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Review
. 2012 Jul;2(7):a007070.
doi: 10.1101/cshperspect.a007070.

Innate immune control of HIV

Mary Carrington  1 , Galit Alter
Affiliations
Review

Innate immune control of HIV

Mary Carrington et al. Cold Spring Harb Perspect Med. 2012 Jul.

Abstract

Mounting evidence suggests a role for innate immunity in the early control of HIV infection, before the induction of adaptive immune responses. Among the early innate immune effector cells, dendritic cells (DCs) respond rapidly following infection aimed at arming the immune system, through the recognition of viral products via pattern recognition receptors. This early response results in the potent induction of a cascade of inflammatory cytokines, intimately involved in directly setting up an antiviral state, and indirectly activating other antiviral cells of the innate immune system. However, epidemiologic data strongly support a role for natural killer (NK) cells as critical innate mediators of antiviral control, through the recognition of virally infected cells through a network of receptors called the killer immunoglobulin-like receptors (KIRs). In this review, the early events in innate immune recognition of HIV, focused on defining the biology underlying KIR-mediated NK-cell control of HIV viral replication, are discussed.

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Figures

Figure 1.
Figure 1.
A model of KIR3DS1+ natural killer (NK)-cell recognition of an HIV-infected target cell. Accumulating evidence suggests that specific amino acid changes in the peptides presented by major histocompatibility complex (MHC) class I can have a profound impact on KIR recognition of peptide/MHC complexes. Along these lines, it is plausible that a viral or stress peptide generated during infection presented by Bw4-80I may alter the affinity of the activating KIR3DS1 receptor expressed on NK cells for its putative ligand, resulting in the potent activation of NK cells and rapid elimination of virally infected cells.
Figure 2.
Figure 2.
A model of two-step NK-cell activation. NK-cell killing of target cells is tightly regulated by a balance of activating and inhibitory signals delivered through the arsenal of NK-cell receptors expressed on the surface of a given NK-cell clone. NK cells survey the body’s cells for normal MHC class-I expression, delivering a potent inhibitory signal to NK cells through inhibitory KIRs (1). Although the missing self-hypothesis states that the loss of MHC class I should trigger NK-cell killing of a target cell, this loss of inhibition is not sufficient to release the cytolytic activity of NK cells (2). Instead, an activating signal (including a stress ligand), to tip the balance toward activation, releases the full cytolytic power of a given NK-cell clone.
Figure 3.
Figure 3.
A model of KIR3DL1+ NK-cell recognition of an HIV-infected target cell. Given that inhibitory KIRs have been recently implicated in NK-cell education, in such a way that inhibitory KIRs expressed at higher levels are associated with the generation of more functional NK-cell clones, it is possible that the expression of KIR3DL1 at higher levels on a developing NK cell in the presence of its ligand may result in the generation of a larger pool of functionally competent cytolytic cells. These more functionally competent cells may then respond more aggressively on HIV infection to cells that have lost MHC class I ligands, that are down-regulated by the HIV Nef protein.
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