Antigen-Dependent and -Independent Mechanisms of T and B Cell Hyperactivation during Chronic HIV-1 Infection

Abstract

Continuous loss of CD4؉ T lymphocytes and systemic immune activation are hallmarks of untreated chronic HIV-1 infection. Chronic immune activation during HIV-1 infection is characterized by increased expression of activation markers on T cells, elevated levels of proinflammatory cytokines, and B cell hyperactivation together with hypergammaglobulinemia. Importantly, hyperactivation of T cells is one of the best predictive markers for progression toward AIDS, and it is closely linked to CD4 ؉ T cell depletion and sustained viral replication. Aberrant activation of T cells is observed mainly for memory CD4؉ and CD8 ؉ T cells and is documented, in addition to increased expression of surface activation markers, by increased cell cycling and apoptosis. Notably, the majority of these activated T cells are neither HIV specific nor HIV infected, and the antigen specificities of hyperactivated T cells are largely unknown, as are the exact mechanisms driving their activation. B cells are also severely affected by HIV-1 infection, which is manifested by major changes in B cell subpopulations, B cell hyperactivation, and hypergammaglobulinemia. Similar to those of T cells, the mechanisms underlying this aberrant B cell activation remain largely unknown. In this review, we summarized current knowledge about proposed antigen-dependent and -independent mechanisms leading to lymphocyte hyperactivation in the context of HIV-1 infection.

The Suv39H1 methyltransferase inhibitor chaetocin causes induction of integrated HIV-1 without producing a T cell response

“…Activated T-cells secrete cytokines such as IL-2, which plays a pivotal role in immune response. T-cell activation is also characterized by increased surface expression of CD69 which acts in T-cell proliferation and signaling [18], and accordingly we observe induction of IL-2 and CD69 in Jurkat cells treated with PMA (Fig. 3A and B).…”

“…In contrast, treatment of cells with chaetocin for 8 h did not cause a change in CD69 or IL-2 expression, indicating that chaetocin is capable of inducing HIV-1 expression without causing global T-cell activation. Activated T-cells undergo a variety of morphological changes including decreased aggregation and adherence to the substratum [18]. This was observed in Jurkat cells treated with PMA, where after 2 h treatment the cells become dispersed, flatten out and attach to the plate (Fig.…”

“…This can be mimicked using agonists such as PMA, which stimulates T-cell responses including enhanced cell adhesion and increased expression of IL-2 and CD69 [18]. Cells stimulated with chaetocin and/or the HDAC inhibitor SAHA do not exhibit these phenotypes.. Stimulation of Jurkat cells with PMA causes activation of the HIV-1 LTR through NFjB [21].…”

“…T-cells normally become activated by T-cell receptor engagement during antigen presentation [18]. This can be mimicked using agonists such as PMA, which stimulates T-cell responses including enhanced cell adhesion and increased expression of IL-2 and CD69 [18].…”

Mannosylated lipopetides as model vaccines for targeting the mannose receptor

“…The OVA protein naturally exists as a glycoprotein, however, it was discovered that the OVA [323][324][325][326][327][328][329][330][331][332][333][334][335][336][337][338][339] and OVA 1-10 sequences of the OVA protein bore a B cell epitope that was capable of inducing a T cell response. This discovery was obtained by T cell mediated IgE responses that were observed against an assumed B cell epitope inside OVA323-339 and OVA1-10 peptides [185].…”