HIV Disease Progression: Overexpression of the Ectoenzyme CD38 as a Contributory Factor?

Abstract

Summary Despite abundant evidence associating CD38 overexpression and CD4 T cell depletion in HIV infection, no causal relation has been investigated. To address this issue, we propose a series of mechanisms, supported by evidence from different fields, by which CD38 overexpression could facilitate CD4 T cell depletion in HIV infection. According to our model, increased catalytic activity of CD38 may reduce CD4 T cells’ cytoplasmic nicotinamide adenine dinucleotide (NAD), leading to a chronic Warburg effect. This would reduce mitochondrial function. Simultaneously, CD38’s catalytic products ADPR and cADPR may be transported to the cytoplasm, where they can activate calcium channels and increase cytoplasmic Ca2+ concentrations, further altering mitochondrial integrity. These mechanisms would decrease the viability and regenerative capacity of CD4 T cells. These hypotheses can be tested experimentally, and might reveal novel therapeutic targets.

Trispecific antibodies enhance the therapeutic efficacy of tumor-directed T cells through T cell receptor co-stimulation

“…CD38 represents an attractive target for myeloma therapy, not only because of its expression on tumor target cells but also for its immunomodulatory functions. Upregulation of CD38 has also been shown on exhausted T cells, including in HIV-1 infection where CD38 upregulation on CD8 + T cells correlated with CD4 + T cell depletion and a worse disease prognosis 54,55 . CD38 upregulation has also been implicated in the suppression of T cell immunity to malignancies, possibly through regulatory T cells 56,57 .…”

Both HCV Infection and Elevated Liver Stiffness Significantly Impacts on Several Parameters of T-Cells Homeostasis in HIV-Infected Patients

“…T-cells activation and exhaustion are important factors in the pathogenesis of HIV disease and thus, the increases we observed in coinfected patients may potentially have relevant clinical implications. Activation of CD8 T-cells has a central role in HIV progression as has been extensively reported [ 36 ]. More recently, T-cells exhaustion has been shown as another important factor involved in HIV disease progression, both in cross-sectional [ 37 ] and longitudinal [ 38 , 39 ] studies.…”

Roles of CD38 in the Immune Response to Infection

“…Interestingly, the levels of CD38 expression associated with prognosis differ depending on the population analyzed (adults versus children) (reviewed in [56]). Overexpression of CD38 on lymphocytes is, in fact, a strong predictor of CD4 + T cell depletion in adult HIV-infected individuals (reviewed in [57]). Early after HIV infection, the expression of CD38 increased in CD4 + and CD8 + T lymphocytes [58][59][60], and high proportions of the CD8 + CD38 + subpopulation were associated with progression to acquired immune deficiency syndrome in adults [61,62].…”

“…In those studies, gp120 increased the homing of a murine T cell line expressing CD4 + into the spleen and intestine and mesenteric lymph nodes, raising the possibility that CD38 could be involved in mediating T cell homing during HIV infection. Nevertheless, despite CD38 overexpression representing a marker of activation and of poor prognosis in HIV infection, whether CD38 enzymatic activities play a role in the pathogenicity of HIV infection in adults remains an open question [57].…”