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Review
. 2023 Feb 1;113(2):109-138.
doi: 10.1093/jleuko/qiac007.

Mapping the interplay between NK cells and HIV: therapeutic implications

Renee R Anderko  1 , Robbie B Mailliard  1
Affiliations
Review

Mapping the interplay between NK cells and HIV: therapeutic implications

Renee R Anderko et al. J Leukoc Biol. .

Abstract

Although highly effective at durably suppressing plasma HIV-1 viremia, combination antiretroviral therapy (ART) treatment regimens do not eradicate the virus, which persists in long-lived CD4+ T cells. This latent viral reservoir serves as a source of plasma viral rebound following treatment interruption, thus requiring lifelong adherence to ART. Additionally, challenges remain related not only to access to therapy but also to a higher prevalence of comorbidities with an inflammatory etiology in treated HIV-1+ individuals, underscoring the need to explore therapeutic alternatives that achieve sustained virologic remission in the absence of ART. Natural killer (NK) cells are uniquely positioned to positively impact antiviral immunity, in part due to the pleiotropic nature of their effector functions, including the acquisition of memory-like features, and, therefore, hold great promise for transforming HIV-1 therapeutic modalities. In addition to defining the ability of NK cells to contribute to HIV-1 control, this review provides a basic immunologic understanding of the impact of HIV-1 infection and ART on the phenotypic and functional character of NK cells. We further delineate the qualities of "memory" NK cell populations, as well as the impact of HCMV on their induction and subsequent expansion in HIV-1 infection. We conclude by highlighting promising avenues for optimizing NK cell responses to improve HIV-1 control and effect a functional cure, including blockade of inhibitory NK receptors, TLR agonists to promote latency reversal and NK cell activation, CAR NK cells, BiKEs/TriKEs, and the role of HIV-1-specific bNAbs in NK cell-mediated ADCC activity against HIV-1-infected cells.

Keywords: HIV; adaptive NK cells; broadly neutralizing antibodies (bNAbs); dendritic cells (DCs); innate immune memory; memory NK cells.

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Conflict of interest statement

Conflict of interest The authors declare no conflict of interest.

Figures

Fig. 1.
Fig. 1.
NK cell control of HIV-1 infection. (A) HIV-1 accessory proteins cause downregulation of MHC class I molecules and upregulation of stress ligands, activating NK cell cytolytic activity and promoting elimination of infected CD4+ T cells. (B) NK cells are also activated via CD16, resulting in ADCC-mediated elimination of infected cells and potent control of HIV-1 infection. (C) Secretion of CCL3, CCL4, and CCL5 by NK cells inhibits viral entry by blocking binding of HIV-1 to the coreceptor CCR5. Figure created with BioRender.com.
Fig. 2.
Fig. 2.
Impact of HIV-1 infection on NK cells. Chronic HIV-1 viremia causes a sequential loss of Siglec-7 and CD56, leading to an accumulation of Siglec-7−CD56− NK cells. This highly dysfunctional subset preferentially expresses iKIRs over activating NKRs, including NKp30 and NKp46. Chronic HIV-1 viremia is also associated with increased expression of NKG2C, combined with loss of NKG2A, resulting in an inversion of the NKG2A to NKG2C ratio. NK cell cytolytic activity is further impaired by cleavage of NKG2D ligands from the surfaced of infected CD4+ T cells by MMPs, which are highly expressed in viremic HIV-1-infected individuals. This proteolytic activity allows HIV-1-infected cells to evade NKG2D-mediated antiviral responses both by decreasing surface expression of NKG2D ligands on infected cells and by inactivating NKG2D on NK cells via the soluble ligands. Figure created with BioRender.com.
Fig. 3.
Fig. 3.
NK cell “memory” populations are phenotypically and functionally distinct. (A) Cytokine-induced memory-like NK cells, with high surface expression of cytokine receptors and CCR7, efficiently integrate immunostimulatory cytokines to drive their differentiation and subsequent recall responses. (B, C) Adaptive NKG2C+ and FcRγ− memory-like NK cells share numerous features, including high-density surface expression of CD57 and iKIRs and potent ADCC responses; however, initial programming and expansion of adaptive NKG2C+ NK cells result from interactions between NKG2C and specific HLA-E–peptide complexes (B). For FcRγ− NK cells, preferential expansion occurs upon encounter with HCMV-infected cells in the presence of HCMV-specific antibodies. They are notably deficient for FcRγ and the transcription factor PLZF and are not restricted by the expression of NKG2C (C). Epigenetic modifications underlie the unique attributes of “memory” observed in all three of these NK cell populations. Figure created with BioRender.com.
Fig. 4.
Fig. 4.
NK cell enhancement of DC-mediated cellular immunity to HIV-1 is driven by antibody. (A) NK cells from HIV-1+ participants mediated superior ADCC against rituximab-opsonized Raji cells as determined by flow cytometry following a 6 h co-culture; n = 5 HIV-1+ and n = 5 HIV-1− participants. (B)NK cells from HIV-1+ participants required a second signal to produce IFNγ in the presence of rituximab-opsonized Raji target cells; n = 6 HIV-1+ participants. (C) Day-4 iDCs were cultured for 48 h either with opsonized Rajis + IFNα in the presence of autologous NK cells (1:1; NK-DC), only with opsonized Rajis + IFNα (DC0), or in the absence of NK cells and Rajis + IFNα (iDC). Two-signal activated NK cells induced the development of high IL-12-producing DCs compared with iDCs and DCs matured in the absence of NK cells (DC0); n = 6 HIV-1+ participants. (D)NK cells enhanced DC-mediated induction of cellular immunity to HIV-1 as demonstrated by CD8+ T cell IFNγ responses to HIV-1-derived 9mer peptide pools (Supplementary Table S1); n = 2 HIV-1+ participants from four independent experiments. Statistical significance was determined by the unpaired Student’s t-test (A), one-way ANOVA (B, C), or the paired Student’s t-test (D) (****P 0.0001; **P<0.01; *P<0.05). Extended methods available in the Online Supplemental Material.
Fig. 5.
Fig. 5.
Schematic depicting the mechanism of NK cell help in DC-mediated adaptive immunity to HIV-1. bNAbs support NK cell-mediated killing of an HIV-1-infected CD4+ T cell via ADCC. IFNα synergizes with antibody-dependent signaling to activate the helper function of NK cells, promoting DC maturation and polarization. The DC, carrying environmental cues from the periphery, produces IL-12 in response to CD40L stimulation by a CD4+ T helper cell, and IL-12 acts with NK cell-derived IFNγ to drive cellular-mediated immunity to HIV-1. Figure created with BioRender.com.
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