High Frequency, Sustained T Cell Responses to PARV4 Suggest Viral Persistence In Vivo

Background. Parvovirus 4 (PARV4) is a recently identified human virus that has been found in livers of patients infected with hepatitis C virus (HCV) and in bone marrow of individuals infected with human immunodeficiency virus (HIV). T cells are important in controlling viruses but may also contribute to disease pathogenesis. The interaction of PARV4 with the cellular immune system has not been described. Consequently, we investigated whether T cell responses to PARV4 could be detected in individuals exposed to blood-borne viruses

High-Frequency, Functional HIV-Specific T-Follicular Helper and Regulatory Cells Are Present Within Germinal Centers in Children but Not Adults

Broadly neutralizing antibodies (bnAbs) against HIV-1 are an effective means of preventing transmission. To better understand the mechanisms by which HIV-specific bnAbs naturally develop, we investigated blood and lymphoid tissue in pediatric infection, since potent bnAbs develop with greater frequency in children than adults. As in adults, the frequency of circulating effector T-follicular helper cells (T-FH) in HIV infected, treatment naive children correlates with neutralization breadth. However, major differences between children and adults were also observed both in circulation, and in a small number of tonsil samples. In children, T-FH cells are significantly more abundant, both in blood and in lymphoid tissue germinal centers, than in adults. Second, HIV-specific T-FH cells are more frequent in pediatric than in adult lymphoid tissue and secrete the signature cytokine IL-21, which HIV-infected adults do not. Third, the enrichment of IL-21-secreting HIV-specific T-FH in pediatric lymphoid tissue is accompanied by increased T-FH regulation via more abundant regulatory follicular T-cells and HIV-specific CXCR5+ CD8 T-cells compared to adults. The relationship between regulation and neutralization breadth is also observed in the pediatric PBMC samples and correlates with neutralization breadth. Matching neutralization data from lymphoid tissue samples is not available. However, the distinction between infected children and adults in the magnitude, quality and regulation of HIV-specific T-FH responses is consistent with the superior ability of children to develop high-frequency, potent bnAbs. These findings suggest the possibility that the optimal timing for next generation vaccine strategies designed to induce high-frequency, potent bnAbs to prevent HIV infection in adults would be in childhood

Identification of a new hTERT-derived HLA-A*0201 restricted, naturally processed CTL epitope

Mechanical stimulation, in the form of fluid perfusion or mechanical strain, enhances osteogenic differentiation and overall bone tissue formation by mesenchymal stems cells cultured in biomaterial scaffolds for tissue engineering applications. In silico techniques can be used to predict the mechanical environment within biomaterial scaffolds, and also the relationship between bone tissue regeneration and mechanical stimulation, and thereby inform conditions for bone tissue engineering experiments. In this study, we investigated bone tissue regeneration in an idealised hydrogel scaffold using a mechano-regulation model capable of predicting tissue differentiation, and specifically compared five loading cases, based on known experimental bioreactor regimes. These models predicted that low levels of mechanical loading, i.e. compression (0.5% strain), pore pressure of 10 kPa and a combination of compression (0.5%) and pore pressure (10 kPa), could induce more osteogenic differentiation and lead to the formation of a higher bone tissue fraction. In contrast greater volumes of cartilage and fibrous tissue fractions were predicted under higher levels of mechanical loading (i.e. compression strain of 5.0% and pore pressure of 100 kPa). The findings in this study may provide important information regarding the appropriate mechanical stimulation for in vitro bone tissue engineering experiments

A molecular switch in immunodominant HIV-1-specific CD8 T-cell epitopes shapes differential HLA-restricted escape

Background Presentation of identical HIV-1 peptides by closely related Human Leukocyte Antigen class I (HLAI) molecules can select distinct patterns of escape mutation that have a significant impact on viral fitness and disease progression. The molecular mechanisms by which HLAI micropolymorphisms can induce differential HIV-1 escape patterns within identical peptide epitopes remain unknown. Results Here, we undertook genetic and structural analyses of two immunodominant HIV-1 peptides, Gag180–188 (TPQDLNTML, TL9-p24) and Nef71–79 (RPQVPLRPM, RM9-Nef) that are among the most highly targeted epitopes in the global HIV-1 epidemic. We show that single polymorphisms between different alleles of the HLA-B7 superfamily can induce a conformational switch in peptide conformation that is associated with differential HLAI-specific escape mutation and immune control. A dominant R71K mutation in the Nef71-79 occurred in those with HLA-B*07:02 but not B*42:01/02 or B*81:01. No structural difference in the HLA-epitope complexes was detected to explain this observation. Conclusions These data suggest that identical peptides presented through very similar HLAI landscapes are recognized as distinct epitopes and provide a novel structural mechanism for previously observed differential HIV-1 escape and disease progression