Nature Reviews Immunology

doi: 10.1038/nri1744pmid: N/A

Honey, Karen

doi: 10.1038/nri1737pmid: N/A

Bell, Elaine

doi: 10.1038/nri1736pmid: N/A

Bird, Lucy

doi: 10.1038/nri1739pmid: N/A

doi: 10.1038/nri1740pmid: N/A

Minton, Kirsty

doi: 10.1038/nri1742pmid: N/A

Honey, Karen

doi: 10.1038/nri1741pmid: N/A

Bird, Lucy

doi: 10.1038/nri1743pmid: N/A

Minton, Kirsty

doi: 10.1038/nri1738pmid: N/A

Fauci, Anthony S.; Mavilio, Domenico; Kottilil, Shyam

doi: 10.1038/nri1711pmid: 16239902

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.