Differential Regulation of HIV-1 Fusion Cofactor Expression by CD28 Costimulation of CD4 ⁺ T Cells

Abstract

Activation of CD4(+) T lymphocytes from human immunodeficiency virus-type 1 (HIV-1)-infected donors with immobilized antibodies to CD3 and CD28 induces a virus-resistant state. This effect is specific for macrophage-tropic HIV-1. Transcripts encoding CXCR4/Fusin, the fusion cofactor used by T cell line-tropic isolates, were abundant in CD3/CD28-stimulated cells, but transcripts encoding CCR5, the fusion cofactor used by macrophage-tropic viruses, were not detectable. Thus, CD3/CD28 costimulation induces an HIV-1-resistant phenotype similar to that seen in some highly exposed and HIV-uninfected individuals.

Chemokine immunobiology in HIV-1 pathogenesis

“…Although IL-2 signaling is associated with an increase in CC chemokine secretion and receptor expression, CD4 ϩ T cell activation by sustained anti-CD3/anti-CD28 activation induces the downregulation of chemokine receptors while enhancing CCchemokine secretion [159][160][161]. These effects corresponded with a much decreased susceptibility of CD3/CD28-activated cells to R5 viral infection [147,159,162]. CD3-mediated up-regulation of CCR5 promoter activity was inhibited after CD28 signaling, suggesting a transcriptional mechanism of action [163].…”

“…CD3-mediated up-regulation of CCR5 promoter activity was inhibited after CD28 signaling, suggesting a transcriptional mechanism of action [163]. Effects of sustained CD28 signaling on CXCR4 expression appear to be more complex: although CXCR4 mRNA is induced and there is no inhibition of X4 HIV-1 infection of activated PBMC [162], down-regulation of CXCR4 expression on IL-4-treated lymphocytes has been described [153]. It remains to be determined whether sustained CD28 costimulation can decrease X4 HIV-1 infection within type 2 polarized T cell lines.…”

Chemokine Receptor CCR4 on CD4+ T Cells in Juvenile Rheumatoid Arthritis Synovial Fluid Defines a Subset of Cells with Increased IL-4:IFN-γ mRNA Ratios

“…Chemokines are often up-regulated in inflammation (8,9) and act mainly on leukocytes inducing migration and release responses. Together this system is capable of supporting host defense and repair functions (10).…”

Potentiation of EBV-Induced B Cell Transformation by CXCR4-Tropic, But Not CCR5-Tropic, HIV gp120: Implications for HIV-Associated Lymphomagenesis

“…5,6 Also, stimulation with a-CD28 þ a-CD3 þ interleukin (IL)-2 reversibly blocked T cell surface expression of CCR5, but not CXCR4, and allowed continuous exponential growth. 7 Although not previously emphasized, this is the best published in vitro evidence of dichotomous roles for these two CKRs in apoptosis. In vivo, Piovan et al interrupted early lymphoma development and metastatic growth in SCID mice transfused with EBV þ peripheral blood mononuclear cells (PBMCs) by blocking CXCR4 signaling.…”