged into HIV virions with viral RNA and destroys it.
"The idea is to incorporate two or more of these strategies into a single vector," Rossi said. "We can block the mRNA for CCR5, prevent Rev binding with aptamers, and include tat and rev ribozymes. And, if all else fails, LYS3 gets incorporated into new virions and destroys the viral RNA."
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