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

IL-7 and CD4 T Follicular Helper Cells in HIV-1 Infection

IL-7 was previously shown to upregulate the expression of molecules important for interaction of CD4+ T cells with B cells. It is poorly studied whether IL-7 has a role in the biology of T follicular helper (Tfh) cells and whether IL-7 dysregulates the expression of B-cell costimulatory molecules on Tfh cells. We review the literature and provide arguments in favor of IL-7 being involved in the biology of human Tfh cells. The CD127 IL-7 receptor is expressed on circulating Tfh and non-Tfh cells, and we show that IL-7, but not IL-6 or IL-21, upregulates the expression of CD70 and PD-1 on these cells. We conclude that IL-7, a cytokine whose level is elevated during HIV-1 infection, may have a role in increased expression of B cell costimulatory molecules on Tfh cells and lead to abnormal B cell differentiation

Dysfunctional phenotypes of CD4+ and CD8+ T cells are comparable in patients initiating ART during early or chronic HIV-1 infection

11sinoneEarly initiation of antiretroviral therapy (ART) is becoming a common clinical practice according to current guidelines recommending treatment to all HIV-1-infected patients. However, it is not known whether ART initiated during the early phase of infection prevents the establishment of abnormal phenotypic features previously reported in CD4+ and CD8+T cells during chronic HIV-1 infection. In this cross-sectional study, blood specimens were obtained from 17 HIV-1-infected patients who began ART treatment shortly after infection (early ART [EA]), 17 age-matched HIV-1-infected patients who started ART during chronic phase of infection (late ART [LA]), and 25 age-matched non-HIV-1-infected controls. At collection of specimens, patients in EA and LA groups had received ART for comparable periods of time. Total HIV-1 DNA was measured in white blood cells by quantitative PCR. The concentration of 9 inflammatory parameters and 1 marker of fibrosis, including sCD14 and b-2 microglobulin, was measured in plasma. Furthermore, expression of markers of abnormal immune activation (human leukocyte antigen-antigen D related [HLA-DR] and CD38), exhaustion (programmed death 1, CD28, CD57) and terminal differentiation (CD127) was measured on CD4+ and CD8+T cells. T-cell proliferation was measured through Ki67 expression. The copies of total HIV-1 DNA in blood were significantly lower (P=0.009) in EA compared with that in LA group. Only the expression of HLA-DR on naïve CD4+ T cells distinguished EA from LA, whereas expression of 3 surface markers distinguished T-cell populations of HIV-1-infected patients from controls. These included HLA-DR distinguishing CD4+ T cells from EA compared with controls, and also CD38 and CD127 on CD4+ and CD8+ T cells, respectively, distinguishing both groups of patients from controls. The sCD14 levels were significantly higher in EA patients, and b-2 microglobulin levels were higher in LA group compared with that in controls. Our results demonstrate an equivalent abnormal expression of activation (HLA-DR and CD38 on CD4+ T cells) and terminal differentiation (CD127 on CD8+ T cells) markers in T cells from both EA and LA patients. The size of total HIV-1 DNA copies in blood of EA was lower compared with LA patients. These findings suggest that some abnormalities taking place in the T-cell compartment during primary HIV-1 infection may not be corrected by early ART.openAmu, Sylvie; Graham, Rebecka Lantto; Bekele, Yonas; Nasi, Aikaterini; Bengtsson, Carina; Rethi, Bence; Sorial, Sam; Meini, Genny; Zazzi, Maurizio; Hejdeman, Bo; Chiodi, FrancescaAmu, Sylvie; Graham, Rebecka Lantto; Bekele, Yonas; Nasi, Aikaterini; Bengtsson, Carina; Rethi, Bence; Sorial, Sam; Meini, Genny; Zazzi, Maurizio; Hejdeman, Bo; Chiodi, Francesc