DCs and NK cells: critical effectors in the immune response to HIV-1

Abstract

Dendritic cells (DCs) and natural killer (NK) cells have central roles in antiviral immunity by shaping the quality of the adaptive immune response to viruses and by mediating direct antiviral activity. HIV-1 infection is characterized by a severe dysregulation of the antiviral immune response that starts during early infection. This Review describes recent insights into how HIV-1 infection affects DC and NK cell function, and the roles of these innate immune cells in HIV-1 pathogenesis. The importance of understanding DC and NK cell crosstalk during HIV infection for the development of effective antiviral strategies is also discussed.

Figure 1. cDCs and pDCs during HIV infection

Conventional dendritic cells (cDCs) are responsible for initiating antiviral adaptive immunity. Evidence indicates that cDC function is impaired during HIV-1 infection either through direct viral interaction (DC-SIGN interaction, autophagy blockade) or through indirect mechanisms, such as interleukin-10 (IL-10) produced during infection. This cDC impairment could contribute to a lack of effective antiviral adaptive immunity. In contrast, plasmacytoid (pDCs) are mediators of innate immunity. pDCs activated by HIV-1 produce type I interferon (IFN), which in addition to inhibiting viral replication, may also contribute to bystander CD4⁺ T cell death. Furthermore, evidence shows that pDCs produce T cell-attracting chemokines, which may facilitate viral spread by providing a source of new T cells for HIV to infect. Finally, HIV-exposed pDCs prime Tregs which could impair cDC function and block effector T cell activity, further blunting adaptive immunity. Thus, pDCs can promote deleterious immunopathology during HIV-1 infection.

Figure 2. NK cell-mediated recognition of HIV-1-infected cells

To date, it is not fully understood how natural killer (NK) cells recognize HIV-1-infected cells, and different mechanisms have been proposed. The expression of ligands for activating NK cells receptors on infected cells, such as NKG2D-ligands, results in the direct activation of NKG2D⁺ NK cells and target cell lysis (a). Changes in the epitopes presented by HLA class I molecules might allow for the engagement of activating killer inhibitory receptors (KIR) receptors, and resulting NK cell activation (b). Similarly, changes in HLA class I presented epitopes on HIV-1-infected cells can result in the disruption of the binding of inhibitory KIRs, leading to NK cell activation (c). Finally, antibodies binding to HIV-1-infected cells can crosslink CD16 and activate CD16⁺ NK cells (d).

Figure 3. DC–NK cell crosstalk

Dendritic cells (DCs) are activated by HIV-1 and secrete pro-inflammatory cytokines, including interleukin-12 (IL-12), IL-15 and type I interferon (IFN) that stimulate natural killer (NK) cells. Activated NK cells secrete IFNγ that promotes DC maturation and skewing towards T helper 1 (T_H1)-type immune responses. Furthermore, NK cells can eliminate incompletely matured DCs, and promote the induction of adaptive T cell immunity through this editing process. HIV-1-induced functional impairment of NK cells, as well as of DCs, interferes with this crosstalk.