Immune activation and the pathogenesis of HIV disease: implications for therapy.
Currently available data suggest that HIV infection causes disease in two phases (Figure 1). The first phase occurs during primary HIV infection and the early part of chronic infection when there is substantial depletion of memory (CCR5+) CD4+ T cells and disruption of the structure and function of secondary lymphoid tissues, especially the gut-associated lymphoid tissue (GALT) of the intestinal tract [1-4]. These early HIV-induced immune defects set the stage for the second phase of HIV disease, which is characterised by a state of persistent immune activation. Although suppression of HIV replication by antiretroviral therapy (ART) reduces immune activation, abnormalities may persist and contribute to residual immune dysfunction and non-AIDS HIV disease. It is therefore important to understand the mechanisms of the immune activation and devise therapeutic strategies to reverse it.
[FIGURE 1 OMITTED]
IMMUNE ACTIVATION IS THE MAJOR CAUSE OF LYMPHOCYTE DEPLETION IN CHRONIC HIV INFECTION
Several lines of evidence indicate that immune activation is the major cause of immune dysfunction in patients with chronic HIV infection (Table 1). The immune activation is reflected in an increased frequency of T cells expressing activatory and pro-apoptotic molecules such as HLA-DR, CD38 and Fas [5,6]. Lymphocytes and monocytes from HIV-infected individuals also display increased production of pro-inflammatory cytokines such as interleukin (IL)-1[beta] IL-6, IL-18 and tumour necrosis factor (TNF)-[alpha] . In addition, there may be increased serum levels of proteins produced by immune cells, such as immunoglobulin A (IgA), neopterin and soluble cytotoxic T lymphocyte antigen 4 (sCTLA-4) . This state of chronic immune activation is associated with a sustained rise in turnover (proliferation and death rates) of both CD4+ and CD8+ T cells [9,10], which in turn further enhances viral replication. Consequently, T cell activation and turnover correlate well with disease progression [11,12] and the rate of CD4+ T cell loss [13-15].
A rapid decrease in the expression of T cell activation markers (in parallel to the control of viral replication) is seen on initiation of ART [5,6,16-19]. Reductions in Fas/FasL expression [19,20], rates of T cell turnover [9,10] and levels of plasma pro-inflammatory cytokines  and plasma-soluble Fas  are observed. However, expression of activation markers may remain elevated compared to nonHIV-infected controls, even after long-term treatment [6,17,23,24]. This is particularly so for serum immune activation markers. For example, analyses undertaken
in patients who had received ART for 6 years with suppression of plasma HIV-RNA levels to <50 copies/ml demonstrated that serum levels of several immune activation markers were persistently increased .
ART-mediated decreases in the activation and turnover of CD4+ T cells are positively associated with the recovery of CD4+ T cells [6,25,26]. Poor recovery of CD4+ T cells in HIV patients on ART correlates with elevated expression of CD38, HLA-DR, Ki67 and CD57 on T cells [6,17,26,27] and increased rates of CD4+ T cell turnover . An inverse relationship between CD8+ T cell activation and the recovery of CD4+ T cells is well established although reports on whether it predominantly influences early or late CD4+ T cell gains vary to some degree [17,28]. We and others have also demonstrated an inverse relationship between proportions of activated CD4+ T cells in the circulation and CD4+ T cell recovery in patients who achieve a virological response to ART [17,27]. Mechanisms linking persistent immune activation with poor CD4+ T cell recovery may include increased susceptibility of T cells to apoptosis [29,30], increased turnover of T cells leading to the accumulation of senescent T cells [25,27,31] and impaired T cell homeostasis resulting from reduced expression of CD127 (a component of the IL-7 receptor) .
Immune activation associated with chronic HIV infection is also associated with collagen deposition and fibrosis in supporting lymphoid tissues [4,33]. Increased expression of pro-inflammatory cytokines in lymph nodes can change the expression of cell surface adhesion molecules and mediate sequestration of T cells in lymph nodes, and alter cell-trafficking [34,35]. This potentially affects the survival of T cells, limits the ability of lymph nodes to support healthy T cell homeostasis and has been associated with reductions in the size of total and naive CD4+ T cell populations [4,33].
HIV-ASSOCIATED IMMUNE ACTIVATION MAY INCREASE THE PROPORTION OF DELETERIOUS T CELL SUBPOPULATIONS
As well as depleting lymphocytes, HIV-associated immune activation may also increase the proportion of T cells that could adversely affect pathogen-specific T cell responses, such as senescent T cells and CD4+ regulatory T (Treg) cells. Treg cells are capable of suppressing T cell activation and proliferation and much research has addressed the role of these cells in disease pathogenesis [36-38]. During untreated HIV infection, Treg cell numbers are depleted in parallel with total CD4+ T cells [39-41]. Although loss of Treg cells has been suggested as a mechanism for increased immune activation in HIV disease, we and others have demonstrated that the frequency of circulating CD4+ T cells with a regulatory phenotype (FoxP3+CD25+ or FoxP3+CD127LO) is elevated in untreated HIV-infected patients compared with uninfected controls [39,42-46], and correlates directly with plasma HIV-RNA level as well as the frequency of activated CD4+ T cells [39,43,44,46]. Furthermore, in untreated HIV disease, patients with low CD4+ T cell counts exhibit higher frequencies of CD4+ Treg cells compared with patients who have higher CD4+ T cell counts [41,44].
There is debate, however, as to whether FoxP3+CD25+ or FoxP3+[CD127.sup.LO] CD4+ T cells in HIV-infected patients are bona fide Treg cells or activated non-regulatory CD4+ T cells. Upregulation of FoxP3 and CD25 without conferment of suppressive function has been demonstrated in CD4+ T cells following cellular activation [47,48], while reduced expression of CD127 is a feature of activated CD4+ T cells in patients with progressive HIV disease . Recent studies by our group and others have shown that a large proportion of FoxP3-expressing CD4+ T cells also co-express markers of immune activation (HLA-DR, CD38, Ki-67, PD-1), and that these cells are most common in patients with untreated disease [42,43,49]. Thus, expression of FoxP3 in T cells of HIV-infected patients may not necessarily discriminate activated bona fide Treg cells from recently activated cells that do not possess suppressive activity [43,50].
MECHANISMS OF IMMUNE ACTIVATION IN CHRONIC HIV INFECTION
The causes of immune activation in chronic HIV infection have not been fully elucidated but recent work has focused upon two potential mechanisms. Following studies that demonstrated the rapid and sustained depletion of CD4+ T cells from mucosal tissues during acute HIV infection [1,3,4], Brenchley et al. hypothesised that the profound loss of CD4+ T cells leads to a breakdown of the gut mucosal barrier and subsequent translocation of microbial products from the intestinal lumen into the circulation where the activation of immune cells may occur . Subsequent studies have demonstrated elevation of bacterial lipopolysaccharide (LPS) and 16S ribosomal DNA levels in the plasma of both untreated and treated HIV-infected subjects as well as associations between these indicators of microbial translocation and levels of immune activation [52,53]. Furthermore, indicators of microbial translocation correlate with blunted CD4+ T cell gains in HIV-infected subjects receiving ART . Together, these data support a role for immune activation induced by microbial translocation as a cause of the CD4+ T cell depletion that characterises HIV disease.
A recent study in a murine model of polyinosinic:polycytidylic acid (poly I:C)-induced thymic ablation suggests that translocation of gut microbial products might be particularly detrimental to naive CD4+ T cell homeostasis . This was not mirrored in the naive CD8+ T cell population. Furthermore, transfer of naive CD4+ and CD8+ T cells into poly I:C-treated mice demonstrated rapid proliferation and acquisition of activation markers among naive CD4+ T cells but not naive CD8+ T cells, suggesting that naive CD4+ T cells alone react to a changed environment in poly I:C-treated mice. Interestingly, our own studies of immune activation in HIV patients receiving ART suggest that the relationship between increased immune activation and poor recovery of naive CD4+ T cell numbers is most clearly evident in patients lacking a thymus .
The downstream sequelae of the interaction between HIV gp120 and the CD4 molecule may also be an important mechanism underlying HIV-associated immune activation. This interaction triggers production of IFN-[alpha] by plasmacytoid dendritic cells (pDC), which increases production of soluble TRAIL as well as upregulation of membrane-bound TRAIL (mTRAIL) and induction of DR5 (a TRAIL receptor) expression on CD4+ T cells. As mTRAIL and DR5 are both expressed on CD4+ T cells but not CD8+ T cells, this model may explain the preferential depletion of CD4+ T cells in HIV infection [55-58]. Further evidence of a role for pDC and IFN-[alpha] in the immune activation of HIV infection has been provided from studies of SIV infection  and the observation that interferon-stimulated gene transcripts are markedly upregulated in activated CD4+ T cells from untreated HIV-infected subjects .
IMMUNE ACTIVATION AND NON-AIDS HIV DISEASE IN PATIENTS RECEIVING ART: THERAPEUTIC STRATEGIES
Persistent immune activation in patients with HIV infection that is 'optimally' suppressed by ART may not only contribute to residual immune dysfunction but also to abnormally high levels of inflammation. This has the potential to be a factor in the pathogenesis of atherosclerotic vascular disease  and possibly type 2 diabetes, osteoporosis and dementia, particularly in HIV patients who are ageing. Several therapeutic approaches to suppressing immune activation are currently under consideration. Patients who apparently have optimal control of HIV replication may continue to experience viral replication that is only detectable by assaying plasma samples using methods that detect HIV-RNA levels much
lower than 50 copies/ml . One approach to controlling residual immune activation is therefore to 'intensify' ART by adding another drug from a different class, such as an HIV integrase inhibitor. In ACTG study A5244, raltegravir was added to the current ART regimen in patients with a plasma RNA level <50 copies/ml after >12 months of treatment. Preliminary results indicate that HIV-RNA levels did not change but that there was an increase in CD4+ T cell counts .
In patients with evidence of increased translocation of microbial products from the intestine into the circulation, decreasing intestinal bacterial load might reduce immune activation. One approach to achieving this is to administer oral bovine colostrum, which contains antibodies that are effective in the gastrointestinal tract. The BITE study evaluated bovine colostrum in combination with other agents that together improve immune function in the gut. Of the 340 ART-naive patients enrolled, participants in the active arm had a significantly slower decline in CD4+ T cell counts compared with patients in the control arm over 1 year . The CORAL study is an ongoing study in Australia in which both hyperimmune colostrum obtained from cattle vaccinated with gastrointestinal bacteria and 'intensification' of ART with raltegravir are being evaluated.
Finally, another approach to controlling persistent HIV-associated immune activation is to suppress pDC activation and production of IFN-[alpha] This approach is being taken in systemic lupus erythematosus (SLE), in which IFN-[alpha] is a mediator of immunopathology  and might contribute to the inflammation underlying the increased risk of atherosclerotic vascular disease in SLE patients .
Immune activation is central to the pathogenesis of immune dysfunction in patients with HIV infection. Although contemporary ART is effective for long periods of time, some patients in whom plasma HIV RNA cannot be detected may have persistent immune activation that adversely affects immune reconstitution and may be a risk factor for non-AIDS HIV disease. The causes of the immune activation have not been completely defined but probably include reservoirs of low-level HIV replication and absorption of microbial products from the intestine because of failure to reconstitute the mucosal immune system. Future treatment programmes for patients with HIV infection might include therapies that suppress immune activation but there is currently insufficient information to predict what these might be.
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Correspondence to: Martyn French, Department of Clinical Immunology, Royal Perth Hospital, GPO Box X2213, Perth WA 6847, Australia Email: firstname.lastname@example.org
SONIA FERNANDEZ (1), ANDREW LIM (1) AND MARTYN FRENCH (1,2)
(1) School of Pathology and Laboratory Medicine, University of Western Australia and (2) Department of Clinical Immunology, Royal Perth Hospital and Path West Laboratory Medicine, Perth, Australia
Table 1. Evidence that HIV-induced immune activation is a major cause of immune dysfunction in chronic HIV infection The frequency of CD4+ T cells infected by HIV in vivo [67,68] is too low to account for the CD4 T cell loss Most apoptotic CD4+ T cells in peripheral blood and  lymph nodes of patients with chronic HIV infection are not infected by HIV Naive CD8+ T cells, memory B cells and NK cells as [70-72] well as CD4+ T cells decline in HIV infection SIV-infected macaques exhibit a persistently activated  immune system and rapidly progress to AIDS, while SIV-infected sooty mangabeys show normal T cell division rates and do not progress to AIDS HIV-2 infection is associated with lower levels of  immune activation, which may explain the slower decline of CD4+ T cells compared with HIV-1 infection In mice, TLR7 stimulation unrelated to a virus infection  induces immune activation and immunopathology similar to that in HIV infection
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|Title Annotation:||LEADING ARTICLE|
|Author:||Fernandez, Sonia; Lim, Andrew; French, Martyn|
|Publication:||Journal of HIV Therapy|
|Date:||Nov 1, 2009|
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