CD4+ NK cells can be productively infected with HIV, leading to downregulation of CD4 expression and changes in function

Bernstein, Helene B.; Wang, Guangwu; Plasterer, Mary C.; Zack, Jerome A.; Ramasastry, Parthasarathy; Mumenthaler, Shannon M.; Kitchen, Christina M. R.

doi:10.1016/j.virol.2009.01.044

Cited by 33 publications

(32 citation statements)

References 29 publications

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“…HIV SS DNA was identified in three (73, 157, and 858 copies/million NK cells) of four separate viremic HIV-infected subject NK cell fractions (Ͼ99% purity). We have previously described an in vitro system of NK cell HIV infection (6). In the latter system, HIV p24 expression was found in 10 to 20% of NK cells.…”

Section: Impaired Nk Cell Response To Ifn-␣ Is Not the Results Of Dimimentioning

confidence: 99%

Impaired Plasmacytoid Dendritic Cell (PDC)-NK Cell Activity in Viremic Human Immunodeficiency Virus Infection Attributable to Impairments in both PDC and NK Cell Function

Conry¹,

Milkovich²,

Yonkers³

et al. 2009

J Virol

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, and this activity was impaired in viremic HIV infection but not in HCV infection. In heterologous PDC-NK cell assays, impaired PDC-NK cell killing activity was largely attributable to an NK cell defect, while impaired PDC-NK cell IFN-␥-producing activity was attributable to both PDC and NK cell defects. Additionally, the response of NK cells to direct IFN-␣ stimulation was defective in viremic HIV infection, and this defect was not attributable to diminished IFN-␣ receptor expression, though IFN-␣ receptor and NKP30 expression was closely associated with killer activity in viremic HIV infection but not in healthy controls. These data indicate that during uncontrolled HIV infection, PDC-dependent NK cell function is impaired, which is in large part attributable to defective IFN-␣-induced NK cell activity and not to altered IFN-␣ receptor, NKP30, NKP44, NKP46, or NKG2D expression.Immature dendritic cells (DC) are key innate mediators of the adaptive immune response. Myeloid DC (MDC) and plasmacytoid DC (PDC) have been identified as two main peripheral DC subsets (43). Numerical and functional defects in these populations have been described for both hepatitis C virus (HCV) and human immunodeficiency virus (HIV) infections, with the impairments distinctly different in each infection (3,12,19,26,33,48,53,56,57). Natural killer (NK) cells are capable of cytotoxic, cytokine-expressing, and chemokine-expressing functions (31, 38). These lymphocytes are vital during the early stages of mouse hepatic viral infection (22, 42) and during human herpes virus infection (5, 7, 10). NK cell cytotoxic function has long been known to be reduced during chronic HIV infection and in subjects with AIDS (32, 44), and unfractionated cell assays of NK cell function indicate an impaired NK cell response to alpha interferon (IFN-␣) (52). Additionally, genetic markers of NK cell phenotype are associated with disease progression rate (36). In contrast, HIVexposed but uninfected subjects appear to have enhanced NK cell function (45), and after highly active antiretroviral therapy (HAART), NK cell numbers and function appear to normalize (1, 4). In the setting of HCV infection, genetic markers of NK cell phenotype appear to predict the outcome after acute exposure (28). During chronic HCV infection, some studies indicate reduced NK cell cytotoxicity (14, 40, 55), while morerecent studies indicate normal NK cell function and reduced peripheral NK cell numbers (18,27,39).DC-NK cell bidirectional cross talk has recently been shown to play a key role in host defense (20,30,34,35,37). This cross talk can be facilitated by Toll-like receptor (TLR) signaling and results in NK cell activation, enhanced NK cell effector function, and DC maturation (15,20,21,30,49). In the setting of viremic HIV infection, recent unfractionated cell system data indicate impairment in PDC-dependent NK cell activity (11). These data may be explained by the previously described numerical defects in PDC or NK cells, though whether there are additional functional defects ...

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Section: Impaired Nk Cell Response To Ifn-␣ Is Not the Results Of Dimimentioning

confidence: 99%

Impaired Plasmacytoid Dendritic Cell (PDC)-NK Cell Activity in Viremic Human Immunodeficiency Virus Infection Attributable to Impairments in both PDC and NK Cell Function

Conry¹,

Milkovich²,

Yonkers³

et al. 2009

J Virol

Self Cite

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“…In this regard, NK cells express HIV-1 receptor and co-receptors such as CD4, CXCR4/CCR5 and Siglec-7 [42, 62–64], thus implying that a direct interaction between NK cells and HIV-1 occurs. However, controversial results were obtained regarding the susceptibility of NK cells to be targeted by HIV-1 since the existence of both viral latency and productive HIV-1 infection of human NK cells has never been demonstrated ex-vivo [22] but only in-vitro [62, 63]. …”

Section: Nk Cells and Hiv-1 Pathogenesismentioning

confidence: 99%

Natural killer cells in HIV-1 infection and therapy

Mikulak

Oriolo

Zaghi

et al. 2017

Aids

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Natural killer (NK) cells are important effectors of innate immunity playing a key role in the eradication and clearance of viral infections. Over the recent years, several studies have shown that HIV-1 pathologically changes NK cell homeostasis and hampers their antiviral effector functions. Moreover, high levels of chronic HIV-1 viremia markedly impair those NK cell regulatory features that normally regulate the cross-talks between innate and adaptive immune responses. These pathogenic events take place early in the infection and are associated with a pathologic redistribution of NK cell subsets that includes the expansion of anergic CD56neg NK cells with an aberrant repertoire of activating and inhibitory receptors. Nevertheless, the presence of specific haplotypes for NK cell receptors as well as the engagement of NK cell antibody dependent cell cytotocity (ADCC) have been reported to control HIV-1 infection. This dichotomy can be extremely useful to both predict the clinical outcome of the infection and to develop alternative anti-viral pharmacological approaches. Indeed, the administration of antiretroviral therapy (ART) in HIV-1 infected patients restores NK cell phenotype and functions to normal levels. Thus, ART can help to develop NK cell-directed therapeutic strategies that include the use of broadly neutralizing antibodies and toll like receptor agonists. The present review discusses how our current knowledge of NK cell pathophysiology in HIV-1 infection is being translated both in experimental and clinical trials aimed at controlling the infection and disease.

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“…A study in non-human primates however suggests a considerably shorter half life for this cell type in vivo [67]. Natural killer cells are cytotoxic lymphocytes that function as part of the innate immune system and they can be infected with HIV-1 ex vivo [68]. Valentin et al found HIV-1 DNA in natural killer cells isolated from participants on ART and recovered replication-competent virus in an outgrowth assay [69].…”

Section: Innate Immune Cells Harbour Latent Hiv-1mentioning

confidence: 99%

HIV-1 Reservoirs During Suppressive Therapy

Barton

Winckelmann

Palmer

2016

Trends in Microbiology

109

114

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The introduction of antiretroviral therapy (ART) 20 years ago has dramatically reduced morbidity and mortality associated with HIV-1. Initially there was hope that ART would be curative, but it quickly became clear that even though ART was able to restore CD4+ T cell counts and suppress viral loads below levels of detection, discontinuation of treatment resulted in a rapid rebound of infection. This is due to persistence of a small reservoir of latently infected cells with a long half-life, which necessitates life-long ART. Over the past few years, significant progress has been made in defining and characterizing the latent reservoir of HIV-1, and here we review how understanding the latent reservoir during suppressive therapy will lead to significant advances in curative approaches for HIV-1.

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CD4+ NK cells can be productively infected with HIV, leading to downregulation of CD4 expression and changes in function

Cited by 33 publications

References 29 publications

Impaired Plasmacytoid Dendritic Cell (PDC)-NK Cell Activity in Viremic Human Immunodeficiency Virus Infection Attributable to Impairments in both PDC and NK Cell Function

Impaired Plasmacytoid Dendritic Cell (PDC)-NK Cell Activity in Viremic Human Immunodeficiency Virus Infection Attributable to Impairments in both PDC and NK Cell Function

Natural killer cells in HIV-1 infection and therapy

HIV-1 Reservoirs During Suppressive Therapy

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