HIV: The escape artist

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A common mutation in an HIV viral peptide not only impedes its recognition by cytotoxic T lymphocytes but also facilitates its binding to ILT (immunoglobulin-like transcript) receptors, impairing the maturation and response of immune cells.

HIV can outsmart the host immune system in many ways. For example, HIV has been shown to escape from recognition by cytotoxic T lymphocytes (CTLs) by mutating key amino-acid residues in the MHC-class-I-bound viral peptide that contact the T-cell receptor (TCR). But until now it was not known whether HIV antigenic peptide variation could also affect recognition by other MHC-class-I-specific receptors, such as the KIRs (killer-cell immunoglobulin-like receptors) and ILT (immunoglobulin-like transcript) receptors. Reporting in The Journal of Experimental Medicine, Lichterfeld et al. show that a viral mutation for CTL escape increases binding to the inhibitory receptor ILT4 on myelomonocytic cells and leads to the functional inhibition of these cells.


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In this study, an HLA-B2705-restricted HIV epitope that is often found to be mutated in HLA-B2705⁺ HIV-infected individuals was studied. The frequently occurring mutation at position 6 of this epitope, involving a leucine to methionine amino-acid substitution (L6M), did not affect its ability to bind to HLA-B2705 but was shown to be poorly recognized, compared with the wild-type epitope, by CTLs from all HLA-B2705⁺ HIV-infected individuals tested during acute infection. This suggests that such a mutation probably arises as a means to escape immune pressure exerted by CTLs.

To determine whether the L6M mutation also affects recognition by other MHC-class-I-specific receptors, the authors generated fluorescently labelled HLA-B2705 pentamers loaded with either the variant or the wild-type epitope. No binding by either pentamer was detectable on natural killer cells or lymphocytes from HLA-B2705^- individuals, indicating that TCR-independent interactions with immunoreceptors on these cells (such as KIRs and ILT2) did not occur. However, both pentamers clearly bound to monocytes and dendritic cells (DCs), with the variant pentamer showing threefold stronger binding than the wild-type pentamer. This binding was abrogated by an ILT4-specific blocking antibody, implicating ILT4 expressed by myelomonocytic cells in the interaction.

Importantly, the authors went on to show that the increased binding of the variant epitope to ILT4 has functional significance. Immature monocyte-derived DCs (MDDCs) exposed to variant pentamers failed to upregulate the expression of maturation and co-stimulatory molecules in maturation-inducing culture conditions, whereas the wild-type pentamers showed no such inhibitory effect. Culturing of immature MDDCs with HLA-B2705⁺ antigen-presenting cells loaded with either the variant or the wild-type epitope, confirmed the inhibitory effect of the variant epitope on MDDCs, and knockdown of ILT4 expression on the MDDCs, confirmed that the inhibition required interaction with ILT4.

So, this study implies a new way in which HIV might evade the immune response, not only by escaping direct recognition by CTLs but also by impairing the function of myelomonocytic cells and potentially their ability to prime new CTL responses effectively.

Lucy Bird

References

Lichterfeld, M. et al. A viral CTL escape mutation leading to immunoglobulin-like transcript 4-mediated functional inhibition of myelomonocytic cells. J. Exp. Med. 204, 2813–2824 (2007) | Article | PubMed |
McMichael, A. J. Triple bypass: complicated paths to HIV escape. J. Exp. Med. 204, 2785–2788 (2007) | Article | PubMed |