Epitope Mapping of HIV-Specific CD8+ T cells in a Cohort Dominated by Clade A1 Infection

CD8+ T cell responses are often detected at large magnitudes in HIV-infected subjects, and eliciting these responses is the central aim of many HIV-1 vaccine strategies. Population differences in CD8+ T cell epitope specificity will need to be understood if vaccines are to be effective in multiple geographic regions.In a large Kenyan cohort, we compared responsive CD8+ T cell HIV-1 Env overlapping peptides (OLPs) to Best Defined Epitopes (BDEs), many of which have been defined in clade B infection. While the majority of BDEs (69%) were recognized in this population, nearly half of responsive OLPs (47%) did not contain described epitopes. Recognition frequencies of BDEs were inversely correlated to epitopic sequence differences between clade A1 and BDE (P = 0.019), and positively selected residues were more frequent in "new" OLPs (without BDEs). We assessed the impact of HLA and TAP binding on epitope recognition frequencies, focusing on predicted and actual epitopes in the HLA B7 supertype.Although many previously described CD8 epitopes were recognized, several novel CD8 epitopes were defined in this population, implying that epitope mapping efforts have not been completely exhausted. Expansion of these studies will be critical to understand population differences in CD8 epitope recognition

A Metabolic Checkpoint for the Yeast-to-Hyphae Developmental Switch Regulated by Endogenous Nitric Oxide Signaling

Summary: The yeast Candida albicans colonizes several sites in the human body and responds to metabolic signals in commensal and pathogenic states. The yeast-to-hyphae transition correlates with virulence, but how metabolic status is integrated with this transition is incompletely understood. We used the putative mitochondrial fission inhibitor mdivi-1 to probe the crosstalk between hyphal signaling and metabolism. Mdivi-1 repressed C. albicans hyphal morphogenesis, but the mechanism was independent of its presumed target, the mitochondrial fission GTPase Dnm1. Instead, mdivi-1 triggered extensive metabolic reprogramming, consistent with metabolic stress, and reduced endogenous nitric oxide (NO) levels. Limiting endogenous NO stabilized the transcriptional repressor Nrg1 and inhibited the yeast-to-hyphae transition. We establish a role for endogenous NO signaling in C. albicans hyphal morphogenesis and suggest that NO regulates a metabolic checkpoint for hyphal growth. Furthermore, identifying NO signaling as an mdivi-1 target could inform its therapeutic applications in human diseases. : Hyphal morphogenesis contributes to virulence of the human fungal pathogen Candida albicans. Koch et al. show that mdivi-1, a putative inhibitor of mitochondrial division, represses hyphal growth of Candida and implicate regulation of endogenous nitric oxide levels in the mechanism of action of mdivi-1 and the regulation of hyphal morphogenesis. Keywords: Candida albicans, mitochondria, hyphae, mdivi-1, nitric oxide, metabolism, morphogenesis, fungal pathogenesis, mycolog

Host HLA B*allele-associated multi-clade Gag T-cell recognition correlates with slow HIV-1 disease progression in antiretroviral therapy-naïve Ugandans.

BACKGROUND: Some HIV infected individuals remain asymptomatic for protracted periods of time in the absence of antiretroviral therapy (ART). Virological control, CD4 T cell loss and HIV-specific responses are some of the key interrelated determinants of HIV-1 disease progression. In this study, possible interactions between viral load, CD4 T cell slopes, host genetics and HIV-specific IFN-gamma responses were evaluated in chronically HIV-1-infected adults. METHODOLOGY/PRINCIPAL FINDINGS: Multilevel regression modeling was used to stratify clade A or D HIV-infected individuals into disease progression groups based on CD4 T cell slopes. ELISpot assays were used to quantify the frequency and magnitude of HIV-induced IFN-gamma responses in 7 defined rapid progressors (RPs) and 14 defined slow progressors (SPs) at a single time point. HLA typing was performed using reference strand conformational analysis (RSCA). Although neither the breadth nor the magnitude of the proteome-wide HIV-specific IFN-gamma response correlated with viral load, slow disease progression was associated with over-representation of host immunogenetic protective HLA B* alleles (10 of 14 SPs compared to 0 of 7; p = 0.004, Fisher's Exact) especially B*57 and B*5801, multiclade Gag T-cell targeting (71%, 10 of 14 SPs compared to 14%, 1 of 7 RPs); p = 0.029, Fisher's Exact test and evident virological control (3.65 compared to 5.46 log10 copies/mL in SPs and RPs respectively); p<0.001, unpaired student's t-test CONCLUSIONS: These data are consistent with others that associated protection from HIV disease with inherent host HLA B allele-mediated ability to induce broader Gag T-cell targeting coupled with apparent virological control. These immunogenetic features of Gag-specific immune response which could influence disease progression may provide useful insight in future HIV vaccine design