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San Francisco investigators have been studying interleukin-7 (IL-7) and its role in HIV disease progression in hopes of better understanding how T-cell production is regulated and how this knowledge might be applied to therapeutic intervention and immunosuppression in either AIDS patients or bone marrow transplant patients. This interest has led to the discovery that IL-7 is produced in response to T-cell depletion, thus facilitating T-cell production — but at the same time fostering HIV-1 disease progression.
"The regulation of T-cell production is not well-understood," says Laura Napolitano, MD, staff scientist with Gladstone Institute of Virology and Immunology in San Francisco. "We really don’t understand how T-cell production might be regulated, and this is of increasing interest as we have more and more patients with immunodeficiency," Napolitano says.
Several years ago, researchers involved in this project studied HIV patients’ thymuses to determine whether they could be made functional in adults, Napolitano says. They found that the thymus was larger in HIV patients than in non-HIV infected people of the same age. "That raised the premise in our mind that perhaps the thymus is getting larger because it’s trying to make new T-cells," Napolitano says.
In the most recent study, researchers asked the question: "As T-cells fall in HIV disease or other conditions, does the body at some point sense that and send a signal that says it needs more T-cells that could result in increased production and expansion of T-cells?" Napolitano relates. Previous research has shown that IL-7 is crucial for the production of T-cells. IL-7 is produced in the thymus, bone marrow, and lymph nodes. There are also low but detectable levels of IL-7 circulating in the blood.
Investigators analyzed the blood of 158 HIV patients to determine whether a rise in IL-7 would follow a decline in CD4 cell counts. "We found that there was a strong correlation so that if the CD4 cell count fell, the other would rise," Napolitano says, adding that this result should be assessed cautiously. "There are other possible interpretations as well," she notes.
The researchers eventually concluded that it was logical to assume that IL-7 was made in the lymph nodes, so they did a marker test, taking microscopic sections and looking for cells producing IL-7. "We found that there was a lot more IL-7 in those samples that didn’t have T-cells," Napolitano says. Further results suggested that as the T-cells become depleted from the lymph nodes, these cells respond by producing IL-7, resulting in T-cell production and expansion, she adds.
While this would appear to be a potential area of clinical application, the findings weren’t that simple. "We looked at 168 patients, who were all adults with HIV infection, we found that those with higher IL-7 levels tended to have higher viral loads, which suggests that something is going on there and needs to be better investigated," Napolitano says.
Possible reasons for this problem could be that IL-7 acts to accelerate HIV infection by stimulating the proliferation of T-cells and making them more susceptible to HIV infection. Alternatively, IL-7 might somehow interact more directly with the virus to enhance its replication, Napolitano speculates. "It’s a theoretical concern, and we need to learn more about what that interaction is and how it occurs, then take into consideration whether this is something that would be a concern if IL-7 were to be given to individuals with HIV infection," Napolitano explains.
"The bottom line for clinicians is there is definitely progress being made in our understanding of how the production of T-cells is regulated," Napolitano says. "And hopefully over the next decade this will lead to trials where therapeutic interventions are developed with factors that might be interleukin-7 or other factors considered more suitable to stimulate T-cell expansion."