Selection of an HLA-C*03:04-Restricted HIV-1 p24 Gag Sequence Variant Is Associated with Viral Escape from KIR2DL3+ Natural Killer Cells: Data from an Observational Cohort in South Africa

Abstract

BackgroundViruses can evade immune surveillance, but the underlying mechanisms are insufficiently understood. Here, we sought to understand the mechanisms by which natural killer (NK) cells recognize HIV-1-infected cells and how this virus can evade NK-cell-mediated immune pressure.Methods and FindingsTwo sequence mutations in p24 Gag associated with the presence of specific KIR/HLA combined genotypes were identified in HIV-1 clade C viruses from a large cohort of infected, untreated individuals in South Africa (n = 392), suggesting viral escape from KIR+ NK cells through sequence variations within HLA class I—presented epitopes. One sequence polymorphism at position 303 of p24 Gag (TGag303V), selected for in infected individuals with both KIR2DL3 and HLA-C*03:04, enabled significantly better binding of the inhibitory KIR2DL3 receptor to HLA-C*03:04-expressing cells presenting this variant epitope compared to the wild-type epitope (wild-type mean 18.01 ± 10.45 standard deviation [SD] and variant mean 44.67 ± 14.42 SD, p = 0.002). Furthermore, activation of primary KIR2DL3+ NK cells from healthy donors in response to HLA-C*03:04+ target cells presenting the variant epitope was significantly reduced in comparison to cells presenting the wild-type sequence (wild-type mean 0.78 ± 0.07 standard error of the mean [SEM] and variant mean 0.63 ± 0.07 SEM, p = 0.012). Structural modeling and surface plasmon resonance of KIR/peptide/HLA interactions in the context of the different viral sequence variants studied supported these results. Future studies will be needed to assess processing and antigen presentation of the investigated HIV-1 epitope in natural infection, and the consequences for viral control.ConclusionsThese data provide novel insights into how viruses can evade NK cell immunity through the selection of mutations in HLA-presented epitopes that enhance binding to inhibitory NK cell receptors. Better understanding of the mechanisms by which HIV-1 evades NK-cell-mediated immune pressure and the functional validation of a structural modeling approach will facilitate the development of novel targeted immune interventions to harness the antiviral activities of NK cells.

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

“…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. Collectively, these findings suggest that KIR-positive NK cells may exert immunological pressure -a hypothesis that can be further explored with rapidly mutating viruses such as HIV and HCV.…”

HIV-1 Control by NK Cells via Reduced Interaction between KIR2DL2 and HLA-C∗12:02/C∗14:03

“…Several studies have reported that peptide sequence variations may enhance the binding of inhibitory KIRs to the pHLA complexes and consequently down-regulate the activity of NK cells (Alter et al, 2011; Fadda et al, 2012; Holzemer et al, 2015; Thananchai et al, 2009; Van Teijlingen et al, 2014). However, we showed that the 9A mutation in Pol-IY10 did not influence the direct binding of KIR2DL2 to the peptide-HLA-C*12:02 complex, even though this mutation resulted in greater KIR2LD2 + NK cell activation and resulted in stronger inhibition of replication of the virus carrying this mutation.…”

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

“…There are different mechanisms by which viral infection can rapidly and radically affect the HLA class I peptide repertoire. Some viruses have evolved to evade NK cell immunity through the selection of mutations in MHC‐presented peptides that enhance binding to inhibitory NK cell receptors including the C‐type lectin‐like CD94:NKG2A heterodimer receptor and KIR2DL3 135, 136. Conversely, virus‐induced changes in peptide repertoire may promote beneficial action through KIR by disrupting HLA class I recognition by inhibitory KIR, releasing constraint on NK cells to mount a positive clearance response to infected cells 135.…”