Listeria monocytogenes is a facultative intracellular pathogen that infects a wide variety of cells, causing the life-threatening disease listeriosis. L. monocytogenes virulence factors include two surface invasins, InlA and InlB, known to promote bacterial uptake by host cells, and the secreted pore-forming toxin listeriolysin O (LLO), which disrupts the phagosome to allow bacterial proliferation in the cytosol.

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Thirty years after its discovery, the hepatitis C virus (HCV) remains a leading cause of liver disease worldwide. Given that many countries continue to experience high rates of transmission despite the availability of potent antiviral therapies, an effective vaccine is seen as critical for the elimination of HCV. The recent failure of the first vaccine efficacy trial for the prevention of chronic HCV confirmed suspicions that this virus will be a challenging vaccine target. Here, we examine the published data from this first efficacy trial along with the earlier clinical and pre-clinical studies of the vaccine candidate and then discuss three key research directions expected to be important in ongoing and future HCV vaccine development. These include the following: 1. design of novel immunogens that generate immune responses to genetically diverse HCV genotypes and subtypes, 2. strategies to elicit broadly neutralizing antibodies against envelope glycoproteins in addition to cytotoxic and helper T cell responses, and 3. consideration of the unique immunological status of individuals most at risk for HCV infection, including those who inject drugs, in vaccine platform development and early immunogenicity trials.

Chronic hepatitis C virus (HCV) infection is characterized by dysfunctional HCV-specific CD8+ T cells, rare CD4+ T responses, and stable high-level viremia. Recovered CD4+ T cell function and unusual declines in viremia have been observed in some women after childbirth. Whether recovered CD4+ T cells are of lineages to help B cells or CD8 T cells is unknown. Preliminary studies suggest both may be true. In 7 women with postpartum viral suppression (>= 1 log10 by 3 months postpartum, “controllers”), and 7 women with more stable viral levels, “non-controllers”, circulating HCV-tetramer+ (tet+) CD4+ T cells expressed chemokine receptors associated with two predominate populations, Th1-biased Tfh (cTfh1) cells and Th1 cells – with a higher cTfh1/Th1 ratio linked to viral control. Here we assessed HCV-specific cTfh1 and Th1 functional responses by combined surface chemokine receptor and intracellular cytokine staining (ICS) after HCV peptide stimulation, and we also assessed expression of lineage-defining transcription factors on HCV-tet+ cells. HCV-specific cytokine+ cells were predominantly cTfh1 or Th1 populations, and multi-functionality correlated with viral control. HCV-tet+ CD4+ T cell Tbet and BCL6 expression levels did not differ by degree of viral control, but both were enhanced in tet+cTfh1 cells relative to bulk cTfh1 cells, and tet+ Th1 cells expressed significantly more BCL6 than bulk Th1 cells. Together, these data point to a postpartum CD4+ T cell recovery driven by transcription factors favoring cTfh1/Th1-biased phenotypes. Understanding how these cells interact with CD8+ T cells and B cell will be vital for understanding this unique instance of natural control of a chronic viral infection. Supported by a grant from the NIH (R01 AI096882).

Chronic hepatitis C virus (HCV) infection is marked by a loss of HCV-specific CD4+ T cells and CD8+ T cell exhaustion. However, recovery of antiviral CD4+ T cells and decreased viremia occurs in some women after pregnancy. We hypothesize that recovery of HCV-specific Th1 and Tfh biased CD4+ T cell populations contributes to viral control postpartum. Here we undertook a detailed phenotypic analysis of lineage-defining chemokine receptor expression on recovering HCV-specific CD4+ T cells using tetramer staining and flow cytometry of PBMCs from 14 women with chronic HCV infection. Seven women had >10-fold decreases in viremia by 3 months postpartum (3PP) (controllers) and the remaining half did not (non-controllers). At 3PP, tetramer+CD4+T cells were predominantly CXCR5+/CXCR3+/CCR6− (cTfh1) with most of the remaining HCV-specific CD4+ T cells being CXCR5−/CXCR3+/CCR6−(Th1). The proportions of cTfh1 cells within tetramer+CD4+ T cell populations were higher in controllers compared to non-controllers (median 74.3% vs. 52.8%, p=0.0262, Mann-Whitney), while the proportions of Th1 cells were higher in non-controllers (p=0.007, Mann-Whitney). Higher cTfh1 frequencies correlated with viral control (p=0.0072, Spearman). In all mothers, over 85% of HCV-specific cTfh1 cells were PD-1+. ICOS expression correlated with reduced viral control. Together, these data suggest that a shift of HCV-specific CD4+ T cell responses towards a cTfh1 phenotype contributes to the unique viral control that occurs in some women after pregnancy.