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

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].

CD38-DEFINED IMMUNE ACTIVATION IN HIV INFECTION

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].

CLINICAL USE OF CD8 T CELL ACTIVATION

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 on and off treatment may have important scientific merits, it is the independent link between levels of T cell activation and clinical progression that elevates the study of T cell activation from one of a number of immunological disturbances associated with HIV infection to the level of a potential clinical surrogate that could be used to guide and modify clinical decisions. Although routine monitoring of lymphocyte subsets and viral load is standard care in developed countries, it is far from routinely available in resource-poor settings [57], therefore alternative markers of viral replication are sought.

The use of flow cytometry to measure immune activation as a surrogate for viral replication is attractive since it uses the same technology and expertise as lymphocyte count testing and therefore has the potential to be widely offered and save substantially in financial terms compared with viral load testing. Furthermore, the proposed incorporation of a CD38 assay into the routine lymphocyte analysis performed in South Africa offers the opportunity to prospectively and routinely gather CD38 data [58].

CD38 EXPRESSION AS A CLINICAL SURROGATE

The main surrogate of clinical progression is the CD4 T cell count, which has been shown to reflect the clinical progression described by the Centers for Disease Control and Prevention (CDC) and other classifications. After commencing ART, the CD4 T cell count and viral load form the mainstay of clinical monitoring; however, these surrogates do not provide a full picture of HIV-1 pathogenesis and disease progression, and therefore immune activation has been proposed as a further surrogate of clinical progression.

The largest study of immune activation predicting clinical and immunological progression reports 289 HIV-1-infected therapy-naive patients followed for 3 years. This study reports T cell activation defined by CD38 and HLA-DR with quantitative assessment of CD38 and compares these measures of immune activation with serological markers, and uses proportional hazards modelling to demonstrate that CD8 T cell activation defined by CD38 expression was the strongest predictor of clinical progression [4].

A number of studies have attempted to use CD8 activation measures to detect virological failure in patients on HAART. In resource-limited settings this could provide a means of limiting cost by reducing expensive viral load testing, however, there is insufficient data to support the use of CD8 T cell activation measures to detect virological failures under HAART. Reported specificities to detect virological failure are above 90% even for viral load values of 50 copies/ml, however sensitivities can be as low as 60%, thereby rendering this test unsuitable as a surrogate for viral load testing [7,51,59-60]

There are few studies addressing the differences in immune activation across ethnic, developmental and geographic boundaries. However, the trends of changes in immune activation associated with HIV-1 have been consistently demonstrated in studies from Europe, North America, Africa and Asia. The studies suggest that although baseline levels of T cell activation may vary and require local definitions of normal populations, there appears to be an HIV-1 effect on T cell activation that exceeds any genetic or environmental effects [7,10,11,59,61].

DEFINING CD8 T CELL ACTIVATION WITH CD38 EXPRESSION

The expression of CD38 on T cells can be assessed by numerous flow cytometric methods. The most simple method uses a negative isotype control, thereby defining all cells with positive CD38 expression, and has been used to define healthy control ranges [62], for pathological classification of chronic lymphocytic leukaemia [63,64], and also by some authors describing the pathology of lymphocyte activation in HIV-1 infection [7,8, 13-15, 65,66] and other viral infections such as EBV [67,68].

The publication ofwork in the mid 1990s suggesting that CD38 expression on CD8 T cell subsets had prognostic significance expanded the field of study and introduced other methods to define and measure CD38 expression on CD8 T cells. HIV-1 prognosis has been linked to the frequency of CD8 T cells co-expressing CD38 and HLA-DR; and with the positive cut-off of both activation antigens defined by negative isotype control antibodies [7,10,18,69]. Other authors demonstrated that it was within the CD45RO subset of memory CD8 T cells where the prognostic CD38-expressing cells of interest can be found [1]. The prognostic nature of CD38 on CD8 T cells was further demonstrated to be dependent on the level of CD38 expression on CD8 T cells. Hence two different approaches have been taken to define this population of CD8 T cells: a quantitative flow cytometry method to give an indication of the number of CD38 antibody binding sites on the cell surface and, alternatively, methods to estimate the frequency of cells expressing the highest levels of CD38.

To quantify the number of CD38 molecules by flow cytometry, the methods used are based upon the mean or median fluorescence value for CD8 T cells gated onto a CD38 histogram. At its most simple this technique allows comparisons between groups [6,70], but with additional calibration steps using commercially available fluorescence quantification kits (Quantibrite[TM], CELLQUANT, QIFIKIT[R]) reference cell lines, or assumptions regarding the number of CD4 molecules found on CD4 T cells, it is possible to quantify the number of CD38 molecules/cell by estimating the CD38 antibody-binding capacity (ABC) of CD8 T cells

ABC techniques have been extensively studied in HIV-1 [5,16,21,56,71-76]. but they require recalibration and extra flow cytometry protocols that may explain why these techniques have not been widely used in assessing routine clinical samples. Another aspect is the reproducibility of the data presented: few published studies examining the pathogenesis of HIV infection with regards to T cell activation show assay performance data. Where this has been shown in a quantitative flow cytometric technique with biological calibration, the coefficient of variation (CV) across time and laboratories was 9.8-13%, which is not good enough for translation to clinical use [75], although recent data from South Africa suggests this technique could be used with CV reportedly less than 5% [58].

As shown above, the CD8 T cells that have prognostic significance are within the CD45RO subset, co-express CD38 and HLA-DR or have high levels of CD38 molecules/cell (typically >5000 molecules/cell [72,74-75]. Another technique to identify these cells uses flow cytometry calibration techniques to identify CD8 T cells that express high levels of CD38. This technique is based upon the differential expression of CD38 on different cell lines. Human umbilical cord blood PBMC characteristically express high levels of CD38, however, a more accessible technique utilises the differential expression of CD38 between monocytes and granulocytes [9,51,77].

The distribution of CD38 expression on CD8+ T cells is continuous and does not show clearly defined negative or positive populations in either healthy or HIV-1-infected individuals, nor does it follow a Gaussian distribution when defined by isotype controls [78]. In healthy adults, monocytes (but very few CD8+ T cells) express high levels of CD38 whereas granulocytes and some naive (CD45RA) CD8+ T cells express low or intermediate levels of CD38. Therefore, a CD38 side scatter dot plot in healthy controls can be used to select the monocyte population as a positive control for CD8+ T cells that strongly express CD38 (CD8+CD38++ T cells) [9]. Again demonstration of assay consistency has been lacking in most published studies (unpublished data from our laboratory suggests CV<5% is possible), underlining the need for some form of external quality control testing.

CONCLUSIONS

Whilst a complete understanding of the pathophysiology of HIV-1 infection remains elusive, there is increasing data to support hypotheses that favour immune activation as a fundamental determinant of HIV immunoparesis. Quantifying immune activation is possible with multiple techniques, however, the questions of which parameter to measure, and how, remain unanswered. New antiretroviral treatments will be assessed by known useful clinical surrogates of CD4 T cell count and levels of viral replication, however, immunomodulatory therapies (mycophenolate mofetil, hydroxycholoroquine and hydroxyurea, IL-2) or treatment escalation/interruption strategies may be better assessed by additional measures of immune activation [79-83]. Without a consensus as to which parameter to study and how, future data will be inherently difficult to interpret.

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ALAN STEEL

Department of Medicine, Chelsea and Westminster Hospital, London, UK

Correspondence to: Alan Steel, Department of Medicine

Chelsea and Westminster Hospital, 369 Fulham Road

London SW10 9NH, UK

Email: a.steel@imperial.ac.uk
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Title Annotation:LEADING ARTICLE; human immunodeficiency virus
Author:Steel, Alan
Publication:Journal of HIV Therapy
Article Type:Report
Geographic Code:4EUUK
Date:Mar 1, 2010
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