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University of Pittsburgh Schools of the Health Sciences

​Boosting Immune Response against Hiv-1 Key to Controlling Infection, Say University of Pittsburgh Researchers

PITTSBURGH, June 29, 1998 — Researchers have focused extensively on suppressing viral levels in AIDS patients. But to effectively control HIV, scientists from the University of Pittsburgh Graduate School of Public Health are emphasizing the need to also boost the virus-killing capability of a small but potent group of immune cells referred to as killer T cells to establish long-term immunity against HIV-1.

Findings presented by Charles Rinaldo, Ph.D., on June 29, at the 12th World AIDS Conference in Geneva, Switzerland, are the first to demonstrate even small numbers of killer T cells present in late-stage AIDS patients after triple therapy can be activated against HIV-1 when treated in laboratory dishes with dendritic cells primed to recognize HIV-1 proteins along with interleukin-12 (IL-12), a substance known to stimulate immune cells to multiply and attack foreign substances.

"This indicates that we may be able to enhance the body’s response to the virus, which is very exciting because it suggests that with some prodding and priming, we may be able to train the immune system to ward off further attacks by HIV," remarked Dr. Rinaldo.

Previous studies have shown that combining protease inhibitors with two reverse transcriptase inhibitors does not completely eliminate HIV from the body, nor does triple therapy offer patients full protection from the virus if they discontinue taking the drugs or expose themselves to repeated infections of HIV.

"If we can boost a patient’s immunity to HIV, we could eventually discontinue the complex regimen of drugs which can involve up to 18 pills a day as well as meticulous monitoring of which drug is taken when and under what conditions," added Dr. Rinaldo. "But, it’s important to note that triple therapy is absolutely necessary to drive down the level of virus, which then allows CD4 T cells to regain a foothold."

A triple therapy regimen of a protease inhibitor (indinavir) with two nucleoside reverse transcriptase inhibitors (zidovudine and lamivudine) also allowed a group of killer T cells, sometimes called memory CD8 T cells, to increase dramatically after two to three months of initiating treatment in five study participants and to maintain these high levels for about a year. The Pitt study is the first to report this initial surge in killer T cells and also the first to show a drastic drop in the numbers after a year. Despite the small amount of killer T cells, levels of virus in these patients remained so low they weren’t detected with a commonly used test known as viral load.

"We’re not quite sure why we see the rise and then fall of memory CD8 cells," commented Dr. Rinaldo, who described a possible inhibitory effect on the killer T cells imposed by high viral activity. "When the virus is suppressed, these immune cells are able to grow freely, without any inhibition. This may help to explain the immediate rise in the number of memory CD8 cells."

Researchers aren’t certain what causes the late drop in numbers of memory killer T cells after triple therapy. "It makes sense that the memory CD8 T cells decline in numbers -- when viral levels are low, there’s no need for these cells to remain in large numbers. In fact, it’s wasteful for the body to maintain such a high number of these cells and the drop in the numbers may be a result of a natural homeostatic mechanism," he added.

"When viral load levels are low, we tend to see a correspondingly low level of these killer T cells. Other researchers have seen this in long-term non progressors, HIV-infected individuals who have maintained unusually low levels of the virus for a very long time, which indicates the body is adjusting to some sort of normal state," commented Dr. Rinaldo.

The crucial question for the researchers was whether the small numbers of memory killer T cells and their precursors, naive CD8 T cells, were capable of mounting a strong response against HIV-1. To answer this, the Pitt researchers used dendritic cells (DC’s), immune cells that can train killer T cells and other cells to destroy foreign substances and also motivate them to attack. DC’s were taken from three HIV-infected study participants, stimulated with IL-12 and exposed to HIV-1 proteins packaged in a liposome, a lipid structure that is often used to deliver genes and other materials safely to a cell’s cytoplasm. By "pulsing" the DC’s two to four times with the HIV-1 proteins and IL-12, they were able to teach the killer T cells in laboratory dishes to recognize the three important viral markers in HIV-infected cells.

"Despite the decline in T cell immunity late after drug treatment in these patients, we were encouraged to see that the killer T cells were ready, alert and attacked when the dendritic cells gave them the signal. By further stimulating naive T cells or boosting residual memory T cells with therapeutic vaccines similar to the one we used in this study, it may be possible to achieve complete immunity in patients which would then allow their immune systems to exert a much stronger control over the HIV-1 infection," said Dr. Rinaldo.

Although this study yielded important insights into how the immune system responds to HIV-1, further studies are needed to determine which specific functions in these key immune cells are destroyed and how much of this functioning can be repaired using strategies to boost the immune system. Also, knowing how immune cells respond to HIV-1 will help other researchers develop vaccines to give to individuals not exposed to HIV-1.

To answer some of these questions, the Pitt research team, led by Dr. Rinaldo, will begin several new studies using primed DC’s to boost immunity, one in humans and the other in rhesus monkeys. The animal trials will begin later this year, leading to human trials which should start in the next two to three years.

 

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