Antiviral Effect and Ex Vivo CD4 ⁺ T Cell Proliferation in HIV-Positive Patients as a Result of CD28 Costimulation

Abstract

Because stimulation of CD4+ lymphocytes leads to activation of human immunodeficiency virus-type 1 (HIV-1) replication, viral spread, and cell death, adoptive CD4+ T cell therapy has not been possible. When antigen and CD28 receptors on cultured T cells were stimulated by monoclonal antibodies (mAbs) to CD3 and CD28 that had been immobilized, there was an increase in the number of polyclonal CD4+ T cells from HIV-infected donors. Activated cells predominantly secreted cytokines associated with T helper cell type 1 function. The HIV-1 viral load declined in the absence of antiretroviral agents. Moreover, CD28 stimulation of CD4+ T cells from uninfected donors rendered these cells highly resistant to HIV-1 infection. Immobilization of CD28 mAb was crucial to the development of HIV resistance, as cells stimulated with soluble CD28 mAb were highly susceptible to HIV infection. The CD28-mediated antiviral effect occurred early in the viral life cycle, before HIV-1 DNA integration. These data may facilitate immune reconstitution and gene therapy approaches in persons with HIV infection.

Lentiviral transduction of human T-lymphocytes with a RANTES intrakine inhibits human immunodeficiency virus type 1 infection

“…The latter approach not only allows ex vivo proliferation of CD4 + T cells, but also transiently renders CD4 + T cells resistant to infection with R5-tropic HIV through down-regulation of the HIV fusion co-receptor CCR-5. 25,26 We used FACS analysis to assess the transduction efficiency of the LOX GFP WPRE vector on primary human T cells stimulated by the methods described above. PBLs from different donors were stimulated with rhIL-2 (20 IU/ml) and PHA (5 g/ml) or with anti-CD3 and CD28 antibodies for 3 days.…”

Chemokine immunobiology in HIV-1 pathogenesis

“…The following discussion is summarized in Figure 4. 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].…”

T-cell reconstitution and expansion after hematopoietic stem cell transplantation: ‘T’ it up!

“…We have developed a novel culture system that uses CD3 and CD28 antibody coated magnetic beads to serve as artificial antigen-presenting cells; by engaging CD3 with the costimulatory signal for CD28, CD4 þ T cells can be expanded several thousand fold and used for adoptive immunotherapy. 34,72,73 This technique avoids possible tolerance induction that can occur when the T-cell receptor is activated without proper costimulation and may bypass innate in vivo tumor-or cytokine-induced T-cell suppression. In addition, expansion through costimulation provides activated T cells with a diverse T-cell repertoire to accelerate immune reconstitution.…”