Translocated microbiome composition determines immunological outcome in treated HIV infection.

The impact of the microbiome on HIV disease is widely acknowledged although the mechanisms downstream of fluctuations in microbial composition remain speculative. We detected rapid, dynamic changes in translocated microbial constituents during two years after cART initiation. An unbiased systems biology approach revealed two distinct pathways driven by changes in the abundance ratio of Serratia to other bacterial genera.

Persistent expansion and Th1-like skewing of HIV-specific circulating T follicular helper cells during antiretroviral therapy.

Background: Untreated HIV infection leads to alterations in HIV-specific CD4 T cells including increased expression of co-inhibitory receptors (IRs) and skewing toward a T follicular helper cell (Tfh) signature. However, which changes are maintained after suppression of viral replication with antiretroviral therapy (ART) is poorly known.

Methods: We analyzed blood CD4 T cells specific to HIV and comparative viral antigens in ART-treated people using a cytokine-independent activation-induced marker assay alone or in combination with functional readouts.

Altered differentiation is central to HIV-specific CD4 T cell dysfunction in progressive disease.

Dysfunction of virus-specific CD4 T cells in chronic human infections is poorly understood. We performed genome-wide transcriptional analyses and functional assays of CD4 T cells specific for human immunodeficiency virus (HIV) from HIV-infected people before and after initiation of antiretroviral therapy (ART). A follicular helper T cell (T cell)-like profile characterized HIV-specific CD4 T cells in viremic infection.

Failed immune responses across multiple pathologies share pan-tumor and circulating lymphocytic targets.

Rationale Tumor infiltrating lymphocytes are widely associated with positive outcomes, yet carry key indicators of a systemic failed immune response against unresolved cancer. Cancer immunotherapies can reverse their tolerance phenotypes, while preserving tumor-reactivity and neoantigen-specificity shared with circulating immune cells. Objectives We performed comprehensive transcriptomic analyses to identify gene signatures common to circulating and tumor infiltrating lymphocytes in the context of clear cell renal cell carcinoma.

Immune Checkpoint Blockade Restores HIV-Specific CD4 T Cell Help for NK Cells.

Immune exhaustion is an important feature of chronic infections, such as HIV, and a barrier to effective immunity against cancer. This dysfunction is in part controlled by inhibitory immune checkpoints. Blockade of the PD-1 or IL-10 pathways can reinvigorate HIV-specific CD4 T cell function in vitro, as measured by cytokine secretion and proliferative responses upon Ag stimulation.

Comparative analysis of activation induced marker (AIM) assays for sensitive identification of antigen-specific CD4 T cells.

The identification and study of antigen-specific CD4 T cells, both in peripheral blood and in tissues, is key for a broad range of immunological research, including vaccine responses and infectious diseases. Detection of these cells is hampered by both their rarity and their heterogeneity, in particular with regards to cytokine secretion profiles. These factors prevent the identification of the total pool of antigen-specific CD4 T cells by classical methods.

RNA flow cytometric FISH for investigations into HIV immunology, vaccination and cure strategies.

Despite the tremendous success of anti-retroviral therapy (ART) no current treatment can eradicate latent HIV reservoirs from HIV-infected individuals or generate, effective HIV-specific immunity. Technological limitations have hampered the identification and characterization of both HIV-infected cells and HIV-specific responses in clinical samples directly ex vivo. RNA-flow cytometric fluorescence in situ hybridisation (RNA Flow-FISH) is a powerful technique, which enables detection of mRNAs in conjunction with proteins at a single-cell level.

Distinctive features of CD4+ T cell dysfunction in chronic viral infections.

Purpose Of Review: To describe recent advances in the understanding of virus-specific CD4 T cell dysfunction in chronic viral infections, with an emphasis on HIV disease. We highlight features that are distinctive for CD4 T cells, as opposed to their CD8 T cell counterparts.

Recent Findings: CD4 T cell activation and differentiation are tightly controlled.

The downregulation of GFI1 by the EZH2-NDY1/KDM2B-JARID2 axis and by human cytomegalovirus (HCMV) associated factors allows the activation of the HCMV major IE promoter and the transition to productive infection.

Earlier studies had suggested that epigenetic mechanisms play an important role in the control of human cytomegalovirus (HCMV) infection. Here we show that productive HCMV infection is indeed under the control of histone H3K27 trimethylation. The histone H3K27 methyltransferase EZH2, and its regulators JARID2 and NDY1/KDM2B repress GFI1, a transcriptional repressor of the major immediate-early promoter (MIEP) of HCMV.

Activation-induced cell death signalling in CD4+ T cells by staphylococcal enterotoxin A.

Staphylococcal enterotoxin A (SEA) is a potent stimulator of CD4+ and CD8+ T cells, the immunotoxic action of which remains unclear. We investigated the in vitro effects of SEA on freshly isolated human peripheral blood lymphocytes depleted of CD8+ T cells. Proliferation and flow cytometry analysis indicated that SEA generated an activation-induced cell death (AICD) phenomenon that was characterized by an increased expression of the chemokine receptor CCR5 on the CD4+/CD45RO+ T cell subset.