Epstein-Barr Virus load and immune activation in Human Immunodeficiency Virus type 1-infected patients

doi:10.1016/j.jcv.2011.12.013

Journal of Clinical Virology

Volume 53, Issue 3, March 2012, Pages 195-200

https://doi.org/10.1016/j.jcv.2011.12.013 Get rights and content

Abstract

Background

Patients infected with HIV-1 are at high risk of developing Epstein-Barr Virus (EBV)-related diseases. Chronic immune activation is a hallmark of HIV-1 pathogenesis and may play a role in B-cell stimulation and expansion of EBV-infected cells.

Objectives

The aim of the study was to define the relationship between parameters of immune activation and EBV load in HIV-1-infected subjects.

Study design

A total of 156 HIV-1-infected patients were studied. EBV types 1 and 2 were quantified on peripheral blood mononuclear cells by multiplex real-time PCR. Plasma levels of cytokines and lipopolysaccharide (LPS) were determined by immunoenzymatic assays. B-cell activation was analyzed by flow cytometry.

Results

EBV-DNA was detected in 114 patients, and in all but 3 was EBV type 1. The median [interquartile] EBV-DNA load was 43[1–151] copies/10⁵ PBMC. EBV-DNA load was higher in patients with detectable HIV-1 plasma viremia, despite good immunological status (CD4 > 500 cells/μl), than in patients with undetectable HIV-1 plasma viremia regardless of immunological status (46[5–136] copies/10⁵ cells vs 17[1–56] copies/10⁵ cells, p = 0.008). Patients with high EBV-DNA load (>median value) had higher levels of LPS and proinflammatory cytokines (IL-6, IL-10 and TNF-α) than patients with low EBV load. Furthermore, percentages of activated B-cells correlated with EBV-DNA load (r_s = 0.754; p < 0.001).

Conclusions

Overall, these findings indicate a strong association between HIV-1 viremia, markers of immune activation and EBV load and suggest that persistence of HIV-1 viremia and immune activation, regardless of peripheral CD4 cell depletion/repopulation, may favor expansion of EBV-infected cells and onset of EBV-related malignancies.

Section snippets

Background

EBV infects B lymphocytes and has a potent transforming ability, capable of inducing uncontrolled proliferation and transformation of infected cells.¹ Patients with HIV-1 infection are at high risk of developing EBV-related diseases, ranging from lymphoproliferatives disorders to B-cell non-Hodgkin's lymphomas (NHL).2, 3

Besides immunodepression, chronic immune activation, a hallmark of HIV-1 pathogenesis,⁴ may play a critical role in the genesis of B-cell lymphomas.5, 6 Cell activation driven

Objectives

The aim of this study was to investigate the relationship between HIV-1 viremia, markers of immune activation and EBV load in HIV-1 infected HAART-naïve and HAART-experienced patients.

Patients and samples

A total of 156 (117 male and 39 female) HIV-1-infected patients who attended the Infectious Diseases Division of Rovigo Hospital consecutively from July 2007 to December 2009 were included in this study. Their median age was 41 (range 18–68) years. At the time of sample collection for the study, 71 (45%) were HAART-naïve, and 85 (55%) HAART-experienced with a median (range) of 6 (1–10) years of HAART. Patients were treated according to current guidelines for HIV-1 infection.17, 18 Among

EBV-DNA levels in relationship to CD4 cell count and HIV-1 load

EBV-DNA was detected in 114 patients; in all but 3 cases EBV was type 1. The median [interquartile, IQR] EBV-DNA load was 43[1–151] copies/10⁵ PBMC. EBV-DNA levels were higher in naïve and out of therapy patients than in those in HAART (overall, p = 0.001) (Table 1).

CD4 cell number was lower in naïve patients and in those out of therapy than in HAART patients (overall, p < 0.0001) (Table 1). Only 17 naïve patients had severe immunodepression (CD4 < 200 cells/μl), whereas 52 (73%) naïve, 21 (33%)

Discussion

Following the introduction of HAART, the incidence of opportunistic infections and AIDS-related diseases, such as Kaposi sarcoma, dramatically decreased.22, 23 However, the impact of HAART in preventing EBV-associated lymphomas seems to be less effective.¹⁵ Chronic immune activation is a hallmark of HIV-1 infection and may contribute to the expansion of EBV-infected cells. Persistence of plasma viremia during HAART, despite immunoreconstitution, is not an infrequent observation,16, 20, 24, 25,

Acknowledgment

We thank Lisa Smith for editorial assistance and Pierantonio Gallo for the artwork.

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Post-transplant lymphoproliferative disorders (PTLD) represent a severe complication in transplanted patients and Epstein-Barr Virus (EBV) is the main driver. Besides immunodepression, immune activation/chronic inflammation play an important role in both virus reactivation and expansion of EBV-positive B cells. The aim of this study was to assess the impact of immunosuppressive strategies on factors involved in the PTLD's pathogenesis. 124 kidney transplanted patients were enrolled in this study: 71 were treated with mycophenolic acid (MPA) and 53 treated with mTOR inhibitor (mTORi), both in combination with different doses of calcineurin inhibitor. At the time of the transplant (T0), profile of inflammation/immune activation and immune senescence didn't differ between the two groups, but after one year of treatment (T1) markers were significantly higher in MPA-treated patients; their immunosenescence process was supported by the greater erosion of telomeres despite their younger age. Percentages of activated B cells and levels of EBV-DNA significantly increased in MPA-treated patients, and at T1 were significantly higher in MPA- than in mTORi-treated patients. Overall, these findings indicate that mTOR inhibitors constrain the inflammation/immune activation and senescence status, thus reducing the expansion of EBV-infected B cells and the risk of virus-associated PTLD in kidney transplant recipients.
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Herpes simplex virus (HSV) infection is associated with increased serum HIV viral load (VL) [7,14]. Cytomegalovirus (CMV) [15,16], chronic HSV [17], human herpesvirus 8 [18], and Epstein-Barr virus [19] co-infections are associated with increased inflammation and immune activation, and STIs may impact systemic immune activation [20]. Because STIs are common among HIV-infected youth [11,21,22] and immune activation promotes HIV disease progression, this exploratory study examined the association between STIs and systemic inflammation and immune activation among a sample of HIV-infected adolescents who were virally suppressed on cART.
Human immunodeficiency virus (HIV) infection is associated with chronic immune activation, and concurrent sexually transmitted infections (STIs) may increase immune activation.
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Forty-nine behaviorally infected U.S. youth ages 18–24 years with baseline CD4⁺ T-cells >350 who maintained viral suppression on therapy by week 48 were included. Evaluation for STIs (herpes simplex virus [HSV], Chlamydia trachomatis, syphilis, Neisseria gonorrhoeae) was conducted as standard of care and reported on case report forms. Measures of T-cell subsets, systemic immune activation, and soluble factors were examined at week 48 for differences between participants with an STI diagnosis during the 48 weeks compared to those without an STI.
Forty-three participants (88%) were male; 57% had baseline CD4+ T-cell counts >500 cells/mm³. Eighteen youth were reported to have ≥1 STI. At week 48, participants with STIs demonstrated lower CD4⁺ T-cell counts (any STI vs. no STI, p = 0.024; HSV vs. no STI, p = 0.022) and evidence of increased systemic immune activation, including higher CD57 intensity, higher HLA-DR intensity, and lower CD28 percentage, when compared to those without STIs. There were no differences in soluble factors between STI groups.
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Epstein-Barr Virus load and immune activation in Human Immunodeficiency Virus type 1-infected patients

Abstract

Background

Objectives

Study design

Results

Conclusions

Section snippets

Background

Objectives

Patients and samples

EBV-DNA levels in relationship to CD4 cell count and HIV-1 load

Discussion

Acknowledgment

Autoimmun Rev

Blood

Adv Cancer Res

J Clin Virol

Eur J Cancer

Eur J Cancer

Lancet Infect Dis

Overview of the epidemiology of immunodeficiency-associated cancers

J Natl Cancer Inst Monogr

Emerging concepts in the immunopathogenesis of AIDS

Annu Rev Med

B-cell stimulation and prolonged immune deficiency are risk factors for non-Hodgkin's lymphoma in people with AIDS

AIDS

B cells in HIV infection and disease

Nat Rev Immunol

Dynamics of Epstein-Barr virus in HIV-1-infected subjects on highly active antiretroviral therapy

AIDS

Differential dynamics of Epstein-Barr virus in individuals infected with human immunodeficiency virus-1 receiving intermittent interleukin-2 and antiretroviral therapy

Haematologica

Regulatory dysfunction of the interleukin-2 receptor during HIV infection and the impact of triple combination therapy

Proc Natl Acad Sci USA

Membrane tumor necrosis factor alfa is involved in the polyclonal B-cell activation induced by HIV-infected human T cells

Nature

Epstein-Barr virus-dependent lymphoproliferative disease: critical role of IL-6

Eur J Immunol

Microbial translocation is a cause of systemic immune activation in chronic HIV infection

Nat Med

Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. HIV Outpatient Study Investigators

N Engl J Med