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

Abstract

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. 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.: Hypothetical model of human surface CD38 based on current information. The circle at the C-terminus of CD38 indicates a region bearing the enzymatic functions as well as some receptor activities (binding sites for hyaluronate and, possibly, CD31). Other possible intermolecular interactions of CD38 are indicated (i.e., lateral associations with other surface molecules and an intracytoplasmic association with the tyrosine kinase lck). ADPR, ADP-ribose; mAb, monoclonal antibody; NAm, nicotinamide.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. 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 coop