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 15, 1999
Daniel J. DeNoon, Senior Editor
The idea seems simple: since HIV specific cytotoxic lymphocytes (CTLs) appear to be important in fighting the virus, why not expand a patient's CTL ex vivo and return them to the scene of the crime?
What actually happens is unexpectedly complex. But new data from human trials suggest that a useful application may at last be just around the corner.
"We know these cells made it to the lymph node. We know they aggregated there," said University of Washington researcher Scott J. Brodie in a presentation to the 6th Conference on Retroviruses and Opportunistic Infections, held January 31-February 4, 1999, in Chicago, Illinois
This finding is important because the lymph node may be precisely where HIV infected cells gather and do the most damage.
Brodie, Philip D. Greenberg, Stanley R. Riddell, and colleagues have for years been working to find a way to enhance CD8(+) CTL responses in patients with HIV infection. In their most recent study, they isolated HIV Gag-specific CD8(+) CTL from three HIV infected subjects, expanded the cloned cells ex vivo, and reinfused the patients with three infusions (3.3x10(9) cells/m(2)) of the unmodified CTL clones at two week intervals. A week later the subjects received two weekly infusions of CTLs modified to express the neomycin marker.
Titers of the infused cells peaked within 24 hours. They were very short lived in the peripheral blood: nearly all were gone in a few days, although a few could be detected for as long as three weeks.
But lymph-node biopsies performed four days after the final infusion showed a 2 to 3 log[10] increase in the lymph node compared to the peripheral blood. And best of all, the cells were seen in close proximity to cells infected with HIV.
No effect was seen at any time point on CD4 cell counts or viral load. But when the researchers looked at the intracellular viral burden, they found a different story.
"When we put these cells in, the intracellular viral load dropped rapidly," Brodie said. "The effect was significant, but transient."
The problem appears to be that CTL function poorly - and soon are eliminated - without help from functioning CD4 cells, which are functionally defective in the context of HIV infection.
Thus the researchers now are working to provide CD4 T-cell help for the infused cells by stimulating them with interleukin 2 in patients responding to ongoing highly active antiretroviral therapy (HAART).
"The effect of this therapy on that kind of patient will be very interesting," Brodie said.
The researchers recently reported on their work in the journal Nature Medicine ("In Vivo Migration and Function of Transferred HIV-1 Specific Cytotoxic T Cells," Nat Med 1999 Jan;5(1):34-41.
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