HIV-1 adaptation to NK-cell-mediated immune pressure

Abstract

Natural Killer (NK) cells play an important role in the control of viral infections, recognizing virally infected cells through a variety of activating and inhibitory receptors1–3. Epidemiological and functional studies have recently suggested that NK cells can also contribute to the control of HIV-1 infection through recognition of virally infected cells by both activating and inhibitory Killer Immunoglobulin-like receptors (KIRs)4–7. However, it remains unknown whether NK cells can directly mediate antiviral immune pressure in vivo in humans. Here we describe KIR-associated amino acid polymorphisms in the HIV-1 sequence of chronically infected individuals on a population level. We show that these KIR-associated HIV-1 sequence polymorphisms can enhance the binding of inhibitory KIRs to HIV-1-infected CD4+ T cells, leading to reduced antiviral activity of KIR+ NK cells. These data demonstrate that KIR+ NK cells can place immunological pressure on HIV-1, and that the virus can evade such NK cell mediated immune pressure by selecting for sequence polymorphisms, as previously described for virus-specific T cells and neutralizing antibodies8. NK cells might therefore play a previously underappreciated role in contributing to viral evolution.

Peptide-dependent HLA-KIR-mediated regulation of NK cell function

“…same authors [19]. This study identified more than 20 positions in the HIV-1 genome at which amino acid polymorphisms were significantly associated with the presence of a specific KIR gene [19]. More recently, the same group confirmed that HIV escape mutations also occur in the context of the specific HLA-C ⁄ 03:04/KIR2DLR3 compound genotype [20] that is now studied by Lunemann et al for HCV.…”

“…(C) Low concentrations of variant peptide (black) can prevent the formation of KIR microclusters in response to the high-affinity peptide (pink) and stall downstream signaling. same authors [19]. This study identified more than 20 positions in the HIV-1 genome at which amino acid polymorphisms were significantly associated with the presence of a specific KIR gene [19].…”

Deciphering the killer‐cell immunoglobulin‐like receptor system at super‐resolution for natural killer and T‐cell biology

“…Through any of these mechanisms, NK cells can exert selection pressure on HIV through KIR 63, 93. Conversely, HIV peptides that complex with HLA allotypes and bind inhibitory KIR with high affinity represent NK cell ‘escape’ variants via inhibition of NK cell function 94, 95…”

Immune responses during spontaneous control of HIV and AIDS: what is the hope for a cure?

“…Interactions between KIR3DL1 and HLA class I alleles carrying the Bw4-80I motif are peptide-specific [62], and some peptide residues are directly involved in the binding of KIR3DL1 to its ligand [63]. Along these lines, compelling evidence of the impact of NK cells on virus control in the context of a particular KIR background comes from the observation that HIV-1 evolves to evade NK-cell-mediated immune pressure by selecting for sequence variants that specifically affect KIR binding to HLA class I ligands [64].…”