AIDSWEEKLY Plus, Monday, 28 April 1997
Daniel J. DeNoon, Senior Editor
It works, but until now no one knew why.
Researchers at the Naval Medical Research Institute, Bethesda, Maryland, announced at the 1996 International Conference on AIDS that without drugs they could make cultures of CD4(+) T cells from people with HIV infection grow to huge numbers (see AIDS Weekly Plus, August 26/September 2, 1996). In an ongoing clinical trial, these expanded cell populations are being used to reconstitute patients' depleted T cells.
Normally, T cells cultured from people with HIV infection succumb to the deadly effects of the virus. But by co- stimulating the cells with immobilized antibodies to the CD28 and CD3 cell-surface molecules, researchers Carl H. June and colleagues found that they could induce HIV resistance in the cells.
At the time, they didn't know why it worked. But now the answer appears clear: CD3/CD28 co-stimulation down-regulates the expression of the CCR5 coreceptor needed for cell entry by macrophage-tropic (M-tropic) HIV-1 strains, preventing T- cells, the primary HIV target, from making the surface protein CCR5.
People with defective CCR5 receptors resist infection with M-tropic strains of the virus, which are responsible for 90 percent of sexual transmission of the virus.
"CD3/CD28 costimulation induces an HIV-1 resistant phenotype [in patients' CD4(+) T cells] similar to that seen in some highly exposed and HIV uninfected individuals," wrote Richard G. Carroll, June, and colleagues.
They reported studies demonstrating that this effect is due to CCR5 down-regulation in the journal Science ("Differential Regulation of HIV-1 Fusion Cofactor Expression by CD28 Costimulation of T Cells," Science, 1997;276:273-5).
"Stimulation of cells with immobilized antibodies to CD3 and CD28 permits the large-scale ex vivo expansion of primary CD4(+) cells, thus removing one of the largest obstacles to gene therapy or immune replacement therapy for HIV-1 infected individuals," Carroll et al. wrote. "Indeed, persistent increased CD4 counts and a lack of spikes in viral load have been noted in a clinical trial that is currently in progress to test the CD28 antiviral effect in patients with intermediate-stage HIV infection."
At the 1996 AIDS conference, June said that his team's findings suggested several approaches to the treatment of HIV disease:
* Vaccines could induce the antibodies that mediate the anti- HIV and proliferative effects, thereby reversing the loss of CD4(+) T cells and inhibiting the spread of the virus.
* Ex vivo proliferation of HIV resistant CD4(+) T cells could permit autologous replacement of cells killed by HIV.
* The new cells expanded ex vivo could, prior to transfusion, be sensitized to mediate immune responses against HIV or opportunistic pathogens.
* The newly expanded cells could provide immunologic help to CD8(+) T cells.
* CD4(+) lymphocytes altered by gene therapies could be expanded using the new technique.
This study was supported by ARMY DAMD17-93-V-3004 and by the Navy Medical Research and Development Command.
The corresponding author for this study is Carl H. June, Henry M. Jackson Foundation for the Advancement of Military Medicine, Rockville, Maryland 20850. Email: rin0cxj@bumed30.med.navy.mil.
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