Upjohn Co. said Tuesday in Amsterdam that its new AIDS drug,BHAP-E, to block growth of the HIV virus is scheduled to enterPhase I clinical safety trials in September. The company claimsthat BHAP-E is the most potent RT inhibitor reported to date,including other compounds such as AZT and ddI.
Also at the Eighth International Conference on AIDS, Jay Levyof the University of California, San Francisco (UCSF), describedthe importance of CD8-Plus cell activity in blocking the AIDSvirus. Levy's team found that CD8-Plus cells make a previouslyundiscovered cytokine -- a type of protein secreted by T cells -- that stops HIV from replicating in CD4-Plus cells in culture.
Upjohn collaborated with medical schools at UCLA and theUniversity of Nebraska on the BHAP-E study. BHAP-E blocksthe activity of an essential viral enzyme known as reversetranscriptase (RT) needed for replication of HIV virus.
"What we've seen in animal test tissue so far shows that alower dose of BHAP-E may have the same effect as a typicaldose of one of the other RT-inhibiting drugs on the market,"said company spokeswoman Nancy Lassen. She added that thegreater potency of BHAP-E does not necessarily mean increasedside-effects usually associated with higher doses of RTinhibitors.
A major problem associated with the non-nucleoside RTinhibitors is that the HIV virus can mutate and acquireresistance to the compounds. "We are seeing mutations of thevirus with other compounds," said Lassen, "but BHAP isoverriding the virus so that it remains susceptible to the RTenzyme."
"These laboratory studies on BHAP-E are important in that theyshow a potential use against drug-resistant strains of HIV," saidUpjohn's President Jerry Mitchell. "Drug resistance has been amajor problem with the RT inhibitors that are currentlyavailable."
Upjohn's first BHAP compound, U-87,201E, an RT inhibitor usedto fight HIV, is currently in Phase II clinical trials.
Levy's team at UCSF is also giving priority to studies involvingthe rapid replication of HIV and the resultant multiple genericvariants that emerge. These resistant strains overcome theimmune system because they can't be neutralized byantibodies.
According to Levy, activated CD8-Plus cells prevent the virusfrom replicating, and if the virus cannot replicate, resistantmutants cannot evolve to cause disease. "Emphasis must begiven to enhancing this cellular immune response," Levy toldthe conference. "It potentially can permit the long-termsurvival of infected individuals."
CD8-Plus cells and CD4-Plus cells are both immune system Tcells, programmed in the thymus and named for telltalemarkers on their surfaces. HIV infects and then destroys CD4-Plus cells, which are important in regulating the immuneresponse. CD8-Plus cells are capable of attacking infected cells,either killing them or suppressing the viruses within them.
Levy's team has also found a subset of HIV replication-preventing CD8-Plus cells that possess cell-surface markerscharacteristic of activated CD8-Plus cells. By tagging thesemarkers with fluorescent labels, an automated cell sorter couldbe used to count activated CD8-Plus cells and serve as aprognostic indicator of AIDS.
The level of CD8-Plus cell activity appears to be the immunesystem variable most closely associated with health status inHIV-infected individuals. "A loss in activity of CD8-Plus cellsprecedes the loss of CD4-Plus cells now used to define thedisease," said Levy. "In long-term survivors, CD8-Plus cellactivity remains strong."
-- Michelle Slade Associate Editor
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