Influence of NKG2C Genotypes on HIV Susceptibility and Viral Load Set Point

NKG2C is an activating NK cell receptor encoded by a gene having an unexpressed deletion variant. Cytomegalovirus (CMV) infection expands a population of NKG2C + NK cells with adaptive-like properties. Previous reports found that carriage of the deleted NKG2C - variant was more frequent in people living with HIV (PLWH) than in HIV - controls unexposed to HIV. The frequency of NKG2C + NK cells positively correlated with HIV viral load (VL) in some studies and negatively correlated with VL in others. Here, we investigated the link between NKG2C genotype and HIV susceptibility and VL set point in PLWH. NKG2C genotyping was performed on 434 PLWH and 157 HIV exposed seronegative (HESN) subjects. Comparing the distribution of the three possible NKG2C genotypes in these populations revealed that the frequency of NKG2C +/+ and NKG2C +/- carriers did not differ significantly between PLWH and HESN subjects, while that of NKG2C -/- carriers was higher in PLWH than in HESNs, in which none were found (p=0.03, χ 2 test). We were unable to replicate that carriage of at least 1 NKG2C - allele was more frequent in PLWH. Information on the pre-treatment VL set point was available for 160 NKG2C +/+ , 83 NKG2C +/- and 6 NKG2C -/- PLWH. HIV VL set point was similar between NKG2C genotypes. The frequency of NKG2C + CD3 - CD14 - CD19 - CD56 dim NK cells and the mean fluorescence intensity (MFI) of NKG2C expression on NK cells was higher on cells from CMV + PLWH who carried 2, versus 1, NKG2C + alleles. We observed no correlations between VL set point and either the frequency or the MFI of NKG2C expression. IMPORTANCE We compared NKG2C allele and genotype distributions in subjects who remained HIV uninfected despite multiple HIV exposures (HESNs) with those in PLWH. This allowed us to determine whether NKG2C genotype influenced susceptibility to HIV infection. The absence of the NKG2C -/- genotype among HESN subjects but not PLWH suggested that carriage of this genotype was associated with HIV susceptibility. We calculated the VL set point in a subset of 252 NKG2C genotyped PLWH. We observed no between-group differences in the VL set point in carriers of the three possible NKG2C genotypes. No significant correlations were seen between the frequency or MFI of NKG2C expression on NK cells with VL set point in cytomegalovirus co-infected PLWH. These findings suggested that adaptive NK cells played no role in establishing the in VL set point, a parameter that is a predictor of the rate of treatment-naïve HIV disease progression.

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Loss of CCR7 Expression on CD56bright NK Cells Is Associated with a CD56dimCD16+ NK Cell-Like Phenotype and Correlates with HIV Viral Load

PLoS ONE ◽

10.1371/journal.pone.0044820 ◽

2012 ◽

Vol 7 (9) ◽

pp. e44820 ◽

Cited By ~ 22

Author(s):

Henoch S. Hong ◽

Fareed Ahmad ◽

Johanna M. Eberhard ◽

Nupur Bhatnagar ◽

Benjamin A. Bollmann ◽

...

Keyword(s):

Viral Load ◽

Nk Cells ◽

Nk Cell ◽

Hiv Viral Load ◽

Ccr7 Expression

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Diagnosis of latent tuberculosis infection is associated with reduced HIV viral load and lower risk for opportunistic infections in people living with HIV

PLoS Biology ◽

10.1371/journal.pbio.3000963 ◽

2020 ◽

Vol 18 (12) ◽

pp. e3000963

Author(s):

Katharina Kusejko ◽

Huldrych F. Günthard ◽

Gregory S. Olson ◽

Kyra Zens ◽

Katharine Darling ◽

...

Keyword(s):

Viral Load ◽

Hiv Transmission ◽

Opportunistic Infections ◽

Latent Tuberculosis ◽

Geographic Region ◽

Transmission Risk ◽

People Living With Hiv ◽

Hiv Diagnosis ◽

Hiv Viral Load ◽

Set Point

Approximately 28% of the human population have been exposed to Mycobacterium tuberculosis (MTB), with the overwhelming majority of infected individuals not developing disease (latent TB infection (LTBI)). While it is known that uncontrolled HIV infection is a major risk factor for the development of TB, the effect of underlying LTBI on HIV disease progression is less well characterized, in part because longitudinal data are lacking. We sorted all participants of the Swiss HIV Cohort Study (SHCS) with at least 1 documented MTB test into one of the 3 groups: MTB uninfected, LTBI, or active TB. To detect differences in the HIV set point viral load (SPVL), linear regression was used; the frequency of the most common opportunistic infections (OIs) in the SHCS between MTB uninfected patients, patients with LTBI, and patients with active TB were compared using logistic regression and time-to-event analyses. In adjusted models, we corrected for baseline demographic characteristics, i.e., HIV transmission risk group and gender, geographic region, year of HIV diagnosis, and CD4 nadir. A total of 13,943 SHCS patients had at least 1 MTB test documented, of whom 840 (6.0%) had LTBI and 770 (5.5%) developed active TB. Compared to MTB uninfected patients, LTBI was associated with a 0.24 decreased log HIV SPVL in the adjusted model (p < 0.0001). Patients with LTBI had lower odds of having candida stomatitis (adjusted odds ratio (OR) = 0.68, p = 0.0035) and oral hairy leukoplakia (adjusted OR = 0.67, p = 0.033) when compared to MTB uninfected patients. The association of LTBI with a reduced HIV set point virus load and fewer unrelated infections in HIV/TB coinfected patients suggests a more complex interaction between LTBI and HIV than previously assumed.

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The Advances and Challenges of NK Cell-Based Cancer Immunotherapy

Current Oncology ◽

10.3390/curroncol28020105 ◽

2021 ◽

Vol 28 (2) ◽

pp. 1077-1093

Author(s):

Synat Kang ◽

Xuefeng Gao ◽

Li Zhang ◽

Erna Yang ◽

Yonghui Li ◽

...

Keyword(s):

Nk Cells ◽

Cancer Immunotherapy ◽

Nk Cell ◽

Tumor Development ◽

Human Leukocyte ◽

Cell Receptor ◽

Clinical Applications ◽

Therapeutic Approaches ◽

Leukocyte Antigens ◽

Recognition Specificity

Natural killer (NK) cells can be widely applied for cancer immunotherapy due to their ability to lyse tumor targets without prior sensitization or human leukocyte antigens-matching. Several NK-based therapeutic approaches have been attempted in clinical practice, but their efficacy is not sufficient to suppress tumor development mainly because of lacking specificity. To this end, the engineering of NK cells with T cell receptor along with CD3 subunits (TCR-NK) has been developed to increase the reactivity and recognition specificity of NK cells toward tumor cells. Here, we review recent advances in redirecting NK cells for cancer immunotherapy and discuss the major challenges and future explorations for their clinical applications.

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Predictors of virological failure among people living with HIV receiving first line antiretroviral treatment in Myanmar: retrospective cohort analysis

AIDS Research and Therapy ◽

10.1186/s12981-021-00336-0 ◽

2021 ◽

Vol 18 (1) ◽

Author(s):

Anita Mesic ◽

Alexander Spina ◽

Htay Thet Mar ◽

Phone Thit ◽

Tom Decroo ◽

...

Keyword(s):

Viral Load ◽

Virological Failure ◽

Antiretroviral Treatment ◽

People Living With Hiv ◽

First Line ◽

Hiv Viral Load ◽

Loss To Follow Up ◽

History Of ◽

Living With Hiv

Abstract Background Progress toward the global target for 95% virological suppression among those on antiretroviral treatment (ART) is still suboptimal. We describe the viral load (VL) cascade, the incidence of virological failure and associated risk factors among people living with HIV receiving first-line ART in an HIV cohort in Myanmar treated by the Médecins Sans Frontières in collaboration with the Ministry of Health and Sports Myanmar. Methods We conducted a retrospective cohort study, including adult patients with at least one HIV viral load test result and having received of at least 6 months’ standard first-line ART. The incidence rate of virological failure (HIV viral load ≥ 1000 copies/mL) was calculated. Multivariable Cox’s regression was performed to identify risk factors for virological failure. Results We included 25,260 patients with a median age of 33.1 years (interquartile range, IQR 28.0–39.1) and a median observation time of 5.4 years (IQR 3.7–7.9). Virological failure was documented in 3,579 (14.2%) participants, resulting in an overall incidence rate for failure of 2.5 per 100 person-years of follow-up. Among those who had a follow-up viral load result, 1,258 (57.1%) had confirmed virological failure, of which 836 (66.5%) were switched to second-line treatment. An increased hazard for failure was associated with age ≤ 19 years (adjusted hazard ratio, aHR 1.51; 95% confidence intervals, CI 1.20–1.89; p < 0.001), baseline tuberculosis (aHR 1.39; 95% CI 1.14–1.49; p < 0.001), a history of low-level viremia (aHR 1.60; 95% CI 1.42–1.81; p < 0.001), or a history of loss-to-follow-up (aHR 1.24; 95% CI 1.41–1.52; p = 0.041) and being on the same regimen (aHR 1.37; 95% CI 1.07–1.76; p < 0.001). Cumulative appointment delay was not significantly associated with failure after controlling for covariates. Conclusions VL monitoring is an important tool to improve programme outcomes, however limited coverage of VL testing and acting on test results hampers its full potential. In our cohort children and adolescents, PLHIV with history of loss-to-follow-up or those with low-viremia are at the highest risk of virological failure and might require more frequent virological monitoring than is currently recommended.

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Cocaine Use, Oxidative Stress and Inflammation Among People Living with HIV in the MASH Cohort in Miami (P19-002-19)

Current Developments in Nutrition ◽

10.1093/cdn/nzz049.p19-002-19 ◽

2019 ◽

Vol 3 (Supplement_1) ◽

Author(s):

Alhanoof Alohaly ◽

Adriana Campa ◽

Leslie Seminario ◽

Marianna Baum

Keyword(s):

Oxidative Stress ◽

Viral Load ◽

Inflammatory Diseases ◽

Antioxidant Defense System ◽

People Living With Hiv ◽

Oxidized Glutathione ◽

Hiv Viral Load ◽

Cross Sectional ◽

Cocaine Use ◽

Living With Hiv

Abstract Objectives HIV infection and cocaine use contribute to oxidative stress; persistent oxidative stress leads to rapid rates of glutathione (GSH) consumption. GSH is an abundant intracellular antioxidant and is synthesized from its precursor amino acids. HIV promotes changes in the components of the antioxidant defense system, resulting in GSH depletion and may cause DNA damage, and is associated with chronic inflammatory diseases. Therefore, the aim is to assess oxidative stress, and biomarkers of inflammation in HIV-infected individuals from the Miami Adult Studies on HIV (MASH) cohort, on stable antiretroviral therapy (ART), with controlled HIV viral load. Methods A cross-sectional study of participants in the MASH cohort in Miami. Participants were consented and blood was collected for C-reactive protein (CRP), oxidized glutathione and % of reduced to oxidized glutathione (GSH: GSSG). Anthropometrics included body fat measured by the bioimpedance analysis machine. Results Mean age was 54.6 ± 6.3 years, 67% were male, and 50% used cocaine, mean BMI was 26.2 ± 3.1, CRP was 7.1 ± 12.4, oxidized glutathione was 34.4 ± 32.4 mmol, and the ratio of GSH: GSSG 4.86 ± 4.7. All participants had undetected viral load and were mainly overweight (70%) with a mean fat% of 28.0 ± 7.1. Cocaine use was strongly related with CRP (r = 401, P = 0.014) and GSH: GSSG (r = −389, P = 0.017) ; BMI was lower with age (r = −0.502, P = 0.024); and fat contain was lower in males (r = −0.474, P = 0.004); males also had significantly higher oxidized glutathione (r = 0.384, P = 0.018); age was inversely correlated with BMI (r = −0.335, P = 0.027). A nutritional supplementation with antioxidants with a longitudinal follow-up of outcomes is in progress. Conclusions Our findings suggest that cocaine use is significantly associated with markers of inflammations and oxidative stress in people living with HIV who are already at risk for these conditions, and interventions with antioxidants and detoxification interventions are important for these participants. Funding Sources National Institute on Drug Abuse.

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Deciphering the Immunological Phenomenon of Adaptive Natural Killer (NK) Cells and Cytomegalovirus (CMV)

International Journal of Molecular Sciences ◽

10.3390/ijms21228864 ◽

2020 ◽

Vol 21 (22) ◽

pp. 8864

Author(s):

Samantha Barnes ◽

Ophelia Schilizzi ◽

Katherine M. Audsley ◽

Hannah V. Newnes ◽

Bree Foley

Keyword(s):

Nk Cells ◽

Natural Killer ◽

Cell Biology ◽

Nk Cell ◽

Cell Receptor ◽

Vital Role ◽

Immune Memory ◽

Target Cells ◽

Cytokines And Chemokines ◽

Adaptive Immune Cells

Natural killer (NK) cells play a significant and vital role in the first line of defense against infection through their ability to target cells without prior sensitization. They also contribute significantly to the activation and recruitment of both innate and adaptive immune cells through the production of a range of cytokines and chemokines. In the context of cytomegalovirus (CMV) infection, NK cells and CMV have co-evolved side by side to employ several mechanisms to evade one another. However, during this co-evolution the discovery of a subset of long-lived NK cells with enhanced effector potential, increased antibody-dependent responses and the potential to mediate immune memory has revolutionized the field of NK cell biology. The ability of a virus to imprint on the NK cell receptor repertoire resulting in the expansion of diverse, highly functional NK cells to this day remains a significant immunological phenomenon that only occurs in the context of CMV. Here we review our current understanding of the development of these NK cells, commonly referred to as adaptive NK cells and their current role in transplantation, infection, vaccination and cancer immunotherapy to decipher the complex role of CMV in dictating NK cell functional fate.

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Daily and near-daily cannabis use is associated with HIV viral load suppression in people living with HIV who use cocaine

AIDS Care ◽

10.1080/09540121.2020.1799922 ◽

2020 ◽

pp. 1-8

Author(s):

Deepika E. Slawek ◽

Julia Arnsten ◽

Nancy Sohler ◽

Chenshu Zhang ◽

Robert Grossberg ◽

...

Keyword(s):

Viral Load ◽

Cannabis Use ◽

People Living With Hiv ◽

Viral Load Suppression ◽

Hiv Viral Load ◽

Living With Hiv

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Effect of interleukins (IL-2, IL-15, IL-18) on receptors activation and cytotoxic activity of natural killer cells in breast cancer cell

African Health Sciences ◽

10.4314/ahs.v20i2.36 ◽

2020 ◽

Vol 20 (2) ◽

pp. 822-832 ◽

Cited By ~ 2

Author(s):

Wahyu Widowati ◽

Diana K Jasaputra ◽

Sutiman B Sumitro ◽

Mochammad A Widodo ◽

Tjandrawati Mozef ◽

...

Keyword(s):

Breast Cancer ◽

Cytotoxic Activity ◽

Nk Cells ◽

Natural Killer ◽

Nk Cell ◽

Cell Receptor ◽

Mcf7 Cells ◽

Activating Receptors ◽

Tnf Α ◽

Ifn Γ

Introduction: Breast cancer is one of the leading cause of cancer deaths in women. Metastasis in BC is caused by immuno- surveillance deficiency, such NK cell maturation, low NK activity and decreasing cytotoxicity. This study was performed to improve activating receptors and cytotoxicity of NK cells using interleukins (ILs). Methods: Human recombinant IL-2, -15, and -18 were used to induce NK cells. We measured the activating and inhibiting receptors, proliferation activity of NK cells, and the cytotoxicity of NK cells on BC cells (MCF7). The effects of ILs were tested on the NK cell receptors CD314, CD158a and CD107a with flowcytometry, proliferation at various incubation times with 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxy methoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay and concen- trations of TNF-α and IFN-γ by NK cells with ELISA. Results: ILs increased NK cell receptor levels (CD314, CD158a, and CD107a) at 24 hours of incubation. ILs increased NK cell viability, which increased with longer incubation. Moreover, ILs-induced NK cells inhibited proliferation in MCF7 cells, as well as increased TNF-α, IFN-γ, PRF1 and GzmB secretion. Conclusion: IL-2, IL-15, and IL-18 improved activating receptors and proliferation of NK cells. IL-induced NK cells in- creased TNF-α, IFN-γ, PRF1 and GzmB secretion and cytotoxic activity on BC cells. High NK cell numbers increased BC cell growth inhibition. Keywords: Activator; breast cancer; interleukins; natural killer; receptor.

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Ly49P recognition of cytomegalovirus-infected cells expressing H2-Dk and CMV-encoded m04 correlates with the NK cell antiviral response

Journal of Experimental Medicine ◽

10.1084/jem.20080954 ◽

2009 ◽

Vol 206 (3) ◽

pp. 515-523 ◽

Cited By ~ 94

Author(s):

Agnieszka Kielczewska ◽

Michal Pyzik ◽

Tianhe Sun ◽

Astrid Krmpotic ◽

Melissa B. Lodoen ◽

...

Keyword(s):

Nk Cells ◽

Deletion Mutant ◽

Viral Infections ◽

Nk Cell ◽

Cell Receptor ◽

Major Histocompatability Complex ◽

Wild Type ◽

Mcmv Infection ◽

Host Protection ◽

Infected Cells

Natural killer (NK) cells are crucial in resistance to certain viral infections, but the mechanisms used to recognize infected cells remain largely unknown. Here, we show that the activating Ly49P receptor recognizes cells infected with mouse cytomegalovirus (MCMV) by a process that requires the presence of H2-Dk and the MCMV m04 protein. Using H2 chimeras between H2-Db and -Dk, we demonstrate that the H2-Dk peptide-binding platform is required for Ly49P recognition. We identified m04 as a viral component necessary for recognition using a panel of MCMV-deletion mutant viruses and complementation of m04-deletion mutant (Δm04) virus infection. MA/My mice, which express Ly49P and H2-Dk, are resistant to MCMV; however, infection with Δm04 MCMV abrogates resistance. Depletion of NK cells in MA/My mice abrogates their resistance to wild-type MCMV infection, but does not significantly affect viral titers in mice infected with Δm04 virus, implicating NK cells in host protection through m04-dependent recognition. These findings reveal a novel mechanism of major histocompatability complex class I–restricted recognition of virally infected cells by an activating NK cell receptor.

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Dual function for the adaptor MIST in IFN-γ production by NK and CD4+NKT cells regulated by the Src kinase Fgr

Blood ◽

10.1182/blood-2005-10-4102 ◽

2006 ◽

Vol 107 (9) ◽

pp. 3647-3655 ◽

Cited By ~ 11

Author(s):

Hiroki Sasanuma ◽

Akiko Tatsuno ◽

Shinya Hidano ◽

Keiko Ohshima ◽

Yumi Matsuzaki ◽

...

Keyword(s):

Nk Cells ◽

Nk Cell ◽

Adaptor Protein ◽

Adaptor Proteins ◽

Cell Receptor ◽

Nkt Cells ◽

Cell Populations ◽

Dual Function ◽

Ifn Γ ◽

Nk Cell Receptor

Natural killer (NK) cells and NKT cells play critical early roles in host defense. Here we show that MIST, an adaptor protein belonging to the SLP-76 family, functions negatively in NK cells but positively in CD4+NKT cells. NK-cell receptor-mediated IFN-γ production was enhanced in NK cells, whereas TCR- or NK-cell receptor-mediated cytokine production was reduced in CD4+NKT cells from MIST-deficient mice. These opposite effects of MIST paralleled the exclusive expression of the Src family kinase, Fgr, in NK cells between the 2 cell populations. We further demonstrated that interaction of MIST with Fgr, mediated by the C-terminal proline-rich region of MIST and the SH3 domain of Fgr, was required for the suppression of NK-cell receptor-induced IFN-γ production. This functional interdependence of signaling molecules demonstrates a new mechanism by which adaptor proteins can act as molecular switches to control diverse responses in different cell populations.

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