Abstract
Elite controllers or suppressors (ES) are HIV-1 infected individuals who maintain undetectable viral loads without anti-retroviral therapy. The HLA-B*57 allele is overrepresented in ES suggesting a role for HIV-specific CD8+ T cells in immune control. Natural killer (NK) cells also play a role in controlling viral replication, and genetic studies demonstrate that specific combinations of killer cell immunoglobulin-like receptor (KIR) alleles and HLA subtypes including HLA-B*57 correlate with delayed progression to AIDS. While prior studies have shown that both HIV-specific CD8+ T cells and NK cells can inhibit viral replication in vitro, the interaction between these two effector cells has not been studied. We performed in vitro suppression assays using CD8+ T cells and NK cells from HLA-B*57 ES either alone or in combination with each other. We found no evidence of antagonism or synergy between the CD8+ T cells and NK cells, suggesting that they have independent mechanisms of inhibition in vitro. Our data has implications for combined immunotherapy with CD8+ T cells and NK cells in HIV cure strategies.
Highlights
Elite suppressors represent a model of a functional cure of HIV-1 infection (Walker and Yu, 2013)
While this assay does not measure direct killing of infected CD4+ T cells, we and others have shown that direct contact between CD8+ T cells and target CD4+ T cells is needed for suppression (Saez-Cirion et al, 2007; Veenhuis et al, 2018) and we show here that direct contact between ES3 target cells and Natural killer (NK) and CD8+ T cells is needed to reduce viral transcription (Supplementary Figure 1)
CD8+ T cell receptors recognize peptides presented on MHC class I molecules whereas NK cells have diverse receptors including the killer-like immunoglobulin receptors that recognize MHC proteins, C-type Lectin-like receptors that recognize stress antigens, and natural cytotoxicity receptors that recognize viral antigens
Summary
Elite suppressors represent a model of a functional cure of HIV-1 infection (Walker and Yu, 2013). The role NK cells play in elite control is less clear, but studies have shown that the combination of some protective HLA- Bw4-80I alleles like HLA-B∗57/5801 and certain KIR2DS1 and KIR3DL1 alleles confer more protection than either allele alone (Martin et al, 2002, 2007, 2018; Kamya et al, 2011). Antagonism between NK cells and CD8+ T cells has been reported for some viral infections (Su et al, 2001; Andrews et al, 2010; Lang et al, 2012; Mitrovicet al., 2012) The interaction between these sets of effector cells in HIV infection will be important to understand if they are to be used together in immunotherapy.
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