July 3, 1998 PITTSBURGH, Penn., June 24--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 (GSPH) are emphasizing the need to also boost the virus-killing capability of a small but potent group of immune cells, CD8 T cells, also 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. To achieve this anti-HIV-1 effect, researchers treated another group of immune cells called dendritic cells (DCs) with HIV-1 proteins and interleukin-12 (IL-12).
Exposing DCs to viral proteins enables them to study the structure and then teach other immune cells to identify any cell infected with these HIV-1 proteins. While the DCs are inspecting the proteins they release substances like IL-12, which 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, who is the chairman of the department of infectious diseases and microbiology at Pitt's GSPH.
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 the drugs or expose themselves to repeated infections of HIV.
"If we can permanently 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. "Nonetheless, 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."
CD4 T cells have been called the "general" in the immune cell army because they direct other immune cells, like killer T cells, to attack HIV-1 and other foreign substances. These important immune cells are targeted and infected by HIV-1 and can drop to dangerously low levels in AIDS patients when the virus continues to replicate, unchecked.
Dr. Rinaldo's research team was the first to find that triple therapy regimen of a protease inhibitor (indinavir) with two nucleoside reverse transcriptase inhibitors (zidovudine and lamivudine) allowed a group of killer T cells, sometimes called memory CD8 T cells, to increase dramatically two to three months after initiating treatment in five study participants. These CD8 T cell levels remained high for about a year. The Pitt study also was the first to show a drastic drop in the numbers after a year. Despite the small amount of killer T cells, levels of freely circulating 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 in memory CD8 T cells," commented Dr. Rinaldo, who described a possible inhibitory effect on the killer T cells imposed by high viral activity. "But, we think that 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 T cells.
"Also, we aren't certain what causes the late drop in numbers of memory killer T cells after one year of triple therapy, but it makes sense that these cells decline in numbers. When viral levels are low, there's no need for killer T 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 their numbers may result from a natural homeostatic mechanism," he added.
"Other researchers have seen low levels of killer T cells in so-called 'long-term non progressors,' HIV-infected individuals who have maintained unusually low levels of the virus for a very long time, which indicates to us that the body is adjusting to some sort of normal state," commented Dr. Rinaldo.
These findings raised the crucial question of 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 DCs, immune cells that can train killer T cells and other cells to destroy foreign substances while at the same time signaling them to attack.
DCs were taken from three HIV-infected study participants, stimulated with IL-12 and exposed to HIV-1 proteins encapsulated in a liposome, a tiny, fatty structure often used to deliver genes and other materials safely to the inside of a cell. The researchers found that DCs "pulsed" two to four times in laboratory dishes with the HIV-1 proteins and IL-12 were able to teach the killer T cells to recognize three important viral markers in HIV-infected cells. Recognizing these viral markers enables killer T cells to identify, attack and kill cells infected with HIV-1.
"We were encouraged to see that the killer T cells were ready, alert and could attack HIV-infected cells after 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. This would then allow a patient's immune system to exert a much stronger control over HIV-1 infection," said Dr. Rinaldo.
Although our study yielded important insights into how the immune system responds to HIV-1, Dr. Rinaldo notes that further research studies are needed to determine which specific functions in these key immune cells are destroyed and how much of their 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, he added.
To answer some of these questions, the Pitt research team, led by Dr. Rinaldo, will begin several new studies using primed DCs to boost immunity, one in HIV-infected humans and the other in rhesus monkeys infected with a virus similar to HIV-1. 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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