Expansion of CD56− NK cells in chronic HCV/HIV-1 co-infection: Reversion by antiviral treatment with pegylated IFNα and ribavirin

The review discusses the genetic polymorphisms involved in the pathogenesis of hepatitis C virus (HCV) infection, that may determine the outcome of disease. In this field earlier both certain major histocompatibility complex (MHC) alleles and some cytokine gene variants have also been studied. Recently, the genome-wide association study (GWAS) and targeted single nucleotide polymorphism (SNP) analysis have revealed that a variant in the promoter region of interleukin-28B (IL-28B) gene is strongly linked to viral clearance and it may be the strongest pretreatment predictor of treatment response in chronic hepatitis C. Last year it was shown that two genetic variants leading to inosine triphosphatase deficiency protect against haemolytic anemia in patients receiving ribavirin during antiviral treatment for chronic HCV infection. Orv. Hetil., 2011, 152, 876–881.

Download Full-text

Interferon Alpha Enhances NK Cell Function and the Suppressive Capacity of HIV-Specific CD8+T Cells

Journal of Virology ◽

10.1128/jvi.01541-18 ◽

2018 ◽

Vol 93 (3) ◽

Cited By ~ 7

Author(s):

Abena K. R. Kwaa ◽

Chloe A. G. Talana ◽

Joel N. Blankson

Keyword(s):

T Cells ◽

T Cell ◽

Nk Cells ◽

Effector Cell ◽

Cell Function ◽

Nk Cell ◽

Suppressive Capacity ◽

Short Course ◽

Shock And Kill ◽

Hiv 1

ABSTRACTCurrent shock-and-kill strategies for the eradication of the HIV-1 reservoir have resulted in blips of viremia but not in a decrease in the size of the latent reservoir in patients on suppressive antiretroviral therapy (ART). This discrepancy could potentially be explained by an inability of the immune system to kill HIV-1-infected cells following the reversal of latency. Furthermore, some studies have suggested that certain latency-reversing agents (LRAs) may inhibit CD8+T cell and natural killer (NK) cell responses. In this study, we tested the hypothesis that alpha interferon (IFN-α) could improve the function of NK cells from chronic progressors (CP) on ART. We show here that IFN-α treatment enhanced cytokine secretion, polyfunctionality, degranulation, and the cytotoxic potential of NK cells from healthy donors (HD) and CP. We also show that this cytokine enhanced the viral suppressive capacity of NK cells from HD and elite controllers or suppressors. Furthermore, IFN-α enhanced global CP CD8+T cell cytokine responses and the suppressive capacity of ES CD8+T cells. Our data suggest that IFN-α treatment may potentially be used as an immunomodulatory agent in HIV-1 cure strategies.IMPORTANCEData suggest that HIV+individuals unable to control infection fail to do so due to impaired cytokine production and/cytotoxic effector cell function. Consequently, the success of cure agendas such as the shock-and-kill strategy will probably depend on enhancing patient effector cell function. In this regard, NK cells are of particular interest since they complement the function of CD8+T cells. Here, we demonstrate the ability of short-course alpha interferon (IFN-α) treatments to effectively enhance such effector functions in chronic progressor NK cells without inhibiting their general CD8+T cell function. These results point to the possibility of exploring such short-course IFN-α treatments for the enhancement of effector cell function in HIV+patients in future cure strategies.

Download Full-text

Anti-TAR Polyamide Nucleotide Analog Conjugated with a Membrane-Permeating Peptide Inhibits Human Immunodeficiency Virus Type 1 Production

Journal of Virology ◽

10.1128/jvi.76.8.3881-3891.2002 ◽

2002 ◽

Vol 76 (8) ◽

pp. 3881-3891 ◽

Cited By ~ 37

Author(s):

Neerja Kaushik ◽

Amartya Basu ◽

Paul Palumbo ◽

Rene L. Myers ◽

Virendra N. Pandey

Keyword(s):

Human Immunodeficiency Virus ◽

Antiviral Treatment ◽

Significant Inhibition ◽

Luciferase Reporter ◽

Luciferase Reporter Gene ◽

Nucleotide Analog ◽

Immunodeficiency Virus ◽

Hiv 1

ABSTRACT The emergence of drug-resistant variants has posed a significant setback against effective antiviral treatment for human immunodeficiency virus (HIV) infections. The choice of a nonmutable region of the viral genome such as the conserved transactivation response element (TAR element) in the 5′ long terminal repeat (LTR) may potentially be an effective target for drug development. We have earlier demonstrated that a polyamide nucleotide analog (PNA) targeted to the TAR hairpin element, when transfected into cells, can effectively inhibit Tat-mediated transactivation of HIV type 1 (HIV-1) LTR (T. Mayhood et al., Biochemistry 39:11532-11539, 2000). Here we show that this anti-TAR PNA (PNATAR), upon conjugation with a membrane-permeating peptide vector (transportan) retained its affinity for TAR in vitro similar to the unconjugated analog. The conjugate was efficiently internalized into the cells when added to the culture medium. Examination of the functional efficacy of the PNATAR-transportan conjugate in cell culture using luciferase reporter gene constructs resulted in a significant inhibition of Tat-mediated transactivation of HIV-1 LTR. Furthermore, PNATAR-transportan conjugate substantially inhibited HIV-1 production in chronically HIV-1-infected H9 cells. The mechanism of this inhibition appeared to be regulated at the level of transcription. These results demonstrate the efficacy of PNATAR-transportan as a potential anti-HIV agent.

Download Full-text

NK cells control HIV‐1 infection of macrophages through soluble factors and cellular contacts in the human decidua

Retrovirology ◽

10.1186/s12977-016-0271-z ◽

2016 ◽

Vol 13 (1) ◽

Cited By ~ 16

Author(s):

H. Quillay ◽

H. El Costa ◽

M. Duriez ◽

R. Marlin ◽

C. Cannou ◽

...

Keyword(s):

Nk Cells ◽

Soluble Factors ◽

Human Decidua ◽

Hiv 1

Download Full-text

The Characteristics of Natural Killer Cells in Chronic Hepatitis B Patients Who Received PEGylated-Interferon versus Entecavir Therapy

BioMed Research International ◽

10.1155/2021/2178143 ◽

2021 ◽

Vol 2021 ◽

pp. 1-14

Author(s):

Weihua Cao ◽

Minghui Li ◽

Lu Zhang ◽

Yao Lu ◽

Shuling Wu ◽

...

Keyword(s):

Chronic Hepatitis ◽

Hepatitis B ◽

Nk Cells ◽

Natural Killer ◽

Chronic Hepatitis B ◽

Nk Cell ◽

Antiviral Treatment ◽

Pegylated Interferon ◽

Cell Frequency ◽

Subgroup Analyses

Background. To explore the role of natural killer (NK) cells in the process of hepatitis B virus (HBV) clearance and whether their phenotype is related to antiviral treatment outcome in chronic hepatitis B (CHB) patients. Method. We performed a single-center prospective cohort study to analyze changes of NK cells at weeks 12 and 24 from baseline in CHB patients who received PEGylated-interferon- (PEG-IFN-) α-2a versus entecavir. The frequencies of NK, CD56bright, CD56dim, IFNAR2+, NKp46+, NKp46bright, and NKp46dim NK cells and mean fluorescence intensity (MFI) of receptors NKp46 and IFNAR2 on the surface of NK cells were measured. Subgroup analyses were performed by comparing treatment responders versus nonresponders with aforementioned parameters in each group. Results. In PEG-IFN-α-treated patients, posttreatment CD56bright NK cell frequency increased, but CD56dim NK cell frequency decreased. Additionally, receptor NKp46 and IFNAR2 expression enhanced. In entecavir-treated patients, although NK cell frequency increased, CD56bright and CD56dim NK cell frequencies and IFNAR2 expression did not differ between baseline and posttreatment. In subgroup analyses, posttreatment CD56bright NK cell frequency and IFNAR2 expression significantly increased in PEG-IFN-α responders from baseline, while changes were absent in PEG-IFN-α nonresponders and entecavir treatment responders. Among patients with HBV viremia after entecavir therapy, NK cell frequency significantly increased, whereas NKp46bright and IFNAR2+ NK frequency and IFNAR2 MFI significantly decreased at 12 and 24 weeks from baseline. Conclusions. In CHB patients, PEG-IFN-α treatment significantly enhanced NK cell frequency and function when compared to entacavir. Positive treatment responses to either interferon or entecavir were associated with NK cell function improvement. This trial is registered with clinical trial registration no. NCT03208998.

Download Full-text

HIV-1-induced cytokines deplete homeostatic ILCs and expand TCF7-dependent memory NK cells: Supplemental Figures and Tables

10.1101/221010 ◽

2017 ◽

Cited By ~ 1

Author(s):

Yetao Wang ◽

Kyle Gellatly ◽

Sean McCauley ◽

Pranitha Vangala ◽

Kyusik Kim ◽

...

Keyword(s):

Nk Cells ◽

Inflammatory Cytokines ◽

Nk Cell ◽

Ex Vivo ◽

Developmental Trajectory ◽

Lymphoid Cells ◽

Infected People ◽

Cell Induction ◽

Hiv 1 ◽

Memory Nk Cells

HIV-1-infected people who take medications that suppress viremia, preserve CD4+ T cells, and prevent AIDS, have chronic inflammation with increased cardiovascular mortality. To investigate the etiology of this inflammation, the effect of HIV-1 on innate lymphoid cells (ILCs) and NK cells was examined. Homeostatic ILCs in blood and intestine were depleted permanently. NK cells were skewed towards a memory subset. Cytokines that are elevated during HIV-1 infection reproduced both abnormalities ex vivo. Pseudotime analysis of single NK cell transcriptomes revealed a developmental trajectory towards a subset with expression profile, chromatin state, and biological function like memory T lymphocytes. Expression of TCF7, a WNT transcription factor, increased over the course of the trajectory. TCF7 disruption, or WNT inhibition, prevented memory NK cell induction by inflammatory cytokines. These results demonstrate that inflammatory cytokines associated with HIV-1 infection irreversibly disrupt homeostatic ILCs and cause developmental shift towards TCF7+ memory NK cells.

Download Full-text

Diversity and function of maternal HIV-1-specific antibodies at the time of vertical transmission

10.1101/776856 ◽

2019 ◽

Author(s):

Laura E. Doepker ◽

Cassandra A. Simonich ◽

Duncan Ralph ◽

Theodore Gobillot ◽

Meghan Garrett ◽

...

Keyword(s):

Vertical Transmission ◽

Single Mother ◽

Antiviral Treatment ◽

Maternal Antibodies ◽

Cell Repertoire ◽

Human Infants ◽

Low Frequencies ◽

Specific Antibodies ◽

Transmitted Virus ◽

Hiv 1

AbstractInfants of HIV positive mothers can acquire HIV infection by various routes, but even in the absence of antiviral treatment, the majority of these infants do not become infected. There is evidence that maternal antibodies may provide some protection from infection, but gestational maternal antibodies have not yet been characterized in detail. One of the most studied vertically-infected infants is BG505, as the virus from this infant yielded an Envelope protein that was successfully developed as a stable trimer. Here, we isolated and characterized 39 HIV-specific neutralizing monoclonal antibodies (nAbs) from MG505, the mother of BG505, at a time point just prior to vertical transmission. These nAbs belonged to 21 clonal families, employed a variety of VH genes, many were specific for the HIV-1 Env V3 loop, and this V3 specificity correlated with measurable antibody-dependent cellular cytotoxicity (ADCC) activity. The isolated nAbs did not recapitulate the full breadth of heterologous nor autologous virus neutralization by contemporaneous plasma. Notably, we found that the V3-targeting nAb families neutralized one particular maternal Env variant even though all tested variants had low V3 sequence diversity and were measurably bound by these nAbs. None of the nAbs neutralized the BG505 transmitted virus. Furthermore, the MG505 nAb families were found at relatively low frequencies within the maternal B cell repertoire: all less than 0.25% of total IgG sequences. Our findings demonstrate the diversity of HIV-1 nAbs that exist within a single mother, resulting in a collection of antibody specificities that can shape the transmission bottleneck.ImportanceMother-to-child-transmission of HIV-1 offers a unique setting in which maternal antibodies both within the mother and passively-transferred to the infant are present at the time of viral exposure. Untreated HIV-exposed human infants are infected at a rate of 30-40%, meaning that some infants do not get infected despite continued exposure to virus. Since the potential of HIV-specific immune responses to provide protection against HIV is a central goal of HIV vaccine design, understanding the nature of maternal antibodies may provide insights into immune mechanisms of protection. In this study, we isolated and characterized HIV-specific antibodies from the mother of an infant whose transmitted virus has been well studied.

Download Full-text

French hepatitis C care cascade: substantial impact of direct-acting antivirals, but the road to elimination is still long

BMC Infectious Diseases ◽

10.1186/s12879-020-05478-6 ◽

2020 ◽

Vol 20 (1) ◽

Author(s):

Cécile Brouard ◽

Josiane Pillonel ◽

Marjorie Boussac ◽

Victor de Lédinghen ◽

Antoine Rachas ◽

...

Keyword(s):

Hepatitis C ◽

Antiviral Treatment ◽

Hcv Infection ◽

World Health ◽

Direct Acting Antivirals ◽

Substantial Impact ◽

Chronic Hcv Infection ◽

Chronic Hcv ◽

Direct Acting ◽

The Impact

Abstract Background Hepatitis C virus (HCV) elimination by 2030, as targeted by the World Health Organization (WHO), requires that 90% of people with chronic infection be diagnosed and 80% treated. We estimated the cascade of care (CoC) for chronic HCV infection in mainland France in 2011 and 2016, before and after the introduction of direct-acting antivirals (DAAs). Methods The numbers of people (1) with chronic HCV infection, (2) aware of their infection, (3) receiving care for HCV and (4) on antiviral treatment, were estimated for 2011 and 2016. Estimates for 1) and 2) were based on modelling studies for 2011 and on a virological sub-study nested in a national cross-sectional survey among the general population for 2016. Estimates for 3) and 4) were made using the National Health Data System. Results Between 2011 and 2016, the number of people with chronic HCV infection decreased by 31%, from 192,700 (95% Credibility interval: 150,900-246,100) to 133,500 (95% Confidence interval: 56,900-312,600). The proportion of people aware of their infection rose from 57.7 to 80.6%. The number of people receiving care for HCV increased by 22.5% (representing 25.7% of those infected in 2016), while the number of people on treatment increased by 24.6% (representing 12.1% of those infected in 2016). Conclusions This study suggests that DAAs substantially impact CoC. However, access to care and treatment for infected people remained insufficient in 2016. Updating CoC estimates will help to assess the impact of new measures implemented since 2016 as part of the goal to eliminate HCV.

Download Full-text

Potential of the NKG2D/NKG2DL Axis in NK Cell-Mediated Clearance of the HIV-1 Reservoir

International Journal of Molecular Sciences ◽

10.3390/ijms20184490 ◽

2019 ◽

Vol 20 (18) ◽

pp. 4490 ◽

Cited By ~ 2

Author(s):

Maria G. Desimio ◽

Daniela A. Covino ◽

Margherita Doria

Keyword(s):

T Cells ◽

Nk Cells ◽

Nk Cell ◽

Ex Vivo ◽

Virus Reactivation ◽

Major Drawback ◽

Virus Eradication ◽

Latent Hiv ◽

Hiv 1

Viral persistency in latently infected CD4+ T cells despite antiretroviral therapy (ART) represents a major drawback in the fight against HIV-1. Efforts to purge latent HIV-1 have been attempted using latency reversing agents (LRAs) that activate expression of the quiescent virus. However, initial trials have shown that immune responses of ART-treated patients are ineffective at clearing LRA-reactivated HIV-1 reservoirs, suggesting that an adjuvant immunotherapy is needed. Here we overview multiple lines of evidence indicating that natural killer (NK) cells have the potential to induce anti-HIV-1 responses relevant for virus eradication. In particular, we focus on the role of the NKG2D activating receptor that crucially enables NK cell-mediated killing of HIV-1-infected cells. We describe recent data indicating that LRAs can synergize with HIV-1 at upregulating ligands for NKG2D (NKG2DLs), hence sensitizing T cells that exit from viral latency for recognition and lysis by NK cells; in addition, we report in vivo and ex vivo data showing the potential benefits and drawbacks that LRAs may have on NKG2D expression and, more in general, on the cytotoxicity of NK cells. Finally, we discuss how the NKG2D/NKG2DLs axis can be exploited for the development of effective HIV-1 eradication strategies combining LRA-induced virus reactivation with recently optimized NK cell-based immunotherapies.

Download Full-text