NK Cells in HIV-1 Infection: From Basic Science to Vaccine Strategies

Abstract

NK cells play a key role in immune response against HIV infection. These cells can destroy infected cells and contribute to adequate and strong adaptive immune responses, by acting on dendritic, T, B, and even epithelial cells. Increased NK cell activity reflected by higher cytotoxic capacity, IFN-γ and chemokines (CCL3, CCL4, and CCL5) production, has been associated with resistance to HIV infection and delayed AIDS progression, demonstrating the importance of these cells in the antiviral response. Recently, a subpopulation of NK cells with adaptive characteristics has been described and associated with lower HIV viremia and control of infection. These evidences, together with some degree of protection shown in vaccine trials based on boosting NK cell activity, suggest that these cells can be a feasible option for new treatment and vaccination strategies to overcome limitations that, classical vaccination approaches, might have for this virus. This review is focus on the NK cells role during the immune response against HIV, including all the effector mechanisms associated to these cells; in addition, changes including phenotypic, functional and frequency modifications during HIV infection will be pointed, highlighting opportunities to vaccine development based in NK cells effector functions.

Keywords: HIV resistance; HIV vaccine; HIV-1; memory NK cells; natural killer cells.

Figure 1

NK cell role during HIV-1 infection. (A) NK cells degranulate in response to activating signals via CD16 (FcγRIII), which binds Abs recognizing HIV proteins; also, by activating signals via NKG2D that binds stress signals like UPBL1, 2 and 3, which are up regulated on infected cells. Down regulation of HLA class I molecules induces activation by absence of inhibitory signals through KIR. (B) NK cells produce IL-22, which induce the production of antimicrobial molecules and IL-10 by epithelial cells. NK cells produce β-chemokines, which exert anti–HIV-1 activity in vitro by displacing the viral envelope glycoprotein gp120 from binding to CCR5 and by promoting CCR5 endocytosis. (C) iDCs uptake apoptotic bodies produced by NK cells activity inducing their maturation. NK cells realize DC editing eliminating iDCs to select mature DCs. DCs induce the activation of NK cells by producing IL-12, IL-18, and type I IFNs and NK cells produce IFN-γ inducing maturation of DCs. NK cells can eliminate CD4+ T cells and follicular helper T cells (Tfh), editing germinal center and affecting Abs production, but at the same time, by eliminating the Tfh, they reduce the HIV reservoirs.

Figure 2

NK maturation and Memory like phenotype. (A) Gating strategy used for the identification of NK cells subpopulation, which includes fully mature (CD56dim CD57+) and Memory like (NKG2Chigh) NK cells; blood sample correspond to healthy donor from our laboratory (Unpublished data). (B) CD56^bright NK cells represent less mature stage of NK cells differentiation, these cells respond to IL12/15 stimulation. These also express NCRs and NKG2A/C and high affinity IL2R (CD25), which reflect their proliferative capacity. After immune licensing process, CD56^dim gain the expression of KIRs and loss expression of cytokines receptor, making them less reactive to cytokine stimuli, they also gain CD16 expression together with an improved cytotoxic capacity. Fully differentiated CD56^dim express CD57 and loss NKG2A and NCRs expression, they respond better trough KIR and NKG2C signaling. Memory like NK cells are thought to develop after CMV infection, they have a high cytotoxic capacity and present epigenetic modifications in IFN-γ, TNF-α, and IL-10 genes allowing them to produce high amounts of these cytokines rapidly after stimuli through KIRs and NKG2C receptors.

Figure 3

CMV and cytokines induced memory like NK cells. Memory like NK cells are developed after CMV infection in the presence of IL-12. These cells show strong cytotoxic capacity and IFN-γ production associated with epigenetic changes, restricted to certain stimulus via KIR and CD16 but no cytokines. Cytokine-induced Memory like NK cells (CIML) share some features of memory NK cells developed after CMV infection like improved IFN production secondary to epigenetic modifications; however, they show different phenotype and different cytotoxic capacity after stimulation.