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Human Immunology

journal homepage:www.elsevier.com/locate/humimm

Interleukin 28B rs12979860 genotype and Human Immunode fi ciency Virus type 1: Susceptibility, AIDS development and therapeutic outcome

Imane Zaidanea,b, Lahcen Wakrimc, Ahd Oulad Lahsend, Rajaa Bensghird, Hajar Chihaba, Fatima Zahra Jadida, Raouia Elfihrya, Hassan Lamdinid, Naouar Faysselc,

Kamal Marhoum El Filalid, Mounia Oudghirib, Soumaya Benjellouna,⁎,1, Sayeh Ezzikouria,⁎,1

aVirology Unit, Viral Hepatitis Laboratory, Institut Pasteur du Maroc, Casablanca, Morocco

bVirology Unit, Immunovirology Laboratory, Institut Pasteur du Maroc, Casablanca, Morocco

cLaboratoire Immunologie et Biodiversité, département de Biologie, Faculté des Sciences Ain Chock, University Hassan II of Casablanca, Casablanca, Morocco

dService des maladies Infectieuses, CHU Ibn Rochd, Casablanca, Morocco

A R T I C L E I N F O

Keywords:

Interferon-λ3 AIDS HAART CD4+ T

A B S T R A C T

Human Immunodeciency Virus type 1 (HIV-1) infection and progression varies widely among individuals.

Interferon-λ3 exerts anti-HIV function by activating JAK/STAT pathway-mediated innate immunity. Therefore, we aimed to investigate the association between single nucleotide polymorphisms of the interleukin 28B (IL28B) gene, and the risk of acquisition, AIDS development and therapeutic outcome of HIV-1 in a Moroccan popula- tion.

A total of 266 HIV-1 seropositive and 158 HIV-1 seronegative subjects were enrolled. Genotyping of rs12979860 of the IL28B was performed using a predesigned TaqMan SNP genotyping assay. No signicant association was found betweenIL28Brs12979860 polymorphism and susceptibility to HIV-1 infection and AIDS development (p > .05). However, in HIV-1 treated patients carrying CC genotype had a more pronounced high levels of CD4+T-cell compared to subjects with TT genotype (p = .0004).

Interestingly, regarding HIV-1 viral load no signicant dierences betweenIL28Bgenotypes in treated and untreated patients were observed (p < .05).

IL28B rs12979860 polymorphism not inuences the susceptibility to HIV-1 and the AIDS development.

However, this polymorphism may aect the response to treatment as measured by CD4+ T cell counts.

1. Introduction

Infection with Human Immunodeficiency Virus type 1 (HIV-1) has become one of the most important causes of morbidity and mortality in the world. According to the recent UNAIDS report, 36.9 million people were living with HIV. In Morocco, 30,000 Moroccans were living with HIV/AIDS [1]. The host pathogen interaction is strikingly complex during HIV infection, severity of disease after infection is variable[2,3].

The natural history and pathogeneses of the HIV-1 infection are vari- able. This natural variation can be attributed to host genetics, pathogen and environmental factors and their interactions and varies greatly among infected individuals. Variations in genes involved in innate immunity may also contribute to the differential susceptibility of hu- mans to HIV-1 infection and the highly variable outcome of the disease

[4,5]. With the exception ofCCR5Δ32homozygosity, which explains a proportion of HIV-1 resistance in Europeans, no reproducible associa- tions of host gene polymorphisms with increased or reduced HIV-1 acquisition have been observed[6]. Moreover, previous data showed that patients carrying the HLA-B35 allele progress to the AIDS stage faster than the others. Likewise patients with HLA-B57 and B27 alleles have a delayed progression of the disease[7]. In addition, the HLA- B57:01 is associated with severe hypersensitivity to Abacavir [8].

Furthermore, previous GWAS investigated the host factors involved in HIV-1 acquisition in 6334 individuals of European ancestry and they found a signicant association linked to the HLA-B57:01 and B27:05 alleles (p = 3.6 × 10−11)[9]. However, these variants have not been identified in recent GWAS[9,10]. Interestingly, recent meta-analyses of published GWAS have replicated the eect ofCCR5Δ32 on reducing

http://dx.doi.org/10.1016/j.humimm.2017.10.011

Received 13 March 2017; Received in revised form 31 August 2017; Accepted 24 October 2017

Corresponding authors at: Virology Unit, Viral Hepatitis Laboratory, Institut Pasteur du Maroc 1, Place Louis Pasteur, 20360 Casablanca, Morocco.

1These authors contributed equally to the study.

E-mail addresses:soumaya.benjelloun@pasteur.ma(S. Benjelloun),sayeh.ezzikouri@pasteur.ma(S. Ezzikouri).

Abbreviations:HIV-1, Human Immunodeficiency Virus type 1; ISGF3, interferon-stimulated gene factor 3;IL28B, interleukin 28B gene; AIDS, acquired immune deficiency syndrome;

HAART, highly active antiretroviral therapy

0198-8859/ © 2017 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.

Please cite this article as: Zaidane, I., Human Immunology (2017), http://dx.doi.org/10.1016/j.humimm.2017.10.011

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HIV acquisition and slowing disease progression, and the effect ofC- CR5P1on increasing HIV viremia[11,12].

Recently, in vitro studies reported that IFN-λ3 exerts anti-HIV function by activating JAK/STAT pathway-mediated innate immunity resulting in the phosphorylation of STAT proteins and forming of in- terferon-stimulated gene factor 3 (ISGF3) complex in macrophages [13–16]. The formed ISGF3 complex binds to the IFN-stimulated re- sponse element and induces ISGs that play important roles in IFN- mediated antiviral activity[13]. The interleukin 28B gene (IL28B) lo- cated on chromosome 19q13, encodes a newly identied cytokine in- terferon lambda 3 (IFN-λ3) with antiviral activity, IFN-λ3 can induce antiviral factors to suppress the replication of broad spectrum of viruses [1720]. The SNP, rs12979860, showed the strongest association with hepatitis C virus (HCV) treatment outcomes and HCV spontaneous re- solution[21–27]. Moreover, a previous association study found that the IL28B CC genotype was independently associated with spontaneous HIV control in white subjects[28]. Whereas, the rs12979869 CC gen- otype was not associated with the HIV control in African Americans individuals[29]. This situation emphasizes the importance to replicate similar studies in other populations. Therefore, we investigated the possible association between theIL28Bpolymorphism rs12979860 and HIV-1 susceptibility, AIDS development and treatment response in HIV infection in a Moroccan population in order tond best markers of HIV- 1 disease.

2. Materials and methods 2.1. Study population

After giving written informed consent for genetic testing, every participant was interviewed and completed a structured questionnaire on sociodemographic parameters, and clinical data (Disease diagnosis, antiretroviral treatment, laboratory values, alcohol consumption and drug use history demographic and clinical) were recorded. From September 2006 to June 2016, 222 HIV-1 seropositive subjects, con- rmed infection by both western blot and plasma HIV-1 loads, were enrolled in a follow-up investigation by the Service of Infectious Diseases, Ibn Rochd Hospital Center, Casablanca, Morocco. Next, the HIV individuals were stratied to subjects who progressed to AIDS according to the CDC classification, i.e. patients who had opportunistic infections, and CD4+counts < 200 cells/mm3, and a non-AIDS group.

Moreover, 206 patients had been treated as showed in the Table 1.

Furthermore, one hundred-fifty eight unrelated healthy controls of mixed berberic and Arabic ethnicity, who were negative for HIV and viral hepatitis markers were recruited at Pasteur Institute of Morocco.

Serological markers for HBsAg, anti-HCV and anti-HIV were tested with commercially available kits (Axsym, Abbott Diagnostics, Wiesbaden- Delkenheim, Germany and Genscreen Ag/Ab HIV Ultra, Biorad, Marnes La Coquette, France). Giving that IL28B polymorphism is highly related to the HCV infection, we excluded patient’s positives for anti-HCV marker. The study protocol was evaluated and approved by the ethics Committee of the Faculty of Medicine of Casablanca and the study was conducted in accordance with the ethical guidelines of the 1975 De- claration of Helsinki as reflected in a priori approval by the institution's human research committee. CD4+T-cell counts were obtained byow cytometry on a three-color FACS Callibur flow cytometer (Becton Dickinson Immunocytometer System), and plasma viral loads were performed routinely for study participants. Automated extraction, am- plification, and quantification were performed with the Cobas Ampli- prep/Cobas TaqMan 48 analyzer system version 2.0 (Roche Diag- nostics, Ltd., Rotkr uez, Switzerland) following the Roche manufacturer's standard guidelines.

2.2. DNA isolation and IL28B rs12979860 polymorphism genotyping Total DNA isolation from peripheral blood leukocyte was performed

using the phenol–chloroform method. Genomic DNA concentration was assessed using a NanoVue plus spectrophotometer (GE Healthcare, US).

The rs12979860 polymorphism was genotyped using a predesigned TaqMan SNP genotyping assay (Applied Biosystems; assay ID C_7820464_10).

2.3. Statistical analysis

Departures from HardyWeinberg equilibrium were determined by comparing the observed genotype frequencies with expected genotype frequencies calculated using observed allele frequencies by aχ2test.

One-way analysis of variance (ANOVA) was conducted to compare two means. Differences inIL28Ballele frequencies between cases and con- trols were determined using a chi-square test. The associations between the rs12979860 polymorphism and susceptibility to HIV-1 infection and AIDS development were estimated by computing the ORs, and their 95% CIs using multivariate logistic regression analyses with adjustment for age, gender, CD4 and viral load. Dierences between continuous variables (CD4+T-cell counts and HIV-1 RNA viral load) were analyzed using the Mann-Whitney U test. Chi-square test was used to assess the signicance of the associations for categorical variables. All statistical analyses were performed using GraphPad PRISM version 6.0e (GraphPad Software, San Diego, CA, USA). A P-value of < .05 was considered statistically significant. All tests were two-sided.

3. Results

The characteristics of the subjects are described inTable 1. A total of 222 HIV-1-infected patients and 158 uninfected Moroccan were en- rolled and analyzed in this study.

3.1. Association of IL28B rs12979860 polymorphism and HIV-1 susceptibility and AIDS development

The distribution ofIL28Bgenotypes was in Hardy–Weinberg equi- librium in individuals infected with HIV-1 and the seronegative control group (p = .515 and p = .581, respectively).

To examine the impact of theIL28Brs12979860 polymorphism on HIV-1 susceptibility in a Moroccan population, we genotyped the polymorphism in subjects infected with HIV-1 and seronegative groups.

Overall, no significant difference was observed regarding allelic and genotypic distributions (P > .05) (Table 1).

The genotype frequencies ofIL28Bvariants in AIDS and non-AIDS groups are presented inTable 2. Genotype and allelic frequency dis- tributions showed no significant association (P > .05).

3.2. Association of IL28B rs12979860 polymorphism and CD4+T-cell counts

To investigate the association between CD4+T cell levels andIL28B variation, two hundred six individuals with baseline data of CD4+T- cells were analyzed. In untreated patients, as shown inFig. 1A, we found no association betweenIL28Bgenotypes and CD4+T-cell counts (p = .075). Moreover, when we compared patients with CC genotype to patients with CT genotype, no signicant dierence was observed (p = .076). In contrast, the median of CD4+T-cell counts was higher in CC group than TT subjects (241vs.103 cells/mm3) (p = .014) (Fig. 1A).

During the follow-up and after highly active antiretroviral therapy (HAART), the CD4+ T-cells levels showed significant difference be- tweenIL28B genotypes (p = .003) (Fig. 1B). Furthermore, in treated patients the median of CD4+T-cell levels was higher in CC group than TT subjects (596.6vs.299.55 cells/mm3, respectively) (p = .0004) and the significance was more pronounced than in untreated group (Fig. 1).

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3.3. Association of IL28B rs12979860 polymorphism and HIV-1 RNA viral loads

We also analyzed the HIV-RNA viral loads in HIV-1 seropositive individuals in the context of their respectiveIL28Bgenotypes. We have found, in untreated subjects, no association betweenIL28Bgenotypes and HIV-1 RNA viral load (p = .425) (Fig. 2A). In addition, no sig- nicant dierence was observed betweenIL28Bgenotypes and HIV-1 RNA viral load after HAART (p > .05) (Fig. 2B).

4. Discussion

HIV/AIDS remains one of the most signicant and challenging in- fectious diseases worldwide despite effectiveness of antiretroviral therapy[30]. The susceptibility to HIV-1 infection, disease progression, and the ecacy of HAART are highly variable between individuals [31,32]. Host genetic variation is an important determinant of HIV-1 acquisition and disease progression[33]. Moreover, variations in the immune system pathways have been demonstrated to account for at least part of these differences[6,31]. A previous study showed that IFN-

λ3 appeared to be more potent in inhibiting HIV replication in mac- rophages than IFN-λ1 or IFN-λ2 through the activation of TLR3 and JAK/STAT pathways[13]. In our previous study, we showed that the IL28B SNP rs12979860 was associated with spontaneous HCV clearance [27]. In the current report, no statistically signicant dierence in IL28Bgenotype distribution between the HIV-positive and HIV-nega- tive cohorts was observed. In addition, there was no correlation be- tween CC genotype or allele frequency and AIDS development. This data seem to be in line with previous reports[17,29,33–35]. In contrast, a previous study demonstrated that the IL28B CC genotype was in- dependently associated with spontaneous HIV control in white in- dividuals [28]. There was considerable ethnic variation in the dis- tribution of this polymorphism. Thus, differences between studies might be due either to variations of genetic background that may modify the impact of rs12979860 polymorphism on HIV-1 control.

In clinical practice, plasma HIV RNA levels and T CD4+cell counts are used to monitor the ecacy of therapy. The current study showed that in untreated patients, no association was found between IL28B variant and CD4+or viral load data. This result is in agreement with a previous study[17]. However, we found for thefirst time, improvement Table 1

Demographic and clinical characteristics of the study subjects.

HIV seropostive subjects (N = 222) Healthy controls (N = 158) OR (95%CI) P-value

Median age [Range], years 38 [17–85] 55 [14–85] < .0001*

Gender (Male/Female) 111/111 75/83

Baseline median CD4+ T-cell count [Range], (cells/mm3) 212.5 [5–1565.1] Baseline median viral load [Range], (log10copies/mL) 4.38 [1.38–6.74]

Median antiretroviral treatment [Range], months 41 [2–168]

Combivir + Efavirenz (%) 91 (44.17)

Efavirenz + Epivir + Stavudin (%) 17 (8.25)

Combivir + Indinavir + Ritonavir (%) 15 (7.28)

Epivir + Retrovir + Efavirenz (%) 14 (6.80)

Efavirenz + Truvada (%) 13 (6.31)

Retrovir + Efavirenz + Videx (%) 11 (5.34)

Indinavir + Epivir + Norvir + Retrovir (%) 9 (4.37)

Combivir + Nevirapin (%) 8 (3.88)

Other therapies (%) 28 (13.59)

Genotypes (%)

CC 115 (51.80) 76 (48.10) 1.00 (reference)

CT 87 (39.19) 65 (41.14) 0.88 (0.57–1.36) .578

TT 20 (9.01) 17 (10.76) 0.78 (0.38–1.58) .485

Recessive model (%) 20 (9) 17 (9.19) 0.82 (0.41–1.62) .570

Dominant model (%) 107 (48.20) 82 (51.90) 0.86 (0.57–1.30) .477

Alleles frequencies ± SD

C 0.71 ± 0.02 0.69 ± 0.03 1.00 (reference)

T 0.29 ± 0.02 0.31 ± 0.03 0.88 (0.64–1.20) .418

OR: Odd ratio, CI: Confidence interval, SD: Standard deviation.

* Mann-Witney test.

Chi square.

Table 2

IL28Bpolymorphism and its association with AIDS development.

AIDS group (n = 135) Non-AIDS group (n = 87) OR (95%CI) P-value

Median age [Range], years 38.5 [17–67] 38.5 [22–85] .999*

Baseline median CD4 cell count [Range], (cells/mm3) 108 [5–840] < .0001*

Baseline median viral load [Range], (log10copies/mL) 4.83 [1.38–6.75] 469 [65–1565.1] .036*

Genotype frequencies (%)

CC 72 (53.33) 43 (49.42) 1.00 (reference)

CT 50 (37.03) 37 (42.52) 0.81 (0.46–1.42) .460

TT 13 (9.62) 7 (8.04) 1.11 (0.41–2.99) .838

Recessive model (%) 13 (9.63) 7 (8.04) 1.22 (0.46–3.18) .687

Dominant model (%) 63 (46.67) 44 (50.57) 0.85 (0.50–1.47) .569

Allele frequencies ± SD

C 0.72 ± 0.03 0.71 ± 0.03 1.00 (reference)

T 0.28 ± 0.03 0.29 ± 0.03 0.94 (0.62–1.44) .791

OR: Odd ratio, CI: Confidence interval, SD: Standard deviation, AIDS: Acquired immune deficiency syndrome.

* Mann-Witney test.

Chi square.

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in CD4+ T-cell counts between CC and CT genotypes after HAART according. In fact, subjects with CC genotype had signicant high levels of CD4+ T cell count compared to patients with TT genotype. However, we observed no significant difference between CC and TT genotypes regarding HIV-1 viremia after HAART. Interestingly, previous study showed that high IFN-λserum levels was prevalent in carriers of the rs12979860 C allele [36]. Interestingly, Hou and colleagues [15]

showed that IFN-λ3 enhanced APOBEC3G and APOBEC3F expression which have the ability to restrict HIV-1[37,38]. Moreover, they showed that IFN-λ3 had the ability to induce the intracellular expression of type I IFNs well known for their ability to inhibit HIV-1 replication[39,40].

All this evidence suggests thatIL28Bmay be involved in the HAART outcomes probably through stimulation of ISGs which play an im- portant role in the immune response [13,41]. However, other in- vestigations are needed to understand the mechanisms underlying the beneficial effect of IL28B SNP rs12979860 during HIV treatment.

In conclusion, our data revealed that theIL28B SNP rs12979860 was not associated with susceptibility to HIV-1 and AIDS development in Moroccan individuals. However, we found that IL28B CC genotype influenced CD4+T cell counts after HAART compared to TT genotype.

Whereas, due to small sample size and alleles frequencies vary ac- cording to ethnicity should be taken into account and future in- vestigations with larger sample sizes and in other populations could provide additional support to our data.

Acknowledgements

The authors would like to acknowledge all patients for theirs par- ticipation in this study and the Association de lutte contre le SIDA (ALCS). We are particularly grateful to Prof. George Y. Wu for pertinent English revision of the manuscript.

Fig. 1.IL28Brs12979860 polymorphism and T CD4+cell counts. A) Association between genotypes ofIL28Bgeno- types and CD4+T-cell counts in untreated patients. B) Impact of IL28B genotypes on CD4+ T-cell counts in treated patients. Data are presented as a scatter plot with median. Statistical tests were performed using Mann Whitney U test and ANOVA test.

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Funding

This work was supported by the Fonds d’Appui aux Structures Partenaires (FASP 2012).

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