Recent Advances in Our Understanding of Human Inflammatory Dendritic Cells in Human Immunodeficiency Virus Infection

Abstract

Anogenital inflammation is a critical risk factor for HIV acquisition. The primary preventative HIV intervention, pre-exposure prophylaxis (PrEP), is ineffective in blocking transmission in anogenital inflammation. Pre-existing sexually transmitted diseases (STIs) and anogenital microbiota dysbiosis are the leading causes of inflammation, where inflammation is extensive and often asymptomatic and undiagnosed. Dendritic cells (DCs), as potent antigen-presenting cells, are among the first to capture HIV upon its entry into the mucosa, and they subsequently transport the virus to CD4 T cells, the primary HIV target cells. This increased HIV susceptibility in inflamed tissue likely stems from a disrupted epithelial barrier integrity, phenotypic changes in resident DCs and an influx of inflammatory HIV target cells, including DCs and CD4 T cells. Gaining insight into how HIV interacts with specific inflammatory DC subsets could inform the development of new therapeutic strategies to block HIV transmission. However, little is known about the early stages of HIV capture and transmission in inflammatory environments. Here, we review the currently characterised inflammatory-tissue DCs and their interactions with HIV.

Keywords: Axl+ Siglec-6+ DC (ASDC); DC3; HIV; epidermal CD11c+ dendritic cells; inflammation; monocyte-derived dendritic cells; plasmacytoid DC (pDC).

Figure 1

Inflammatory DC interactions with HIV in anogenital tissue. HIV enters inflamed anogenital tissue through breaches in the epithelium. Upon HIV exposure, plasmacytoid dendritic cells (pDCs) secrete IFN-I to induce an antiviral immune response and chemokines CCL3-5, which recruit CD4 T cells to infection sites and block the binding of HIV to the CCR5 co-receptor. Both Al⁺ siglec-6⁺ dendritic cell (ASDC) subsets are capable of polarising T cells into Th2, Th9, Th17 or Th22. CD11c⁺ ASDCs tended to be more efficient at first-phase transfer via HIV bending to lectin receptors (MR, langerin, DC-SIGN and Siglec-1), whilst CD123⁺ ASDCs tend to be more efficient at second-phase transfer via the entry receptors CD4/CCR5 and productive infection. DC3s can induce Th1 and Th17 polarisation. It has not yet been determined if they are capable of HIV binding and transfer; however, they express the HIV entry receptors CD4/CCR5 and Siglec-1 mRNA. Monocyte-derived dendritic cells (MDDCs) can also induce Th1 and Th17 polarisation. They can mediate first-phase transfer via Siglec-1 and likely another unidentified lectin receptor. MDDCs are also highly efficient at CD4/CCR5-mediated second-phase transfer. Epidermal CD11c⁺ DCs can efficiently bind and transmit HIV through both first- and second-phase transfer.

Figure 2

CD34⁺ hematopoietic stem cells produce granulocyte-monocyte common progenitor (GMDP) and lymphoid progenitors. Based on IRF8 expression, GMDP gives rise to the common DC progenitors (cDP), pre-DC3 and the common monocyte progenitor (cMoP). While cDP generate DCs (pDCs, ASDCs, DC1, DC2), pre-DC3 gives rise to DC3 and cMoP gives rise to monocytes. The developmental pathway of ASDCs from pre-pDCs or directly from pre-DCs remains to be fully characterised. PDCs and ASDCs migrate from blood to inflamed tissues. DC1, DC2 and DC3 are present in healthy and inflamed tissues but become more enriched in inflamed tissues. In inflammation, CD14 monocytes migrate from blood to tissues, and they differentiate into MDM and/or MDDCs.

Figure 3

Human inflammatory and steady-state mononuclear phagocyte phenotypes.