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

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.

List of scientific papers

I. Ruffin N, Lantto R, Pensieroso S, Sammicheli S, Hejdeman B, Réthi B, Chiodi F. Immune activation and increased IL-21R expression are associated with the loss of memory B cells during HIV-1 infection. J Intern Med. 2012 Nov;272(5):492-503.
https://doi.org/10.1111/j.1365-2796.2012.02550.x

II. Sammicheli S, Ruffin N, Lantto R, Vivar N, Chiodi F, Réthi B. IL-7 modulates B cells survival and activation by inducing BAFF and CD70 expression in T cells. J Autoimmun. 2012 Jun;38(4):304-14.
https://doi.org/10.1016/j.jaut.2012.01.012

III. Lantto R, Nasi A, Sammicheli S, Amu S, Fievez V, Moutschen M, Pensieroso S, Hejdeman B, Chiodi F, Réthi B. Increased extrafollicular expression of the B-cell stimulatory molecule CD70 in HIV-1 infected individuals. AIDS. 2015 Sep 10;29(14):1757-66
https://doi.org/10.1097/QAD.0000000000000779

IV. Amu S, Lantto Graham R, Bekele Y, Nasi A, Bengtsson C, Réthi B, Sorial S, Meini G, Zazzi M, Hejdeman B, Chiodi F. Dysfunctional phenotypes of CD4+ and CD8+ T cells are comparable in patients initiating ART during early or chronic HIV-1 infection. Medicine (Baltimore). 2016 Jun;95(23):e3738
https://doi.org/10.1097/MD.0000000000003738