Serum Immune Activation Markers Are Persistently Increased in Patients with HIV Infection after 6 Years of Antiretroviral Therapy despite Suppression of Viral Replication and Reconstitution of CD4(+) T Cells

School of Pathology and Laboratory Medicine, University of Western Australia, and Department of Clinical Immunology and Immunogenetics, Royal Perth Hospital and PathWest Laboratory Medicine, Perth, Australia.
The Journal of Infectious Diseases (Impact Factor: 6). 10/2009; 200(8):1212-5. DOI: 10.1086/605890
Source: PubMed


The effect of long-term antiretroviral therapy on serum immune activation markers was assessed in a cohort of 63 patients
before and after 6 years of boosted lopinavir–based antiretroviral therapy. High levels of most markers were associated with
lower CD4+ T cell counts at baseline and at year 6, with the exception of soluble cytotoxic T lymphocyte antigen-4 (sCTLA-4); high levels
of sCTLA-4 were associated with higher CD4+ T cell counts at year 6. Abnormalities of serum immune activation markers persisted after 6 years of ART but probably had
different causes. Further investigation of the clinical usefulness of assaying immunoglobulin A, neopterin, and sCTLA-4 levels
to assess the effectiveness of treatments for human immunodeficiency virus (HIV) disease are warranted

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Available from: Martyn Andrew French, Feb 04, 2016
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    • "Recent studies have demonstrated that elevated levels of certain soluble markers of inflammation or hyperactivation of the innate immune system can independently predict progression to AIDS, immune reconstitution inflammatory syndrome (IRIS), and death in HIVinfected patients (Boulware et al., 2011; Sandler et al., 2011; Marchetti et al., 2013). Specifically, soluble markers of monocyte turnover, inflammation , and fibrosis, including soluble CD14 (sCD14), lipopolysaccharide, interleukin (IL)-6, IL-8, interferon gamma-induced protein 10 (IP-10), hyaluronic acid, and C-reactive protein (CRP) have been shown to be associated with increased risk of progression to AIDS and death (Boulware et al., 2011; Hasegawa et al., 2009; Neuhaus et al., 2010; French et al., 2009). "
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    ABSTRACT: In recent years, chronic immune activation and systemic inflammation have emerged as hallmarks of HIV disease progression and mortality. Several studies indicate that soluble inflammatory biomarkers (sCD14, IL-6, IL-8, CRP and hyaluronic acid), as well as surface markers of T-cell activation (CD38, HLA-DR) independently predict progression to AIDS and mortality in HIV-infected individuals. While co-infections have been shown to contribute to immune activation, the impact of latent tuberculosis infection (LTBI), which is widely endemic in the areas most affected by the global AIDS epidemic, has not been evaluated. We hypothesized that both active and latent states of Mycobacterium tuberculosis co-infection contribute to elevated immune activation as measured by these markers. In HIV-infected individuals with active, but not latent TB, we found elevated levels of soluble markers associated with monocyte activation. Interestingly, T-cell activation was elevated individuals with both latent and active TB. These results suggest that in the highly TB- and HIV-endemic settings of southern Africa, latent TB-associated T-cell activation may contribute to HIV disease progression and exacerbate the HIV epidemic. In addition, our findings indicate that aggressive campaigns to treat LTBI in HIV-infected individuals in high-burden countries will not only impact TB rates, but may also slow HIV progression. Significance Latent tuberculosis, which affects an estimated 1/3 of the world's population, has long been thought to be a relatively benign, quiescent state of M. tuberculosis infection. While HIV co-infection is known to exacerbate M. tuberculosis infection and increase the risk of developing active TB, little is known about the potential effect of latent TB infection on HIV disease. This study shows that HIV-infected individuals with both active and latent TB have elevated levels of inflammation and immune activation, biomarkers of HIV disease progression and elevated risk of mortality. These results suggest that, in the context of HIV, latent TB infection may be associated with increased risk of progression to AIDS and mortality.
    Full-text · Article · Mar 2015 · EBioMedicine
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    • "The absence of effects of HAART on plasma sCD14, as previously reported by us and others [17] [21], as well as the increase in CCL4, is consistent with ongoing chronic inflammation due to sustained activation of monocytes/macrophages , even in the face of virally suppressive therapy, and may persist for several years [21] [35]. In this setting, the persistent activation of monocytes/macrophages, predominantly the subtype which coexpresess CD14 and CD16, is most likely driven by the process of microbial translocation [21] [24] [36]. "
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    ABSTRACT: Few studies have examined immune activation profiles in patients with advanced HIV-1 subtype C infection or assessed their potential to predict responsiveness to HAART. BioPlex, ELISA, and nephelometric procedures were used to measure plasma levels of inflammatory biomarkers in HIV-1 subtype C-infected patients sampled before and after 6 months of successful HAART (n = 20); in patients failing HAART (n = 30); and in uninfected controls (n = 8). Prior to HAART, CXCL9, CXCL10, β 2M, sTNF-R1, TGF- β 1, IFN- γ , IL-6, TNF, and sCD14 were significantly elevated in HIV-1-infected patients compared to controls (P < 0.01). All of these markers, with the exception of sTNF-R1, were also elevated in patients failing HAART (P < 0.05). The persistently elevated levels of CXCL9, CXCL10, and β 2M in patients failing therapy in the setting of a marked reduction in these markers in patients on successful HAART suggest that they may be useful not only to monitor immune activation during HAART, but also to distinguish between good and poor responders. In the case of sCD14 and TGF- β 1, the levels of these biomarkers remained persistently elevated despite HAART-induced virological suppression, a finding that is consistent with ongoing monocyte-macrophage activation, underscoring a potential role for adjuvant anti-inflammatory therapy.
    Full-text · Article · Apr 2014 · Mediators of Inflammation
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    • "Most treatment guidelines recommend early initiation of ART, based mainly on nucleoside reverse transcriptase inhibitors (NRTI) combined with non-nucleoside reverse transcriptase inhibitors (NNRTI) or protease inhibitors (PI) [3,4]. However, despite viral suppression and quantitative immune restoration in most patients, signs of immune activation and inflammation persist [5,6]. This may be due in part to ongoing low-level viral replication [7], the coinfection with other chronic viruses such as cytomegalovirus and Epstein-Barr virus [8,9] and to the consequences of mucosal immune dysfunction that is characterized by a profound depletion of CD4 + T-cells during the early acute infection, and a progressive loss of the ability to maintain the intestinal barrier function, allowing translocation of the intestinal microbial flora into the systemic circulation which induces immune activation and inflammation cascades [10]. "
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    ABSTRACT: Few studies have compared the impact of different antiretroviral regimens on residual immune activation and inflammation with discordant results. Aim of the study was to investigate the impact of various antiretroviral regimens on markers of immune activation and inflammation during the first two years of effective therapy. We studied HIV-infected antiretroviral-naive patients who began cART with either abacavir/lamivudine or tenofovir/emtricitabine, combined with ritonavir-boosted lopinavir (LPV/r), atazanavir (ATV/r) or efavirenz (EFV). All the patients had a virological response within 6 months, which was maintained for 2 years with no change in their ART regimen. C-reactive protein (hs-CRP), interleukin-6 (IL-6), soluble CD14 (sCD14), monokine induced by interferon-gamma (MIG) and interferon-gamma-inducible protein-10 (IP-10) were measured in stored plasma obtained at cART initiation and 24 months later. Mean changes from baseline were analyzed on loge-transformed values and multivariable linear regression models were used to study the effect of the treatment components, after adjusting for factors that might have influenced the choice of ART regimen or biomarker levels. Differences were expressed as the mean fold change percentage difference (Delta). Seventy-eight patients (91% males) with a median age of 43 years met the inclusion criteria. Their median baseline CD4 cell count was 315/mm3 and HIV-1 RNA level 4.6 log10 copies/ml. During the 2-years study period, IL-6, IP-10 and MIG levels fell significantly, while hs-CRP and sCD14 levels remained stable. IP-10 and MIG levels declined significantly less strongly with ATV/r than with EFV (IP-10Delta -57%, p = 0.011; MIGDelta -136%, p = 0.007), while no difference was noted between LPV/r and EFV. The decline in IL-6 did not differ significantly across the different treatment components. After the first 2 years of successful cART, IL-6, IP-10 and MIG fell markedly while hs-CRP and sCD14 levels remained stable. The only impact of ART regimen was a smaller fall in markers of immune activation with ATV/r than with EFV. Our results suggest that these markers could be worthwhile when evaluating new antiretroviral drugs.
    Full-text · Article · Mar 2014 · BMC Infectious Diseases
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