CD28-B7 Costimulatory Blockade by CTLA4Ig Delays the Development of Retrovirus-Induced Murine AIDS

Abstract

Mouse AIDS (MAIDS) induced in C57BL/6 mice by infection with a replication-defective retrovirus (Du5H) combines extensive lymphoproliferation and profound immunodeficiency. Although B cells are the main target of viral infection, recent research has focused on CD4+ T cells, the activation of which is a key event in MAIDS induction and progression. A preliminary observation of increased expression of B7 molecules on B cells in MAIDS prompted us to address the possible involvement of the CD28/B7 costimulatory pathway in MAIDS. Mice infected with the MAIDS-inducing viral preparation were treated with murine fusion protein CTLA4Ig (3 × 50 μg/week given intraperitoneally), a competitive inhibitor of physiological CD28-B7 interactions. In CTLA4Ig-treated animals, the onset of the disease was delayed, lymphoproliferation progressed at a much slower rate than in untreated mice, and the loss of in vitro responsiveness to mitogens was reduced. Relative expression of Du5H did not differ between treated and untreated animals. These results suggest that the CD28/B7 costimulatory pathway contributes to MAIDS development.

CD40-deficient mice infected with the defective murine leukemia virus LP-BM5def do not develop murine AIDS but produce IgE and IgG1in vivo

“…However, studies with cytokine knockout mice have only partially supported this hypothesis [1]. In addition, co-stimulatory molecules, which are known to mediate cognate cell-cell interactions, have been proposed to be involved in the development of MAIDS [8,9]. Interactions of CD40 on B cells with CD40 ligand (CD40L) on activated T cells are known to transduce a co-stimulatory signal essential for activation and differentiation of B cells [10,11].…”

Cyclo-oxygenase type 2-dependent prostaglandin E2 secretion is involved in retrovirus-induced T-cell dysfunction in mice

“…It has therefore been suggested that MAIDS may develop as paraneoplastic syndrome. However, as mentioned above, both B-and T-cells are required for disease development [2][3][4], and several cell contact-dependent interactions involved in normal B-and T-cell interactions have been shown to be required as well [9][10][11][12]. This may lead to the hypothesis that Pr60 gag induces aberrant activation of infected B-cells, which activate T-cells in the vicinity of lymphoid tissues in an antigen non-specific manner, but by applying co-stimulatory pathways and adhesion proteins normally involved in antigen-specific immune responses.…”

“…Direct cell contact-dependent interactions between T-and B-cells play a key role in the disease development. Blocking these interactions with anti-CD40L [9], CTLA4Ig [10,11] or antibodies to intercellular cell-adhesion molecule 1 and lymphocyte function associated antigen [12] inhibits the disease progression to various degrees. Several lines of evidence also suggest that soluble factors may be involved [13], although these remain unknown.…”

Mice transgenic for a soluble form of murine cytotoxic T lymphocyte antigen 4 are refractory to murine acquired immune deficiency sydrome development

“…15 In mice inoculated with the MAIDS-inducing preparation and treated with CTLA4 immunoglobulin (CTLA4Ig) (3 r 50 mg/week), lymphoproliferation progressed at a much slower rate than in untreated mice and the loss of in vitro responsiveness to mitogens was reduced. 14 However, the inhibitory effects of CTLA4Ig were circumvented with time, so the importance of CD28/B7 interactions for MAIDS induction was actually dif®cult to discern in this model. To investigate this question, we analysed the fate of MAIDS virus inoculation in mice transgenic for mCTLA4-Hc1 [a fusion protein between mouse CTLA4 and human immunoglobulin G1 (IgG1)].…”