IL-21 Therapy Controls Immune Activation and Maintains Antiviral CD8⁺ T Cell Responses in Acute Simian Immunodeficiency Virus Infection

Abstract

Human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) replicate during acute infection in lymphocytes of the gastrointestinal tract, before disseminating systemically. Localized replication and associated loss of gut-resident CD4 T cells occur regardless of the portal of entry of the virus (e.g., intravenous vs. rectal). Thus, HIV and SIV are tropic for gut tissue, and their pathogenesis requires the special environment of the intestine. T helper 17 (Th17) cells are important contributors to microbial defense in the gut that are vulnerable to HIV infection and whose loss is associated with translocation of microbial products to the systemic circulation, leading to chronic immune activation and disease progression. Interleukin (IL)-21 promotes differentiation and survival of Th17 cells and stimulates CD8 T cell function. By promoting Th17 cell survival, IL-21 could limit bacterial translocation and immune activation in the setting of acute or rebounding HIV/SIV disease. In this study, we tested the effect of recombinant IL-21-IgFc treatment, given at the time of infection, on SIV infection. We found that rIL-21-IgFc decreases immune activation and maintains effective antiviral responses by CD8 T cells in blood, but this maintenance is not associated with lower viral loads. rIL-21-IgFc treatment also did not generally support Th17 cell populations, but Th17 cells remained strongly and independently associated with control of plasma viremia. For example, the single animal exhibiting greatest control over viremia in our study also manifested the highest levels of IL-21 in plasma, Th17 cell maintenance in blood, and Th17 cells in intestinal tissue. These findings provide rationale for further exploration of IL-21 treatment as a support for host CD8 T cell responses in HIV cure strategies.

Increased Expression of sST2 in Early HIV Infected Patients Attenuated the IL-33 Induced T Cell Responses

“…Previous studies have revealed the role of the cytokine cascade in acute HIV infection and disease progression (4, 5). But the role of some cytokines, which are considered crucial immune modulators with pleiotropic activities, has not been clearly elucidated in early HIV infection (6, 7). IL-33, a recently discovered member of IL-1 family, exercising its role as an alarm signal (alarmin) in response to cellular damage induced by infection or injury to alert immune cells expressing the ST2 receptor (IL-1RL1) (8).…”

The protective and pathogenic roles of IL-17 in viral infections: friend or foe?

“…Learning to beneficially control the regulation of viral-specific CD8 + T-cell activation to promote viral clearance is vital information. It has been observed that a higher Th17 percentage is associated with increased T-cell proliferation and more potent simian immunodeficiency virus (SIV)-specific CTL responses in SIV-infected rhesus macaques [38,39]. In this model, prior transfer of Th17 cells was shown to enhance the induction of antigen-specific CTLs following vaccination with an adenovirus vector [40].…”

A Stable Nano-Vaccine for the Targeted Delivery of Tumor-Associated Glycopeptide Antigens

“…The expression levels of IL-21 are important because it is known to stimulate levels of NK/NKT and CD8 + cells that have proved essential in killing of certain tumors 89–91 as well as viral-infected cells. 92–94 The profiles were similar for both the peptide and glycopeptide vaccinations, and the antibody responses were highly specific for our MUC4 constructs, much as the mAb produced by standard KLH-conjugate in a prelude to the present study. 70…”