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Role of CD38 in HIV-1 infection: an epiphenomenon of T-cell activation or an active player in virus/host interactions?

Savarino, Andreaa; Bottarel, Flaviab; Malavasi, Fabioc; Dianzani, Umbertob

Editorial Review

From the aLaboratory of Cell Biology, Department of Genetics, Biology and Biochemistry, University of Turin, Turin, the bDepartment of Medical Science, University `A. Avogadro' of Eastern Piedmont, Novara, and the cInstitute of Biology and Genetics, University of Ancona, Ancona, Italy.

Received: 5 January 1999;

revised: 9 February 2000; accepted: 9 February 2000.

Sponsorship: This work was made possible by the Special Projects `AIDS' (Istituto Superiore di Sanità, Rome), `Biotechnology' (CNR/MURST, Rome) and `Telethon' (Rome). Compagnia di San Paolo and Cariverona Foundations, Regione Piemonte and the Italian National Association against AIDS (ANLAIDS: Torino and Rome) provided valuable financial contributions.

Requests for reprints to: A. Savarino, M. D., Laboratory of Cell Biology, University of Turin Medical School,Via Santena 19, I-10126 Torino, Italy.

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Introduction

The analysis of CD38 expression on lymphocytes has become an important tool for monitoring patients during HIV-1 infection and has recently been proposed for use in the follow-up of highly active antiretroviral therapy (HAART). The prognostic value of such analyses is attributed to the ability of CD38 to mark activation of the immune response. However, studies of the prognostic value of CD38 expression are subject to several interpretations; recent observations suggest that CD38 plays an active role in HIV-1 infection. These findings and discrepancies are reviewed here in the light of the biological behavior of CD38.

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CD38: an ectoenzyme, an adhesion receptor, and a signaling molecule

CD38, which was identified in the early 1980s by Reinherz et al. [1], was initially considered an activation antigen and mainly adopted in the phenotyping or classifying of leukemias. It is a type II surface glycoprotein with an apparent molecular weight of 45 kDa. It has a short intracytoplasmic tail, a single transmembrane region, and a long extracellular domain; the last contains four potential glycosylation sites and two hyaluronate-binding motifs (Fig. 1) [2,3]. In the peripheral blood, CD38 is expressed by natural killer (NK), T, and B lymphocytes and, to a lesser extent, by platelets and erythrocytes. The levels of lymphocyte expression of CD38 vary during the course of the human lifespan: neonatal lymphocytes express higher levels than adult cells [4]. Among T cells, it is detectable at high levels on mature thymocytes and activated T cells and at low levels on resting (i.e., HLA-DR−−CD25−−CD69−−) naïve cells (CD45RA+/R0−− cells), whereas it is undetectable on resting memory cells (CD45RA−−/R0+ cells) [5,6]. Among B cells, it is an indicator of immature cells, is newly expressed by activated cells and is one of the few available plasma cell markers [5]. The molecule is also expressed by pancreatic islets, prostatic epithelial cells, astrocytes and Purkinje cells [7]. Other CD38-expressing tissues are smooth and striated muscle, renal tubules and retinal gangliar cells [5].

Fig. 1.

Fig. 1.

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Enzymatic activity

In 1992, interest was re-fueled in human CD38 when it was shown to share similar characteristics with an enzyme purified from the mollusk Aplysia californica [8]. CD38 was then found to behave as a multifunctional ectoenzyme and to produce compounds involved in the regulation of cytoplasmic calcium levels [5]. Indeed, purified CD38 is able not only to produce nicotinamide (NAm) and cyclic ADP-ribose (cADPR) from NAD+ but also to degrade cADPR to ADP-ribose (ADPR), thus revealing its nature as a bifunctional ectoenzyme (ADP-ribosylcyclase and cADPR hydrolase) [9] (reviewed by Berthelier et al. [10]). The mechanism by which cADPR produced on the outer surface of the cell reaches its sites of action (intracellular calcium stores) is still to be determined. Several hypotheses have been advanced; one of the latest suggests that CD38 homotypic interactions occurring on cell membranes may lead to the formation of a dimer that acts as a cADPR transporter [11–13]. A further crucial issue to be addressed concerns the topological paradox represented by CD38: how does an ectoenzyme operate in the extracellular environment where its substrate, NAD+, is present only in trace amounts? One possibility is that the enzymatic function of CD38 is mainly active in microenvironments with high local concentrations of NAD+, such as in the presence of large amounts of dying cells releasing their intracellular NAD+. In line with this possibility, CD38 is highly expressed in primary and secondary lymphoid organs and in inflammatory tissues, where high levels of cell death occur. Most intriguingly, CD38 has recently been observed in the inner membrane of the nucleus [14], suggesting that this molecule also plays a role in this cell compartment.

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Adhesive activity and ligand

The involvement of surface CD38 in cell-to-cell adhesion was suggested following the observation that patterns of cell migration into tissue vary according to the level of expression of CD38. CD4+CD45RA+ T cells constitutively express low amounts of CD38 and preferentially migrate from the blood to lymph nodes, whereas CD4+CD45R0+ T cells do not express CD38 and preferentially reach lymph nodes via peripheral tissues and the afferent lymph. Moreover, activated T cells express high levels of CD38 and tend to migrate into peripheral tissues. Since homing of lymphocytes depends on a cooperative network of adhesion receptors expressed by lymphocytes and human endothelial cells (HEC), we suggested that CD38 could be involved in this network [15]. In line with this possibility, we observed that anti-CD38 monoclonal antibodies (mAb) inhibited the adhesion to HEC of CD38+ cells [6] when the assay was performed in conditions minimizing the integrin function. This finding suggested that CD38 mediates weak adhesive interactions between leukocytes and HEC. The production of a wide panel of mAb specific for HEC membrane made it possible to isolate the Moon-1 mAb capable of blocking the CD38-mediated cell adhesion to HEC that operates on the HEC side [16]. The CD38 ligand proved to be a ∼130 kDa single-chain protein constitutively present on HEC and variably expressed by T lymphocyte subsets, NK cells, monocytes, granulocytes and platelets. The structure was later identified as CD31 according to several criteria [17].

The involvement of CD31 in the CD38-mediated adhesion was assessed by evaluating the ability of anti-CD31 mAb to inhibit adhesion of CD38+ cell lines to HEC and to murine fibroblasts transfected with human CD31. The conclusions from these experiments are that CD31 is a counter-receptor for CD38 on HEC, that the blocking effects on CD31 depend on the domain recognized by the mAb (the second loop of the molecule is determinant) (Fig. 2a), and that the process is favored by unidentified molecules expressed by HEC but not by the murine transfectants. The hypothesis infers that the CD38/CD31 interaction mediates weak adhesive events between lymphocytes and HEC and is involved in lymphocyte homing (Fig. 2b).

Fig. 2.

Fig. 2.

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Signals delivered by CD38

The role of CD38 as a signaling molecule is suggested by the observation that CD38 triggering is involved in T cell costimulation, B cell maturation, and induction of cytokine production by several cell types [4,5,18,19] (Table 1). These signals are not a prerogative of a single cell lineage but are shared by B, T, and myeloid cells. CD38 signaling inhibits the growth of immature B cells in the bone marrow microenvironment, suggesting that it represents a novel regulatory mechanism of B lymphopoiesis [19]. In mature germinal center B cells, CD38 delivers rescue signals that protect cells from apoptosis and upregulate Bcl-2 (a molecule associated with antiapoptotic effects) in a manner similar to that observed with triggering of CD40, which is known to deliver costimulatory signals to the B cell [23]. In purified T cells, CD38 signaling induces production of high levels of interleukin (IL) 6, granulocyte-macrophage colony-stimulating factor, interferon γ, and IL-10 and low levels of IL-4 and IL-2 (i.e., a cytokine profile shared by T helper 1 and 2 cells) [22].

Table 1

Table 1

But how does signal transduction occur, and what role do the enzymatic activities play? It is true that the agonistic epitopes either overlap with or lie very close to the enzymatic domain [24]. Yet the relationship between signal transduction and enzymatic activities remains difficult to explain, given that the enzymatic activities are totally unaffected by ligation of the molecule, whether by agonistic or non-agonistic mAb.

According to one current view, the apparent structural unsuitability of CD38 to direct signaling (it has a very short cytoplasmic tail) could be overcome through the establishment of lateral interactions with other molecules capable of transducing signals across the membrane. The use of co-capping tests indicated associations of CD38 with the T cell receptor, the B cell receptor, and the NK receptor CD16, the common trait of these molecules is their specialization in transmembrane signaling [25]. Moreover, a coordinated regulation of membrane expression characterizes the relationship between CD38 and other related ectoenzymes, such as prohormone convertase-1 (a cell surface protease) and CD73 (an ecto-5′-nucleotidase) [21,26]. Further analyses were conducted using the fluorescence resonance energy transfer technique, which allows detection of lateral association of CD38 to the ectoenzymes CD26 (a dipeptidyl-peptidase IV) and CD39 (an apyrase acting on NAD+) [26,27]. These findings suggest that CD38 is a forerunner of a large family of molecules with similar characteristics that are partly expressed on the membrane, partly active inside the cells (cytosol and internal membranes), and partly released outside the cell (soluble molecules).

However this view seems to be contradicted by recent results showing that CD38 is capable of direct signaling through its intracytoplasmic tail. CD38 and lck, a cytoplasmic component of the signaling chain, are physically associated through the cytoplasmic tail and the SH2 domain, respectively [28] (Fig. 1).

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The gene for CD38

After isolation of complementary DNA (cDNA) of human CD38 [29], the human gene (CD38) was cloned by both Nata et al. [30] and Ferrero et al. [31,32]. Ferrero's results indicate that human CD38 is encoded by a large, complex, single-copy gene that extends over 60 kb; the overall length remains to be established (Fig. 3). The gene consists of eight exons and seven introns of heterogeneous length, the most remarkable being the first, which seems to be over 20 kb long. The putative promoter region lacks canonical TATA and CAAT boxes, and primer extension analysis revealed that transcription is initiated at multiple sites. Notably, this region also presents potential binding sites for several immunologically relevant transcription factors, such as ternary complex factors, the nuclear factor activated by IL-6, and the interferon regulatory factor 1. Furthermore, the observation that CD38 was induced by retinoic acid on HL-60 cells led to the identification of an retinoic acid response element in the first intron of CD38 [32,33].

Fig. 3.

Fig. 3.

Comparison of CD38 with the genes of homologous molecules [the gene for human BST-1/CD157 (another ecto-NADase with ADP-ribosylcyclase activity) [34], murine BST-1 [35], and Aplysia ADP-ribosylcyclase [8]] revealed the striking conservation of their exon–intron organization. There are two implications of this finding. First, it strongly suggests that the three genes evolved from a common ancestor. Second, it shows that CD38 and BST-1 are paralogs, i.e., they were derived from gene duplication before the divergence of humans and rodents. Indeed, human CD38 and BST-1/CD157 are syntenic and map to the same bands of chromosome 4 (4p15).

Another issue currently under investigation is the existence of genetic polymorphism, evidence for which stemmed from the observation of a phenotypic variability in the levels of CD38 expression on peripheral blood mononuclear cells in different subjects. This heterogeneity also involves cytokine and proliferation response of lymphocytes to anti-CD38 mAb [22] and levels of soluble CD38 in serum [36]. A Pvu II restriction fragment length polymorphism associated with CD38 has recently been disclosed by defining two constituent alleles (CD38*A and CD38*B), the latter being predominant in the Italian Caucasian population [37].

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CD38 expression in HIV-1-infected individuals

As in most viral infections, HIV-1 infection causes activation of B and T cells (both CD4 and CD8 cells), which consequently upregulates the surface expression of CD38 and other activation markers. CD38 upregulation can be detected on uninfected cells, indicating that this expression is not caused by direct infection. Furthermore, in vitro models showed that CD38 expression is down- rather than upmodulated by HIV-1 infection [38]. Therefore, the basis for upregulation should be sought within the dynamic interactions occurring in vivo between HIV-1 and the immune response. Important insights to this question have been provided by studies conducted during the 1990s to evaluate the prognostic value of CD38 as a marker of disease progression.

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Prognostic value of CD38 expression in adults

The T-cell subset best investigated for CD38 expression is that carrying CD8. In these cells, CD38 expression is upregulated at seroconversion; it is maintained at high levels in those who are short progressors or decreases in subjects with stable CD4 cell levels [39]. In general, CD38 is higher in subjects in the asymptomatic phase than in healthy controls [39,40]. CD38 expression on CD8+ T cells can increase again before full-blown AIDS [41]. By contrast, other authors have reported that upregulation of CD38 is stable in CD8+ T cells during the entire progression of the disease in most subjects [42].

The notion that high proportions of CD8+CD38+ T cells predict progression in HIV-1-infected adults has been recognized since the late 1980s [43]. Conclusive evidence was furnished by the results of a 6-year follow-up study conducted by the Multicenter AIDS Cohort Group. Data from the study indicated not only that CD8+CD38+ lymphocyte proportions have prognostic value for development of AIDS but also that their prognostic value is additive to that of CD4 T cell counts [44]. These findings have been attributed to the ability of CD38 to mark activation of the immune system. Moreover, some of the CD8+CD38+ lymphocytes displayed cytotoxic activity against CD4 cells expressing viral antigens, possibly contributing to CD4+ T cell depletion [20]. More recently, others have shown that high proportions of CD8+CD38+ T cells predicted the subsequent decline of CD4+ T cell counts [45], and cross-sectional studies showed that CD8+CD38+ T cells correlated with viral load in subjects treated with HAART [46]. The prognostic value of CD38 expression on CD8 cells may be further improved by evaluating expression in CD45R0+CD8+ T cells: relative proportions of CD8+CD45R0+ CD38+ T cells correlate with the subsequent decline of CD4+ T lymphocytes better than simple proportions of CD8+CD38+ T cells [45]. These findings may be explained by the observation that CD8+CD45RA+ T cells (mainly resting/naive cells) constitutively express CD38 even in normal controls and offer no significant contribution to the prognosis. By contrast, while CD8+CD45R0+ T cells (mainly memory cells) do not normally express CD38, they do express it upon cell activation, making CD38 a good marker for activated T cells only in the CD45R0+ subset. The prognostic value of CD38 expression on CD8 cells may also be improved by evaluating the mean intensity of CD38 expression rather than just the proportion of positive cells [47,48]. Intensity values avoid subjective variability of cursor placement in cytofluorimetric analysis when scoring positive cells (complete details on the methods for quantifying CD38 expression on CD8 cells can be found in Gratama et al. [49]). Moreover, intensity values are sensitive to the relative component of CD38 expressed by CD45RA+ or CD45R0+ T cells since resting CD45RA T cells express CD38 at low intensity (CD38low) whereas activated CD45R0+ T cells express it at high intensity (CD38bright). Liu et al. showed that the intensity of expression of CD38 on CD8 T cells had predictive value for progression and was partly independent of the predictive value of plasma viral load and CD4+ T cell counts [50,51]. The same authors also showed that survival of subjects with less than 50 × 106 cells/l CD4+ T cells was more closely associated with the level of expression of CD38 than with the plasma virus load or virus chemokine coreceptor usage [52].

High CD38 expression on CD4+ T cells is also a marker of poor prognosis. This issue was debated for some time, but a cross-sectional study by Benito et al. has convincingly shown that CD38 expression on CD4 cells correlates with disease stage when associated with expression of CD45R0 or HLA-DR [53] (i.e., when analysis excluded CD38 constitutively expressed by CD45RA cells). More recently, Giorgi et al. showed that high levels of CD38 expression on CD4 cells were strongly associated with short survival in subjects with advanced infection [52]. Intriguingly, the virus load correlated with the number of CD38 molecules on CD8 but not on CD4 cells.

CD38 is also upregulated on CD19+ B cells during HIV-1 infection. In a preliminary study, CD38 expression on B cells strongly correlated with viral load [42].

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Prognostic value of CD38 expression in children

Results in children are quite different: high levels of CD38 expression are a favorable prognostic marker in many studies. In particular, Schlesinger et al. showed that high proportions of CD8+CD38+ T cells are a favorable prognostic marker, and other investigators showed that high proportions of CD4+CD38+ T cells both at birth and after 5 years are positively correlated with survival [54–56].

One interesting model explaining the contrasting prognostic value of CD38 expression in adults and children was proposed by de Martino et al., who considered differences in renewal of T lymphocytes in the two populations (Fig. 4) [56]. The model was based on the assumption that the CD38+ T cells expanded by HIV-1 infection are mostly short-lived terminally activated effector cells with low replicative potential in adults. In contrast, they are mostly long-lived recent thymic emigrants with high replicative potential in children. Based on Ho's model of lymphocyte dynamic turnover in HIV-1 infection [57], de Martino et al. suggested that release of long-living recent thymic emigrants in children would stand better chances of counterbalancing the virus-mediated destruction of CD4+ T cells than would peripheral expansion of short-living effector T cells in adults. In line with this possibility, several authors showed that most CD38+HLA-DR+ `activated' T cells display an incomplete pattern of activation molecules in HIV-1-infected adults, since they do not express CD25 [42,58]. The implication is that a proportion of these cells may be anergized or exhausted cells undergoing spontaneous apoptosis. Indeed, several authors showed that activated T cells undergo spontaneous apoptosis in HIV-1 infection [59,60]. However, studies on telomere length suggest that HIV-1 infection causes only a modest increase of lymphocyte turnover, which may not result in exhaustion of regenerative capacity [61]. Therefore, CD38 expression would not necessarily be associated with terminal activation of lymphocytes or exhaustion of their regenerative capacity. Finally, studies on HAART recipients have brought into question the underlying assumptions of de Martino's hypothesis; they suggest that CD8+CD38+ cells are not anergic in HIV-1-infected adults [62].

Fig. 4.

Fig. 4.

In summary, lymphocyte lifespans alone cannot account for the different prognostic value of CD38 in adults and children, and other explanations based on CD38 functions are needed.

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CD38 and highly active antiretroviral therapy

Two lines of observation suggest that expression of CD38 may be a useful tool for monitoring HAART. The first showed that HIV-infected subjects displaying high proportions of CD8+CD38+ cells will respond to antiretroviral therapy more rapidly than individuals with low levels. This evidence suggests that these cells may contribute to viral clearance and become effective when HAART decreases viral load [62]. The second line showed that decreased CD38 expression on CD8+ T cells is a marker of effective response to HAART, probably because it follows the decreased viral load induced by therapy [46,63–65]. Our experience confirmed these observations and showed that the decreased proportions of CD8+CD38+ T cells marking positive response to antiretroviral therapy can already be detected 1 month after the start of therapy (C. Cantamessa, unpublished observations). Further evidence was supplied by Carcelain et al., who reported decreased expression of CD38 on both CD8+ and CD4+ T cells in patients with acute primary infection treated with combined nucleoside analog therapy [66]. In addition, Viganòet al. showed that persistence of high expression of CD38 on CD8+ T cells is a marker of therapeutic failure in HIV-1-infected children [67].

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CD38 as an active player in HIV-1 infection

CD38 as a compensatory molecule

CD38 expressed by lymphocytes from HIV-1-seropositive individuals are fully active NADases [68], and some of their products seem to display protective activity against several steps of infection. The best-known product of the catalytic activity of CD38 is NAm, which crosses the plasma membrane and exerts its activity intracellularly. NAm inhibits HIV-1 replication at a postintegrational level and increases survival of HIV-1-infected cells [69–71]. Moreover, NAm prevents apoptosis both in T cells acutely infected in vitro and in T cells from HIV-1-infected individuals [72,73]; it also prevents intracellular NAD+ depletion induced by HIV-1 infection in CD4+ T cells in vitro [74]. According to Furlini et al., infection may increase levels of poly(ADPR) polymerase, which catabolyzes NAD+; the resulting NAD+ depletion may cause cell death [75].

Others have suggested that the increased expression of CD38 on T and B cells from HIV-1-infected individuals is a compensatory mechanism for the re-use of pre-existing nucleotides by nucleotide-starved cells [42,68,76]. Resting lymphocytes from HIV-1-infected subjects show defective purine and pyrimidine synthesis, which is further decreased after stimulation [42]. Overexpression of CD38 would assist in the recycling of nucleotides derived from dead cells and, thus, aid cell survival. However, the transmembrane trafficking of ADPR and cADPR is still debated. On the whole, these findings suggest that CD38 enzyme activity may protect lymphocytes from cell death induced by NAD+ or nucleotide depletion.

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Lateral association between CD38 and CD4: interference with CD38 adhesive function and HIV-1 attachment/entry

CD38 displays complex lateral interactions on the cell membrane, docking at several surface receptors including CD4. This association is normally displayed on the cell surface and is potentiated by cell incubation with the HIV-1 gp120 envelope glycoprotein (Fig. 5) [77–79]. The ability of gp120 to recruit CD38 seems to be highly conserved and was displayed by all gp120 preparations tested (derived from the HIV-1 strains IIIB, MN, SF2, and 451) [78]. Induction of association was not mediated by inside-out signaling via the CD4-associated tyrosine kinase lck, since it was not induced by anti-CD4 mAb nor inhibited by tyrosine kinase inhibitors [78]. Moreover, it was not mediated by chemokine receptors interacting with gp120. Indeed, CXCR-4 and CCR5 do not associate with CD38 in the presence or absence of gp120 (U. Dianzani, unpublished observations) and chemokines do not alter the CD4/CD38 association [78]. We suggested that the CD4-bound gp120 also interacts with third-player molecules or induces conformational changes of CD4, thus increasing association with CD38. The role envisaged for gp120-induced CD4/CD38 lateral association during HIV-1 infection could involve either modification of CD38 function or modulation of viral entry into cells. We found data supporting both possibilities.

Fig. 5.

Fig. 5.

The first possibility is supported by observations that gp120 potentiated the CD38/CD31-mediated lymphocyte adhesion to vascular endothelial cells in vitro and altered their homing in vivo by potentiating homing into the gut and mesenteric lymph nodes [79]. These effects may result from intermolecular aggregations on the T cell surface, forming adhesive patches. We suggested that this gp120 effect may play a role in the pathogenesis of infection. By increasing lymphocyte homing into lymphoid tissues associated with mucosae, it would contribute to depletion of uninfected peripheral CD4+ T cells and favor their infection in a tissue that often is the main entrance route of HIV-1. Moreover, by affecting lymphocyte recirculation, it would decrease the probability of encounters between antigens and lymphocytes, alter the spread of effector lymphocytes into peripheral tissues, and contribute to immune deficiency. In line with this possibility, Hengel et al. showed that CD4+ T cells that expressed both CD62 ligand (CD62L) and CD38 recirculated preferentially through lymphoid tissues and were preferentially `consumed' in the steady state of HIV-1-infection [80]. The authors focused on the role of CD62L in these phenomena; however, the role of CD38 should also be considered.

The second possibility (that CD4/CD38 lateral association modulates viral entry into cells) is supported by observations that CD38 inhibited early phases of the HIV-1 replication cycle, probably acting at the level of virus attachment/entry. Using laboratory X4 HIV-1 strains and X4 and X4/R5 primary isolates, we found that the level of CD38+ expression was negatively correlated with cell susceptibility to infection. This correlation was first suggested by results obtained in a panel of human CD4+CXCR-4+ T cell lines expressing different levels of CD38 [70] and then demonstrated using CD38+ transfectants of MT-4 cells (the line with the lowest CD38 expression) [81]. To address whether CD38 affected HIV-1 attachment to CD4, we used mouse T cells expressing human CD4 and/or CD38. This approach allowed us to evaluate the effects of human CD38 on gp120/CD4-dependent HIV-1 attachment to cells in the absence of human coreceptors. The data indicated that human CD38 expression inhibited the association of HIV-1 or purified gp120 with CD4 cells [81]. These results suggest that human CD38 inhibits gp120/CD4-dependent HIV-1 attachment to cells. These findings may explain the observation that CD38 expression on CD4 cells has a favorable impact on disease progression only in children. Indeed, the cells in children expressing high levels of CD38 are mostly recent thymic emigrants and naive cells, whereas in adults they are primarily activated T cells [82]. Activated T cells express a different pattern of the molecules involved in viral binding and entry (such as chemokine receptors CD26, or CD44) and are much more efficient than resting cells in supporting viral replication at post-entry levels, which may overwhelm inhibition by CD38 [83–85]. Therefore, CD38-mediated protection may be evident in children, whose CD38bright cells are predominantly resting cells, but not in adults, where they are predominantly activated. Data obtained in vivo by Zhang et al. support the possibility that HIV-1 preferentially infects CD38−− cells and suggest that the higher levels of HIV-1 gene expression displayed by activated compared with resting T cells may be the result of post-entry events [86]. These authors, in fact, showed that most HIV-1-infected cells are CD38−− (resting memory cells?) in early stages of infection, although infected activated cells produce the highest levels of HIV-1 RNA. However, infected T cells are more frequently activated in advanced stages, which suggests that they derive from resting memory cells harboring proviral DNA [87].

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The role of CD38 revisited

We propose a model that encompasses most of the information currently available on the CD38 molecule. HIV-1 induces lymphocyte activation and increased expression of CD38, which might be a mechanism that helps the survival of nucleotide-starved cells. Some of these activated cells are endowed with cytotoxic activity and are involved in fighting the infection. However, the final effect of lymphocyte activation is detrimental since activation favors cell infection by upregulating molecules involved in HIV-1 replication. We speculate that, in HIV-1 infection, the recruitment of lymphocytes into lymphoid tissues (a site for their infection and activation) is favored by viral gp120, which induces or potentiates CD38 association with CD4, altering the organization of the lymphocyte adhesive patches. The CD4/CD38 association would be `paid for' by the virus in terms of efficiency of CD4-dependent HIV-1 attachment, but this effect would be compensated by the upregulation of molecules cooperating with virus replication in activated T cells. Therefore, the final prognostic value of CD38 expression may depend on the balance between positive effects (increased survival of nucleotide-starved cells, inhibition of gp120/CD4 binding, and cytotoxic activity of CD8+CD38+ lymphocytes) and negative effects (expression by activated cells and modulation of T cell homing); the relative influence of these may vary under different conditions (Fig. 6). In untreated adults, the negative effects prevail, and the prognostic value is unfavorable given that viral load is high, many resting T cells are CD38−− memory cells, and most CD4+ CD38bright cells are activated cells that optimally support viral replication. At start of a HAART regimen, high expression of CD38 predicts a rapid response to therapy [62], since virus levels subsequently decrease and consequently permit the antiviral effects to prevail. Yet, the decreased expression of CD38 paralleling successful HAART is not surprising: indeed, the levels of CD8 anti-HIV-1 suppressor activity (a factor long known to inhibit HIV-1 replication [88]) also decrease in response to HAART [89]. The positive effects of CD38 prevail in children, and the prognostic value is favorable, since most CD38bright cells are naive cells that hardly support viral entry and replication and few resting T cells are memory CD38 cells.

Fig. 6.

Fig. 6.

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Concluding remarks

The reports reviewed here suggest that CD38 is not only an important prognostic marker but also an active player in HIV-1 infection. To sum up, the recent findings on the antiviral effects of CD38 may help to explain the favorable prognostic value represented by the expression of this molecule in HIV-1-infected children. By comparison, the link between CD38 expression and lymphocyte activation, coupled with its contribution to lymphocyte homing, may determine the negative prognostic value in adults. These data are reminiscent of those reported for RANTES, a chemokine that exerts antiviral effects and yet high levels are associated with poor prognosis in HIV-1-infected adults [90]. Similarly to what is postulated for CD38, the discrepancy has been attributed to a preferential expression of RANTES upon lymphocyte activation.

The elucidation of the exact role of CD38 in HIV-1 infection may contribute to a better understanding of the immune correlates of infection and the early stages of virus replication, such as gp120/CD4 binding. In turn, this explanation could lead to improvements in the follow-up of HAART recipients and in the research for new therapies and vaccines.

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Acknowledgements

The authors thank to Drs Silvia Deaglio and Enza Ferrero, University of Turin, Italy, for providing information and suggestions.

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Keywords:

CD38,; lymphocyte activation,; lymphocyte homing,; HIV-1 attachment HIV entry

© 2000 Lippincott Williams & Wilkins, Inc.