Dysfunctional phenotype of T cells and their contribution to impaired B cell function during HIV-1 infection

University dissertation from Stockholm : Karolinska Institutet, Dept of Microbiology, Tumor and Cell Biology

Abstract: Microbial translocation and increased immune activation have been involved in functional T cell impairments and disease progression during HIV-1 infection. The impact of microbial translocation on the phenotype of memory B cells in HIV-1 infected patients was studied in paper I. The expression of activation marker IL-21R was higher in HIV-1 infected patients compared with controls. An inverse correlation was observed between IL-21R expression and frequency of resting memory (RM) B cells in blood; IL-21R+ RM B cells were more sensitive to apoptosis and their frequency correlated with sCD14, a marker of microbial translocation. Furthermore, TLR triggering by microbial products resulted in IL- 21R expression on memory B cells in vitro. These results suggest a direct link between microbial translocation and an impaired B cell phenotype. In paper II we showed that IL-7 induced upregulation of CD70 expression on T cells. Increased CD70 expression, by triggering the CD27 receptor on B cells, can lead to alteration of the B cell phenotype and IgG production. In addition, IL-7 led to an increased production of BAFF by T cells, which enhanced B cell survival in vitro. In the context of HIV-1 infection, the mechanisms mediated by increased CD70 expression on T cells might be implicated in establishment of B cell activation, a characteristic of immune pathology in infected patients. The role of CD70 in B cell dysfunction during HIV-1 infection was further studied in paper III. We found an increased expression of CD70 on CD4+ T cells which correlated with CD4+ T cell depletion and viremia in HIV-1 infected patients. CD4+ CD70+ T cells expressed pro-inflammatory cytokines and, based on their chemokine profile, it was predicted that they can migrate to sites of inflammation. A potential role for CD4+ CD70+ T cells in B cell activation in HIV-1 infected individuals was suggested by the association with CD38 and CD95 expression in memory B cells, with increased B cell proliferation and plasma IgG levels. The mechanism leading to CD70 up- regulation on T cells during HIV-1 infection remains elusive. Although treatment with ART can lead to a nearly complete suppression of HIV-1 replication, ART does not fully target the increased immune activation found in HIV-1 infected patients. We showed in paper IV that ART initiation during primary HIV-1 infection (PHI) (early ART=EA) did not prevent the establishment of phenotypical changes of T cells, previously reported in HIV-1 infected patients starting treatment during the chronic phase of infection (late ART=LA). The phenotypical changes of T cells, comparable in the EA and LA groups, consisted in increased expression of immune activation markers HLA-DR and CD38 and reduced expression of CD127, which characterizes differentiated CD8+ T cells. It is worrisome that ART initiation during PHI does not correct for abnormal immune activation. It is however interesting that the number of HIV-1 DNA copies in blood of EA patients was significantly lower compared to LA patients; the correlation between T cell phenotype and size of the HIV-1 reservoir should be studied further. The frequency of B cell sub-populations in blood of EA and LA patients did not differ (preliminary results) and was not significantly altered compared to non-infected controls.

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