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.

Fig. 1.

Potential mechanisms contributing to aberrant T cell activation in HIV-1 infection. (A) Costimulation resulting in enhanced antigen-dependent (CD4⁺) T cell activation can be mediated by interaction of HIV-1 envelope glycoprotein gp120 with the CD4 coreceptor or by stimulation of TLR2, -5, or -7/8 via bacterial lipopeptides, flagellin, and HIV-1-derived ssRNA, respectively, or by proinflammatory cytokines such as IL-15 and IFN-α and/or costimulatory molecules expressed by (partially) activated dendritic cells. (B) In the absence of TCR stimulation, bystander activation of T cells may be induced by intracellular expression of HIV-1 Nef protein or by synergizing effects of TLR stimulation by IL-15 or IL-2 and/or different combinations of proinflammatory cytokines such as IL-2, IL-6, TNF-α, IL-12, or IL-15. Furthermore, lymphopenia-driven and cytokine-mediated homeostatic proliferation leads to acquisition of activation phenotypes in T cells. Only the mechanisms that most likely directly act on (CD4⁺) T cells are depicted.

Fig. 2.

Mechanisms potentially contributing to polyclonal B cell activation in HIV-1 infection. Polyclonal B cell activation independent of BCR stimulation can be induced by interaction of the HIV-1 envelope glycoprotein gp120 with the coreceptors DC-SIGN and CD21 or with VH3⁺ BCRs, by TLR9 stimulation via bacterial or virus-derived CpG DNA, and/or by T cell-mediated CD40/CD40L interaction in combination with cytokines (including IL-10, IL-2, IL-3, and IL-4) and exposure to increased levels of BAFF and ferritin. HIV-1 Nef and Tat were also shown to promote B cell activation with contradicting results for Nef, which was also reported to inhibit class switch recombination in B cells. Only the mechanisms that are most likely to act directly on B cells are depicted.