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.
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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
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...