Role of CD40 Ligand Signaling in Defective Type 1 Cytokine Response in Human Immunodeficiency Virus Infection

Abstract

The pathogenesis of defective interleukin (IL)-12 and interferon (IFN)-gamma production in human immunodeficiency virus (HIV)-infected patients remains to be elucidated. This study investigated the possibility that perturbations in CD40 ligand signaling are involved in this defect. CD40 ligand trimer (CD40LT) stimulated peripheral blood mononuclear cell (PBMC) production of IL-12 in response to Toxoplasma gondii and cytomegalovirus (CMV). Regardless of the CD4 cell count, CD40LT restored IL-12 secretion in response to T. gondii in HIV-infected patients. In the presence of CD40LT, PBMC from both HIV-infected patients and control subjects produced high levels of IL-12 in response to CMV. CD40LT restored T. gondii- and CMV-triggered IFN-gamma secretion by T cells and PBMC from HIV-infected patients with a CD4 cell count >200 cells/microL. CD4 cells from HIV-infected patients, even those with a CD4 cell count >500 cells/microL, had defective CD40L induction after T cell stimulation mediated by antigen-presenting cells. Together, impaired CD40L induction is likely to contribute to defective IL-12 and IFN-gamma production in HIV infection.

CD40 Ligand Dysregulation in HIV Infection: HIV Glycoprotein 120 Inhibits Signaling Cascades Upstream of CD40 Ligand Transcription

“…The capacity to up-regulate CD40L on purified CD4 ϩ T cells becomes progressively impaired in HIV infection, in parallel with overall immunosuppression (9,18). Underlying mechanisms of CD40L impairment likely involve interactions between the major HIV-1 surface glycoprotein, gp120, and the CD4 receptor on the surface of CD4 ϩ T cells (in our study and in Ref.…”

“…Among the APC functions that have been reported defective in HIV infection is a marked impairment of production of IL-12 by PBMC and macrophages from HIV-infected (HIV ϩ ) patients (1)(2)(3)(4)(5)(6)(7)(8)(9). This defect in IL-12 production does not reflect a global deficiency in secretion of proinflammatory cytokines by APC, as production of TNF-␣ and IL-1␤ are not reduced (1,2).…”

“…Blunted up-regulation of surface expression of CD40L has been shown in HIV ϩ donors (9,18). Because expression of this marker is tightly regulated, with different levels of regulation (transcription, posttranscription, posttranslation), the first focus of our studies was to determine the level of dysregulation in HIV ϩ donors.…”

Altered CD4+ T Cell Phenotype and Function Determine the Susceptibility to Mucosal Candidiasis in Transgenic Mice Expressing HIV-1

“…Nevertheless, the CD4C/HIV MutA transgene reduced the percentage of DCs expressing IL-12, consistent with the impaired maturation of BMDCs from CD4C/HIV MutA Tg mice (16). Expression of the HIV env gene product gp120 in APCs and impaired CD40L induction on CD4 ϩ T cells activated by Ag have been shown to impair IL-12 and IFN-␥ production by APCs, thereby preventing a protective Th1 response (30,31). Interestingly, the CD4C/HIV MutA Tg mice express Env, Rev, and Nef of HIV-1, and CD4 ϩ T cells from these mice express low levels of CD40L (14).…”

CD40, autophagy and Toxoplasma gondii

“…Impaired CD154 induction is particularly more pronounced in preterm babies (Kaur et al 2007), a finding relevant to toxoplasmosis in newborns since this is an infection acquired prior to birth. The CD40-dependent pathway of host protection is also relevant to HIV-1 + patients because these individuals exhibit a defect in CD154 induction in their CD4 + T cells (Subauste et al 2001, 2007b, Zhang et al 2004.…”