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  • Review Article
  • Published:

NK cells in HIV infection: Paradigm for protection or targets for ambush

Nature Reviews Immunology volume 5, pages 835–843 (2005)Cite this article

An Erratum to this article was published on 01 December 2005

This article has been updated

Key Points

  • Natural killer (NK) cells are a subset of lymphoid cells that function as important mediators of the innate immune defence mechanisms against viruses and tumour cells. As a crucial component of the innate immune system, NK cells might have an important role in host defence against HIV infection, as well as in the control of HIV replication in vivo.

  • NK cells mediate suppression of viral replication in both a cytolytic manner and a non-cytolytic manner. The balance between the activation of inhibitory NK-cell receptors (iNKRs) and activating NK-cell receptors is fundamental to the regulation of NK-cell cytotoxic activity.

  • HIV is known to selectively downregulate the expression of MHC class I molecules at the surface of infected cells in vitro, thereby escaping recognition and lysis by CD8+ T cells and lysis by NK cells.

  • NK cells produce abundant amounts of CC-chemokines and have been shown to suppress HIV replication in vitro by inhibiting HIV entry to target cells. However, NK cells from individuals with HIV viraemia secrete reduced amounts of CC-chemokines and cannot adequately suppress HIV replication.

  • NK cells can eliminate infected cells during the effector phase of immune responses by mediating antibody-dependent cell-mediated cytotoxicity (ADCC). However, NK-cell-mediated ADCC is defective in HIV-infected individuals, which further compromises host immune defences against HIV.

  • The presence of the activating killer-cell immunoglobulin-like receptor (KIR) allele KIR3DS1 and the HLA-B allele HLA-Bw4 Ile80 is associated with delayed progression of HIV infection to AIDS, indicating that NK cells have a protective role against HIV-disease progression.

  • HIV viraemia induces several phenotypic and functional abnormalities in NK cells, including downregulation of expression of CD56 and activating NK-cell receptors, and upregulation of expression of iNKRs. Together, these changes contribute to the defective NK-cell function that has been described for HIV-infected individuals.

  • Expansion of a highly dysfunctional CD16hiCD56− NK-cell population in HIV-viraemic individuals is at least partially responsible for the observed defects in NK-cell function.

  • NK cells interact with dendritic cells (DCs) and regulate the maturation and function of DCs, thereby linking the innate and the adaptive immune responses. NK cells from HIV-infected individuals have decreased expression of NKG2A (NK group 2, member A) and NKp30 (NK-cell protein 30), as well as decreased secretion of interferon-γ, tumour-necrosis factor and granulocyte/macrophage colony-stimulating factor associated with the HIV-viraemic state, indicating that abnormal NK-cell–DC interactions occur in HIV-infected individuals.

  • Improvements in NK-cell function are observed with the initiation of antiretroviral therapy and the subsequent control of HIV viraemia.

Abstract

Natural killer cells are a crucial component of the innate immune response to certain tumours and to various viruses, fungi, parasites and bacteria. HIV has infected more than 60 million people worldwide and has led to more than 23 million deaths. At present, there are ∼40 million people who are living with HIV infection, and there were 5 million new infections in 2004. As part of the innate immune system, natural killer cells might have an important role in host defence against HIV infection, as well as in the control of HIV replication in vivo. In this regard, it is important to understand how natural killer cells and HIV interact. This Review focuses on the role of natural killer cells in controlling HIV infection and on the impact of HIV and HIV-viraemia-induced immune activation on natural-killer-cell function.

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Figure 1: Natural-killer-cell recognition of target cells.
Figure 2: Cytolytic and non-cytolytic mechanisms that are mediated by natural killer cells for the control of HIV infection.
Figure 3: Effect of HIV viraemia on natural-killer-cell function.

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Change history

  • 23 October 2005

    When originally published, the thirteenth row in Table 1 contained incorrect information.

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Acknowledgements

The authors acknowledge A. Moretta for critical comment on the manuscript, J. Weddle for assistance with figure designs, and J. Jackson and D. Kim for appraising the manuscript.

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Authors and Affiliations

  1. Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Building 31, Room 7A04, 31 Center Drive, MSC 2520, Bethesda, 20892-2520, Maryland, USA

    Anthony S. Fauci, Domenico Mavilio & Shyam Kottilil

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  1. Anthony S. Fauci
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  2. Domenico Mavilio
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Correspondence to Anthony S. Fauci.

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DATABASES

Entrez Gene

2B4

CCL3

CCL4

CCL5

CCR5

CD16

CD56

CD94

CXCR4

GM-CSF

IFN-γ

KIR3DS1

LIR1

NKG2D

NKp30

NKp44

NKp46

NKp80

NTBA

TNF

FURTHER INFORMATION

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Glossary

ANTIBODY-DEPENDENT CELL-MEDIATED CYTOTOXICITY

(ADCC). A cytotoxic mechanism by which an antibody-coated target cell is directly killed by a leukocyte that expresses Fc receptors, such as a natural killer (NK) cell, macrophage or neutrophil. A specific receptor for the constant region of IgG, FcγRIII (also known as CD16), is expressed at the surface of most NK cells and mediates ADCC.

ANTIRETROVIRAL THERAPY

(ART). Combination treatment regimens of antiretroviral drugs that effectively suppress HIV replication and delay progression to AIDS. In general, ART includes three or more drugs, such as two nucleoside reverse-transcriptase inhibitors (NRTIs), one protease inhibitor and/or one non-NRTI. One new class of antiretroviral agent is a fusion inhibitor (enfuvirtide), which blocks the entry of HIV to cells, and it is generally used to treat individuals who are infected with multidrug-resistant HIV.

R5 VIRUS

An HIV strain that uses CC-chemokine receptor 5 (CCR5) as the co-receptor to gain entry to target cells.

X4 VIRUS

An HIV strain that uses CXC-receptor 4 (CXCR4) as the co-receptor to gain entry to target cells.

MOUSE CYTOMEGALOVIRUS

(MCMV). Immune responses to this herpesvirus-family member can suppress viral replication but do not completely eliminate the virus, leading to persistent infection. MCMV is highly homologous to human cytomegalovirus and is therefore often used as an in vivo model of chronic viral infection in a natural host.

SEROCONVERSION

The development of antibodies specific for HIV antigens. When individuals develop antibodies specific for HIV, they seroconvert from an antibody-negative state to an antibody-positive state. After infection with HIV, it might take from as little as 1 week to several months (or more) for antibodies to the virus to develop.

EPISTATIC ASSOCIATION

In genetic epidemiology, an epistatic effect is the modification of the risk that is conferred by one marker by the presence of a marker from an unrelated gene (that is, an unlinked gene–gene interaction).

TOLL-LIKE RECEPTORS

(TLRs). A family of receptors that are homologous to Drosophila melanogaster Toll. TLRs recognize conserved molecular patterns that are present in pathogens, such as lipopolysaccharide in the bacterial cell wall.

CPG-CONTAINING OLIGODEOXYNUCLEOTIDE

(CpG ODN). An ODN that includes a cytosine residue joined by a 5′-to-3′ phosphodiester linkage to a guanine residue as part of a normal DNA strand. This sequence is highly immunogenic and induces an innate immune response through interaction with Toll-like receptor 9.

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Fauci, A., Mavilio, D. & Kottilil, S. NK cells in HIV infection: Paradigm for protection or targets for ambush. Nat Rev Immunol 5, 835–843 (2005). https://doi.org/10.1038/nri1711

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