Natural Killer Cells in Antibody Independent and Antibody Dependent HIV Control

Abstract

Infection with the human immunodeficiency virus (HIV), when left untreated, typically leads to disease progression towards acquired immunodeficiency syndrome. Some people living with HIV (PLWH) control their virus to levels below the limit of detection of standard viral load assays, without treatment. As such, they represent examples of a functional HIV cure. These individuals, called Elite Controllers (ECs), are rare, making up <1% of PLWH. Genome wide association studies mapped genes in the major histocompatibility complex (MHC) class I region as important in HIV control. ECs have potent virus specific CD8+ T cell responses often restricted by protective MHC class I antigens. Natural Killer (NK) cells are innate immune cells whose activation state depends on the integration of activating and inhibitory signals arising from cell surface receptors interacting with their ligands on neighboring cells. Inhibitory NK cell receptors also use a subset of MHC class I antigens as ligands. This interaction educates NK cells, priming them to respond to HIV infected cell with reduced MHC class I antigen expression levels. NK cells can also be activated through the crosslinking of the activating NK cell receptor, CD16, which binds the fragment crystallizable portion of immunoglobulin G. This mode of activation confers NK cells with specificity to HIV infected cells when the antigen binding portion of CD16 bound immunoglobulin G recognizes HIV Envelope on infected cells. Here, we review the role of NK cells in antibody independent and antibody dependent HIV control.

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“…Decreased HLA-A expression correlates with HIV control, being seen in the EC patients that have reduced HLA-A levels [ 107 ]. In addition, -21T amino acid variation at the signal peptide HLA-B has been associated with being HLA-Bw4 [ 9 , 20 ]. For that reason, homozygosis at HLA-B -21T, likely associated with Bw4 homozygosis, contributes to HIV control [ 80 ].…”

“…For that reason, homozygosis at HLA-B -21T, likely associated with Bw4 homozygosis, contributes to HIV control [ 80 ]. Some KIR3DL1/Bw4 combinations also are associated with HIV control [ 9 ]. In this context, HLA alleles carrying HLA-B -21T, such as Bw4 and low-expression HLA-A allotypes, codify HLA molecules that reduce HLA-E levels -n HIV-infected CD4 + T cells.…”

“…Depending on the balance between these NK receptors (NKR) and their HLA ligands, NK cells will either be activated to kill the target cell or inhibited, allowing the target cell to survive. NK cells are an heterogeneous population harboring multiple subsets that differentially expressed NK receptors such as: killer cell immunoglobulin-like receptors (KIRs), natural killer group 2 such as NKG2A, NKG2C and NKG2D, and natural cytotoxicity receptors (NCRs), for example NKp30, NKp40 or NKp46 [ 8 , 9 ]. The main activating and inhibiting NK receptors and their respective target cell ligands are shown in Figure 2 A.…”

“…For NK cell activation, additional activating signal are necessary [ 15 ]. NK cells are activated when the ratio of inhibitory and activator NKR signaling favors activation [ 9 ] ( Figure 2 B). Many inhibitory KIRs from NK cells interact with HLA alleles.…”

“…On the one hand, HLA-B -21M alleles contribute more effectively to NKG2A-mediated education, which suppresses NK cell activation when the target cell expresses stabilized levels of HLA-E. HLA-B -21T alleles mainly contribute to education through inhibitory KIRs, especially KIR3DL1 [ 15 ], as HLA-B -21T and HLA-Bw4 are genetically linked. Then, the HLA-Bw4 alleles are, in fact, HLA antigens encoded by -21T, able to interact and educate through KIR3DL1/HLA-Bw4, allowing the NK cell cytotoxicity upon “missing self” recognition [ 9 , 20 ] ( Figure 2 B).…”