Abstract
Chronic, low-grade, systemic, and mucosal inflammation correlates with increased morbidity and poor clinical outcomes among patients living with human immunodeficiency virus (HIV). These long-term complications are linked to the disruption of gastrointestinal (GI) tract epithelial barrier integrity and subsequent microbial translocation. However, the mechanisms responsible for these downstream effects of infection are unknown. Here, we demonstrate that during the disruption of the GI tract and increased microbial translocation, we find inflammatory cytokines (e.g., interferon gamma [IFN-γ] and tumor necrosis factor alpha [TNF-α]) produced by innate lymphoid cells (ILCs) located in the colon secondary to simian immunodeficiency virus (SIV) infection. To do this, we used viably cryopreserved colon cells from SIV-infected and uninfected rhesus macaque monkeys and determined the make-up of the ILC subpopulations and the cytokines they expressed constitutively. Our studies revealed that the interleukin-22 (IL-22)/IL-17-producing ILCS was not altered during SIV infection. However, the percentage of IFN-γ+ ILCs in infected colons was 5- to 10-fold higher than that in uninfected colons. ILCs from infected tissue that produced IFN-γ also expressed TNF-α and IL-22. The coexpression of inflammatory cytokines with IL-22 is linked to the ability of ILCs to coexpress T-bet and RORγT/Ahr. The expression of IFN-γ/TNF-α by ILCs and NK cells combined likely triggers a pathway that contributes to chronic mucosal inflammation, GI barrier breakdown, and microbial translocation within the context of SIV/HIV infection.IMPORTANCE There is a slow yet significant uptick in systemic inflammation secondary to HIV infection that has long-term consequences for the infected host. The systemic inflammation most likely occurs as a consequence of the disruption of the gut epithelial barrier, leading to the translocation of gut microbial products. This disruption may result from mucosal inflammation. Here, we show in an animal model of HIV that chronic SIV-infected gut contains innate lymphoid cells producing inflammatory cytokines.
Highlights
IMPORTANCE There is a slow yet significant uptick in systemic inflammation secondary to human immunodeficiency virus (HIV) infection that has long-term consequences for the infected host
These findings indicate that IL-22 is not the only cytokine expressed by NKp44-expressing innate lymphoid cells (ILCs) and that NKp44ϩ ILC1s from infected colons are capable of producing IFN-␥
We found that the number of ILC3s, ILC1s, and natural killer cells (NKs) within the colon tissue was not changed as a result of infection (Fig. 3)
Summary
IMPORTANCE There is a slow yet significant uptick in systemic inflammation secondary to HIV infection that has long-term consequences for the infected host. We previously reported that innate lymphoid cells (ILCs) are a source of IFN-␥ in the colons of individuals with chronic untreated HIV-1 infection and were associated with gut dysbiosis and mucosal immune activation [14]. These findings suggest a link between inflammatory ILCs and HIV mucosal pathogenesis. A more recent study that utilized a more extensive panel of markers to identify ILC3s found significantly higher frequencies of ILC3s with the potential to express IL-22, despite an overall reduction in cell numbers in the colon of HIV-infected patients undergoing cART compared to that of healthy controls [31]. Another study indicates that the frequency of ILC3s was lower in the jejunum but not in the colon of chronic SIV-infected animals [36]
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