Heterodimeric interleukin-15 (hetIL-15) is a native stable form of the cytokine that activates and expands cytotoxic T and NK cells. Based on its properties and extensive preclinical data, hetIL-15 is currently evaluated in humans for the treatment of cancer. We study the effects of hetIL-15 in infected macaques to evaluate its use in HIV infection and especially in the reduction of SIV/SHIV reservoir towards a functional cure.
Rhesus macaques, either chronically infected by SHIV or uninfected received injections of hetIL-15 over 2 weeks using increasing doses of cytokine (step-dosing). At the end of the treatment, the animals were sacrificed and the hetIL-15 effects on different lymphocyte populations isolated from tissues collected at necropsy were monitored by multi-parametric flow cytometry and quantitative multiplexed confocal microscopy (histo-cytometry). Cell-associated viral RNA and plasma viral load was measured by quantitative PCR.
This protocol was safe in rhesus macaques and resulted in systemic expansion of CD8+ T lymphocytes and NK cells with higher granzyme B content. These expanded cell populations were found in both effector sites, such as liver, vagina and rectum, and secondary lymphoid tissues. Importantly, a significant increase in cytotoxic effector memory CD8+ T cells was found in lymph nodes (LN) from all hetIL-15-treated macaques. CM9 tetramer staining demonstrated that the increase of CD8+ effector T cells in lymphoid organs included actively proliferating SIV-specific T cells with higher granzyme content. Imaging analysis by histo-cytometry revealed that these effector CD8+ T cells infiltrated the B cell follicles where chronically infected follicular helper CD4+ T cells are located. Following hetIL-15 treatment, cell-associated RNA was decreased in LN and plasma viral load was also decreased. Treatment of macaques under Antiretroviral Therapy (ART) with this regimen was also safe and induced cytotoxic CD8+ accumulation in LN follicles.
Step-dose administration of hetIL-15 is a well-tolerated regimen that results in systemic activation and expansion of cytotoxic leukocytes that infiltrate areas where chronic HIV-infected cells reside. These results suggest that hetIL-15 could be useful in disrupting sanctuary sites within the B cell follicles and reducing long-term viral reservoirs in HIV-1 infected individuals, thus contributing to a functional cure of the infection.