Th17 CD4+ T-Cell as a Preferential Target for HIV Reservoirs

Abstract

Among CD4+ T-cells, T helper 17 (Th17) cells play a sentinel role in the defense against bacterial/fungal pathogens at mucosal barriers. However, Th17 cells are also highly susceptible to HIV-1 infection and are rapidly depleted from gut mucosal sites, causing an imbalance of the Th17/Treg ratio and impairing cytokines production. Consequently, damage to the gut mucosal barrier leads to an enhanced microbial translocation and systemic inflammation, a hallmark of HIV-1 disease progression. Th17 cells' expression of mucosal homing receptors (CCR6 and α4β7), as well as HIV receptors and co-receptors (CD4, α4β7, CCR5, and CXCR4), contributes to susceptibility to HIV infection. The up-regulation of numerous intracellular factors facilitating HIV production, alongside the downregulation of factors inhibiting HIV, helps to explain the frequency of HIV DNA within Th17 cells. Th17 cells harbor long-lived viral reservoirs in people living with HIV (PLWH) receiving antiretroviral therapy (ART). Moreover, cell longevity and the proliferation of a fraction of Th17 CD4 T cells allow HIV reservoirs to be maintained in ART patients.

Keywords: CD4-positive T cells; HIV infections; HIV reservoir; T-helper 17 cells; lymphocytes; mucosal immunology.

Figure 1

Th17 differentiation process. A description of the Th17 orientation process through different activation factors (black arrows): cytokines environment, induction by STAT3 and activation by a transcription factor RORC and the inhibition of the Th17 orientation process by the Th1 and Th2 cells (red arrows). IL-23 stabilizes the Th17 orientation.

Figure 2

Interactions and functions of Th17 cells. A representation of the interactions of Th17 cells with other cell types: Through their production ligands for receptors on the surface of Th17 cells (IL-23R, CD161, CCR4 and CCR6), macrophages, monocytes and dendritic cells (CCL17, CCL22 and IL-23 production), T cells (LLT1, CLEC2D and PILAR) and epithelial cells (CCL20) participate in the activation of Th17 cells and their production of IL-17 cytokines. The IL-17 cytokines produced by Th17 cells activate epithelial cells, fibroblasts, and keratinocytes via their IL-17R surface receptor. Following this activation, these cells produce chemotactic factors (IL-6, CXCL2 and CXCL8) which participate in the recruitment of neutrophils. These cells also produce G-CSF and GM-CSF, which are involved in the differentiation of resident monocytes into resident macrophages and the increased production of macrophages and neutrophils in the bone marrow.

Figure 3

HIV entry process in Th17 cells. Activating (black arrows) or inhibiting (red arrows) factors are involved in HIV entry into Th17 cells. Mucosal migration receptors (α4β7 and CCR6) and HIV gp120 binding to co-receptors (CD4, CCR5, CXCR4 and α4β7) increase HIV permissiveness in these Th17 cells where these receptors are preferentially expressed. ATRA inhibits the production of classical ligands of the CCR5 receptor (CCL3, CCL3L1) thereby promoting the interaction of CCR5 with gp120. ATRA also increases the expression of KLF2 in Th17 cells, a positive regulator of CCR5 transcription.

Figure 4

HIV post-entry process and replication in Th17 cells. Th17 cells and HIV have different interactions (activating in black arrows and inhibiting in red arrows) to promote HIV replication in these cells. (A) In the mTOR pathway: at an early stage of the infection, HIV stops the autophagy mechanism directed by mTORc1 to block the elimination of invading viruses. At a later stage, HIV interacts with mTORc1 to hijack the autophagy mechanism to help form new viruses. By interacting with HIV or its proteins (Env, Tat, or Nef), mTORc1 also increases Th17 proliferation, HIV protein production, HIV replication, and latency. (B) by interaction with NF-κB: increased production of TNFα and TLR2 ligation increase in Th17 cells NF-κB translocation and activity, leading to increased HIV replication. Increased NF-κB activity also increases the activity of the mTORc1 pathway and the activation and survival of T cells. (C) Th17 cells exhibit Vif-mediated degradation of the HIV restriction factor, APOBEC3G. (D) SAMHD1 and Grb2 are downregulated in Th17 cells, allowing increased HIV transactivation and replication. (E) RNase2, RNAse3, and RNAse6 genes known to inhibit viral replication are downregulated in Th17 cells.