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AIDS:
doi: 10.1097/QAD.0b013e32835ecb8b
Opinion

Persistent immune activation in chronic HIV infection: do any interventions work?

Rajasuriar, Reenaa,b,c; Khoury, Gabrielac,d; Kamarulzaman, Adeebaa; French, Martyn A.e,f; Cameron, Paul U.c,d,g; Lewin, Sharon R.c,d,g

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aCentre of Excellence for Research in AIDS (CERiA)

bDepartment of Pharmacy, Faculty of Medicine, University Malaya, Kuala Lumpur, Malaysia

cDepartment of Infectious Diseases, Monash University

dCentre for Virology, Burnet Institute

eSchool of Pathology and Laboratory Medicine, University of Western Australia

fDepartment of Clinical Immunology, Royal Perth Hospital and PathWest Laboratory Medicine, Perth

gInfectious Diseases Unit, Alfred Hospital, Melbourne, Australia.

Correspondence to Sharon R. Lewin, Department of Infectious Diseases, 2nd Floor Burnet Institute, 85 Commercial Road, Melbourne, 3004 VIC, Australia. Tel: +61 3 976 8491

Received 26 September, 2012

Revised 8 January, 2013

Accepted 9 January, 2013

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Introduction

The availability of combination antiretroviral therapy (cART) has led to substantial reduction in morbidity and mortality in HIV-infected patients; however, life expectancy remains reduced especially in HIV-infected patients who initiate cART with CD4 T-cell counts less than 200 cells/μl [1]. Increased immune activation in patients on long-term suppressive cART [2–4] has been associated with increased mortality [5,6] and both AIDS and non-AIDS-defining illnesses [7–10], suggesting that chronic immune activation may have a potential role in driving increased morbidity and mortality.

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Causes of HIV-associated immune activation

The mechanisms driving systemic immune activation in chronic HIV infection are multifactorial (reviewed in [11], Fig. 1) [12] and include the translocation of microbial products from the gastrointestinal tract [13,14], low-level HIV viremia [15,16], and coinfections with other persistent viral pathogens including cytomegalovirus (CMV) and hepatitis C virus (HCV) [17]. A recent study in simian immunodeficiency virus-infected macaques demonstrated a significant increase in immune activation and coagulation markers, including D-dimers, following exogenous administration of lipopolysaccharide (LPS) [18]. The excessive production of interferon alpha (IFN-α) [19–22] and pro-inflammatory cytokines leading to upregulation of pro-apoptotic molecules [23–26], lymph node fibrosis [27], dysfunction of CD4 T-regulatory cells (T-regs) [28,29], and depletion of CD161++/(mucosal-associated invariant T cells, MAIT) [30,31] are likely to also contribute.

Fig. 1
Fig. 1
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Strategies to reduce persistent immune activation in HIV-infected patients

Pharmacological agents

Multiple clinical trials have been completed (Table 1) [32–76], or are in development (Table 2) [27,77–86], to reduce immune activation in HIV-infected patients and have also been recently reviewed in [87].

Table 1-a Therapeuti...
Table 1-a Therapeuti...
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Table 2
Table 2
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Statins
Table 1-b Therapeuti...
Table 1-b Therapeuti...
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The use of statins in HIV-infected patients on and off cART has reported variable changes in T-cell activation and highly sensitive C-reactive protein (hsCRP) levels [32–35] but no effect on CD4 T-cell counts [32,33,36]. However, in two large observational studies of cART-treated patients, the use of statins was associated with reduced mortality [37] and reduced incidence of non-Hodgkin lymphoma (NHL) [38]. No immunological correlates were assessed in these two studies and a greater understanding of the mechanisms underlying the benefits of statins is needed.

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Chloroquine and hydroxychloroquine

Chloroquine and hydroxychloroquine inhibit endosomal acidification in plasmacytoid dendritic cells (pDCs) and Toll-like receptor 7 (TLR-7) signaling by HIV-1 single stranded (ss)RNA and also inhibit IFN-α production [88,89]. In vitro, chloroquine inhibited pDC activation and maturation, reduced IFN-α-mediated CD8 T-cell activation, and downmodulated indolamine 2–3 dioxygenase (IDO) and PD-L1 expression on pDCs, which are negative regulators of T-cell responses [90].

A recent randomized controlled trial (RCT) in cART-naive patients (n = 13) found chloroquine was associated with decreased memory CD8 T-cell activation, CD4 and CD8 T-cell proliferation, and LPS levels compared to baseline but there were no changes in plasma HIV RNA [39]. In contrast, a RCT of hydroxychloroquine in cART-naive patients demonstrated no change in CD8 and CD4 T-cell activation and proliferation, an increase in HIV RNA, and decrease in CD4 T-cell counts [40]. In a small nonrandomized study (n = 20), administration of hydroxychoroquine to patients receiving suppressive cART was associated with a reduction in multiple markers of immune activation but no significant increase in CD4 T-cell recovery [41]. Given these promising findings, numerous clinical trials are currently being conducted with choloroquine (NCT00819390) and hydroxychloroquine (NCT01232660).

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Selective cyclooxygenase-2 inhibitors

Selective cyclooxygenase-2 (COX-2) inhibitors are anti-inflammatory agents that modulate T-cell activation via inhibition of prostaglandin E2 and the cyclic adenosine 3′,5′-monophosphate (cAMP)-protein kinase A pathway ([91,92], reviewed in [93]). In cART-treated patients, selective COX-2 inhibitors were associated with increased T-cell proliferation [94], a nonsignificant reduction in T-cell activation, and increased perforin-containing CD8 T cells [42]. A recent RCT of high-dose celecoxib in untreated HIV-infected patients (n = 31) reported a significant reduction in immune activation levels [43].

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Leflunomide

A77 1726, the active metabolite of the antirheumatoid arthritis agent leflunomide, has anti-HIV activity [95,96], inhibits pyrimidine synthesis [96,97], and reduces proliferation of activated T cells in vitro[98]. A small RCT in cART-naive patients (ALETHIA, A Study of Leflunomide to Target Immune Activation in HIV; n = 16), found no significant change in CD4 and CD8 T-cell counts or HIV RNA levels in patients treated with leflunomide compared to placebo [44]. Furthermore, more grade 1 and 2 adverse events were reported with leflunomide. However, short-term leflunomide use was associated with reduced T-cell cycling and activation. It is currently unclear whether similar immunological effects will be seen in patients receiving cART.

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Biological agents
Bovine colostrum, micronutrients, and prebiotics/probiotics

Multiple approaches are now being taken to directly reduce microbial load and translocation in HIV patients. These include supplementation with micronutrients, bovine colostrum, probiotics, and prebiotics, all of which have previously been shown to reduce HIV-associated diarrhea [99–101,45,46]. These strategies may also alter the composition of gut microflora, which may be important in modulating microbial translocation-driven immune activation [102,103]. Most of these studies have been in cART-naive patients and some have reported increases in CD4 T-cell counts [45,46,47–51] (Table 1). In a RCT of orally administered hyperimmune bovine colostrum (that contains antibodies to LPS), there was no effect on immune activation or CD4 T-cell recovery in patients receiving suppressive cART [52].

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Antiretroviral intensification

Chronic immune activation in patients receiving cART may also be driven by low-level HIV viremia [15,16,104,105]. In multiple observational and RCT studies, the addition of raltegravir to suppressive cART resulted in no significant immune activation reduction in plasma, cerebrospinal fluid, or tissue [52,53–58] nor any change in endothelial function, a surrogate marker of cardiovascular disease [106]. There have, however, been two studies that have shown that the addition of raltegravir led to a significant reduction in T-cell activation markers in a subset of patients and a reduction in reservoir size [59,60]. Further larger randomized studies are still needed to definitively determine the impact of raltegravir intensification on immune activation.

Several studies of maraviroc intensification have shown a reduction in immune activation [61–63]; however, one study reported an unexpected increase in immune activation [64] (Table 1). CCR5 antagonists inhibit the binding and signaling of CCR5 ligands (including CCL3, CCL4, and CCL5) leading to an increase in their plasma concentration. This increase could potentially activate monocytes/macrophages via CCR1 [62] and/or increase antigen-specific T-cell and antibody responses, which has been observed in some [107] but not all studies [108]. Further studies are needed to better characterize the immunological changes associated with maraviroc use.

The timing of cART initiation may be an important parameter that influences immune activation. Studies of patients treated during chronic infection have demonstrated persistently elevated immune activation levels post-cART compared to uninfected controls [2–4]. A recent prospective study of cART initiated during acute infection demonstrated reduced immune activation to normal levels after 48 weeks [109]. Prospective or randomized trials need to be performed to determine the effect of early versus delayed cART on immune activation in patients with chronic infection.

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Treatment of coinfections
Anti-cytomegalovirus treatment: valgancyclovir

Increased CMV-specific antibodies and/or T cells have been associated with atherosclerosis [110,111] and impaired CD4 T-cell reconstitution [112] in HIV-infected patients on cART, suggesting that CMV coinfection may be a driver of persistent immune activation. A RCT with valgancyclovir in CMV-seropositive cART-treated patients (n = 30) found that both CMV DNA and expression of CD38+HLA DR+ on T cells declined significantly during valgancyclovir therapy [65]. It is currently unclear whether this approach will translate to clinical benefits and the feasibility of prolonged administration of valgancyclovir may be limited by significant toxicities of the drug.

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Anti-hepatitis C virus treatment: interferon alpha and ribavirin

HCV-specific treatment with IFN-α and ribavirin in HIV/HCV coinfected patients receiving cART has been associated with a significant reduction in markers of T-cell activation [66] and endothelial dysfunction [113]; however, its impact on clinical end-points is currently unknown.

Other strategies including treatment with intravenous immunoglobulin (IVIG) and minocycline have also been trialed in small studies but have yielded negative results (see Table 1).

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Challenges in designing clinical trials to reduce immune activation

There are multiple challenges in designing clinical trials to reduce chronic immune activation in patients receiving suppressive cART. First, these studies will require patients who are otherwise clinically well to take an additional drug(s) that may be associated with toxicities. Therefore, the risks and benefits need to be carefully assessed. Second, there are multiple markers of immune activation and inflammation that have been studied and it is currently unclear which best predicts AIDS and non-AIDS-related morbidities in patients receiving suppressive cART. Biomarkers such as IL-6, D-dimer, and sCD14 show promise as they are relatively easy to standardize from measurements in plasma but whether they are indeed robust markers for predicting clinical outcomes following specific interventions needs further evaluation. Finally, given that clinical events are rare in patients on suppressive cART, relatively large samples sizes will be required to demonstrate a clinically relevant impact of any intervention to reduce immune activation.

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Conclusion

To date, most studies aimed at reducing immune activation have only included a small number of patients and/or shown an effect on biomarkers of immune activation and have not had the power to assess any effects on clinical outcomes. Given that there are several candidate approaches that have shown promise in small proof-of-concept trials, these compounds warrant evaluation in larger randomized clinical trials that systematically evaluate both immune activation biomarkers and clinical outcomes.

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Acknowledgements

R.R. and S.L. wrote the article. G.K., A.K., M.F., and P.U.C. provided helpful comments and edited the article.

R.R. and A.K. receive funding from the HIR/MOHE grant (UM.C/625/1/HIR/MOHE/MED01), R.R. from UMRG (RG377/11HTM) and S.R.L. from the National Institutes of Health (U19 AI096109 and 1R56AI095073-01A1. S.R.L. is an Australian National Health and Medical Research Council (NHMRC) Practitioner Fellow. G.K. is a recipient of a NHMRC postgraduate scholarship.

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Conflicts of interest

There are no conflicts of interest.

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Keywords:

chronic immune activation; combination antiretroviral therapy; HIV; non-AIDS-defining illness; T-cell activation

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