The Editorial on the Research Topic
Role of HLA and KIR in Viral Infections
The immune system continuously protects its host against pathogens. During viral infections,
both innate and adaptive immune cells contribute to an effective immune response.
Natural killer (NK) cells can respond quickly to eliminate pathogens and infected
cells and suppress dissemination to other tissues. Subsequently, activation of virus-specific
CD8+ cytotoxic T cells results in specific killing of infected cells and activation
of virus-specific CD4+ T cells further supports the immune response. Human leukocyte
antigens (HLA) play an essential role in activation of both NK cells and T cells.
This research topic contains eight articles highlighting the latest insights into
the various effects of HLA molecules on both NK cell and T-cell reactivity upon viral
infection.
Natural Killer cell activation is regulated by a variety of activating and inhibitory
receptors, including killer-cell immunoglobulin-like receptors (KIRs). KIRs bind to
HLA class I molecules, which are expressed on all nucleated cells. As HLA and KIR
molecules are highly polymorphic, each individual expresses a unique set of these
molecules. The wide range of combinations of HLA and KIR expression results in differences
in binding strengths and variation in NK cell activation (1). In this research topic,
a review by Walter and Ansari illuminates the associations of HLA and KIR polymorphisms
with the outcome of experimental simian immunodeficiency virus infection in rhesus
macaques, a model used to study human immunodeficiency virus (HIV) infection. Not
only do these associations show which interactions contribute to disease resistance,
they also pinpoint combinations that increase susceptibility to disease. Such associations
of HLA and KIR with disease progression have also been found in hepatitis C virus
(HCV) infection. In her review, Gardiner summarizes current insights into these associations,
and further illustrates how NK cells modulate disease outcome in HCV infection. Furthermore,
this review highlights the ongoing search for the NK cell subsets required for protective
host responses.
In addition to KIRs, NK cells express C-type lectin receptors, including NKG2C, which
regulate activation via ligation to non-classical HLA-E molecules. Della Chiesa et
al. summarize the role of activating KIRs and NKG2C in several virus infections, including
human cytomegalovirus (HCMV) and HIV. In addition, they discuss the induction of memory-like
NK cells, which show enhanced responses upon reinfection and may play a role in controlling
recurrent or chronic infections. Expression of NKG2C has also been associated with
expansion of NK cells during viral infection. This expansion of NKG2C+ NK cells with
expression of self-HLA class I-specific KIRs has been observed in HCMV infection (2).
The force driving these NK cell expansions is largely unclear. In this collection,
Beziat et al. investigate the importance of HLA class I expression levels in host
defense using data derived from transporter associated with antigen processing (TAP)-deficient
individuals who express less than 10% of normal HLA class I levels. They demonstrate
that self-HLA class I molecules shape the KIR repertoire of NKG2C+ NK cells, but are
not a requirement for expansion.
Besides influencing innate NK responses via ligation to KIRs, HLA induces adaptive
immune responses by presenting pathogen-derived peptides to T cells. Recognition of
HLA:peptide complexes by a peptide-specific T-cell receptor leads to activation of
specific CD8+ cytotoxic T cells or CD4+ T helper cells. In HCMV infection, effective
CD8+ T-cell responses have been shown to be dominated by peptides derived from immediate-early
1 (IE-1) protein (3–5). Whether IE-1 is also the dominant peptide source for CMV-specific
CD4+ T cell responses is unclear. Using cells derived from healthy HCMV-positive donors,
Ameres et al. generated multiple IE-1-specific CD4+ T cell clones with a highly diverse
repertoire and found that IE-1-specific CD4+ T cells participate in the antiviral
response. Since both CD4+ and CD8+ T cells respond to IE-1-derived peptides, it might
be an interesting target for immunotherapeutic approaches.
Infection with measles virus is known to induce a strong T cell response (6, 7), but
information regarding the specific measles virus antigens that are responsible for
activation of these cells is limited. Schellens et al. investigated which measles
peptides are presented by HLA class I molecules by eluting naturally presented peptides
from virus-infected cells. They show that a broad spectrum of the measles peptidome
is presented by different HLA class I molecules. Furthermore, they found that while
HLA-B molecules present the most diverse set of peptides, the abundant epitopes were
eluted from HLA-A and HLA-C molecules, suggesting that the HLA loci also influence
peptide presentation.
Due to the polymorphic nature of HLA molecules, a great diversity of peptides are
typically presented, resulting in T-cell activation of variable strengths. In HCV
infections, some HLA molecules (e.g., HLA-B27 and HLA-B57) are significantly associated
with viral clearance (8, 9). However, it is not yet known why such HLA molecules provide
an advantage during HCV infections. Using known HCV epitopes combined with in silico
predictions, Rao et al. demonstrate that HLA-B27 preferentially presents epitopes
from the HCV protein NS5B, which is highly conserved and, therefore, might be one
of the underlying mechanisms behind the protective effect of this molecule during
HCV infection. Preferential presentation of peptides derived from conserved regions
was also found for HIV (10–12). However, the induction of effective immune responses
also puts pressure on the virus to adapt toward escape variants. The generation of
escape variants often comes with significant costs, such as reduced viral replicative
capacity. In the final paper of this issue, a review by KlØverpris et al. illustrates
the effects of viral escape variants within the HIV-infected patient as well as the
consequences of transmission of these variants at the population level.
Together, the research and reviews in this research topic provide an up-to-date overview
of the importance of HLA and KIR molecules in host responses to viral infection. Given
the central role of HLA in modulating both innate and adaptive immune responses, it
is important to expand our knowledge on the role of different HLA molecules in various
diseases. A better understanding of the differences between the individual immune
responses, especially when it fails to protect against pathogens, should ultimately
help to develop better – and possibly more individualized – treatment options.
Author Contributions
JW, JB, CK, and DB wrote the editorial.
Conflict of Interest Statement
The authors declare that the research was conducted in the absence of any commercial
or financial relationships that could be construed as a potential conflict of interest.