Lymphocyte activation in HIV-1 infection: time for quality control.

AuthorSteel, Alan
PositionLEADING ARTICLE - Human immunodeficiency virus - Report

Studies of HIV-infected subjects, before the advent of highly active antiretroviral therapy (HAART) revealed a profound elevation in the levels of lymphocyte activation markers [1-6]. Since some of these immunological disturbances tended towards normal under HAART, there have been attempts to use activation profiles of lymphocytes to develop the understanding of the pathophysiology of HIV-1 and to use this in monitoring of patients on ART [7-17].

With the advent of HAART and suppression of viral replication, there was a huge decrease in circulating viral proteins, therefore removing the most obvious source of viral antigen and assumed primary driver of immune activation (reviewed previously, Fernandez, Lim and French, Journal of HIV Therapy, 2009, 14.3, 52-56). There was a decrease in the levels of lymphocyte activation; however, levels of T cell activation remained significantly elevated, and with this persistent lymphocyte activation there continued to be continued loss of CD4 T cells with a functional deficit of those remaining and hence disease progression [13-14, 18-20].

While CD4 T cells are characteristically activated and depleted in HIV-1 infection, the activation of the immune system is not limited to CD4 T cells [18-19, 21-24]. There is evidence of CD8 T cell, B cell, natural killer (NK) cell, dendritic cell (DC) and macrophage phenotypic activation. There is evidence of functional as well as phenotypic activation shown by elevated levels of pro-inflammatory cytokines and chemokines, in addition to increased levels of T cell turnover and proliferation [25-26].

Immune activation can be quantified by flow cytometry detection of cell surface antigens, which characterise the differentiation and activation status of the cell. Cell surface antigens that are used to define an activated phenotype vary across cell lineages but for T lymphocytes, CD25, CD38, CD69 and HLA-DR are most commonly used [1, 4, 13-14, 27-29]. Detection of soluble markers in serum can provide an alternative definition of immune activation but lacks the specific cellular definition that can be provided by flow cytometry. Soluble markers that have been studied in HIV include IgA, IgG, neopterin, 2 microglobulin, soluble CD8, soluble CD25 and soluble TNF and IL-2 receptors [4,29-32]. With the advent of emerging multiplex array technology that is able to measure a large array of cytokines and chemokines in plasma, there is now the ability to define more complex immunological disturbances but as yet this technology has not produced consistent findings and consequently has, at this point in time, limited clinical application [33-35].


The most established marker of immune activation in HIV-1 infection is the expression of CD38 on CD8+ T cells. Observations of changes in CD38 expression on CD8 T cells in HIV-1-infected patients have shown that CD8 CD38-expressing T cells give an insight into viral replication [2,7,9-12,15-16,36].

The understanding of CD38 expression has largely been driven by its use as a marker for cellular activation in estimating disease prognosis in patients with HIV-1 infection [1,3-6,13-14] and more recently in chronic lymphocytic leukaemia (CLL) [37-39]. CD38 belongs to an increasingly recognised large number of lymphocyte ecto-enzymes (CD157, CD39 and CD73), which are involved in adenosine triphosphate (ATP) and nicotinamide adenine dinucleotide (NAD) metabolism. Human CD38 is a bifunctional ecto-enzyme that catalyses the conversion of NAD+ to cyclic ADP-ribose, and its hydrolysis to ADP-ribose [40]. Cyclic ADP-ribose is a nucleotide that promotes calcium release from intracellular organelles and plays a crucial role in intracellular calcium homeostasis. Ligation of CD38 on lymphocytes promotes: proliferation; cytokine secretion (including IL-6); and inhibition of apoptosis [41]. Activation of memory CD8 T cells upregulates CD38 expression, which makes it a good marker of cellular activation in this subset. The ligand for CD38 is CD31, which is known to promote lymphocyte binding to vascular endothelial cells [42], thereby playing a role in lymphocyte migration [43].

It is not known whether upregulation of CD38 on T cells in HIV-1 infection is simply a marker of immune activation characteristic of this infection or if it has any direct contribution to the pathogenesis of this condition. A number of studies have put forward the hypothesis that increased expression of CD38 (by rapidly proliferating CD4 and CD8 memory T cells in retroviral illness) is a compensatory mechanism aimed at scavenging nucleotides to prevent apoptosis from nucleotide starvation [44-45]. It has been noted that increased CD38 expression in CD4 T cells inhibits in vitro HIV-1 attachment and entry [46] but the clinical significance of this observation is not known. It fails to account for more recent findings in non-human primate models of retroviral infection that substrate availability (number of target activated/recently activated CD4 T cells) drives viral replication [47-48].

The link between CD8 T cell activation and viraemia is not clear. Published data suggest persistent antigen load in blood, lymph nodes, or gastrointestinal associated lymphoid tissue (GALT) is the driving force behind persistent T cell activation after successful suppression of plasma viraemia. Whether this is low-level viral replication, below the normal limit of detection of 50 copies/ml, or circulating non-viable viral particles such as p24 or immune-complexed antigens remains to be demonstrated [11, 49-51].

Furthermore, since T cell activation markers have been shown to rise with 'blips' in viral replication and decay at rates slower than the rate of suppression of viral replication, it has been postulated that T cell activation reveals the presence of latent pools of viral replication [2,12,16]. Pools of latent virus have been suspected since the first studies of cessation of HAART and have been confirmed by studies detecting proviral DNA capable of in vitro infectious virus production or by documenting universal viral rebound with concomitant falls in CD4 T cell counts and percentages in patients discontinuing HAART [52-55].


Studies of T cell activation have shown that high levels of activation can predict the decline of CD4 T cell counts in therapy-naive patients [1,21]. Moreover, it has been shown that elevated levels of T cell activation can predict limited immunological recovery on HAART independent of known surrogates of disease progression such as CD4 T cell counts and HIV RNA viral load [2-5,12-13,20,56].

While monitoring levels of immune activation in response to viral suppression or rebound...

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