Project description:Individuals living with chronic HIV experience similar immune impairments as HIV-negative elderly however they manifest symptoms (e.g. suboptimal responses to vaccination) at a younger age. Mechanisms underlying premature immune-senescence are unclear. In this study, we aimed to identify molecular signatures of aging and vaccine response in HIV infected (HIV) individuals as compared to age-matched healthy-control participants (HC). Using RNA-sequencing, we evaluated transcriptomic profiles in peripheral blood mononuclear cells in study participants before and 1-week after influenza vaccination. Despite that fewer differentially expressed genes between young (<40yrs) and old (>59yrs) were observed in HIV, metabolic and innate immune activation pathways were associated with increasing age in both HIV and HC. Age was also associated with pathways involved with T cell immune activation in HC, and with Interferon signaling pathways in HIV. Predictive and correlative models of vaccine response using gene expression were different in HC and HIV. In this study, molecular signatures were defined for aging and vaccine response in HC and HIV. We observed signs of precocious immune aging at the transcriptional level in HIV and described a transcriptional perturbation associated with innate immunity and glucose metabolism induced by aging in both HC and HIV in resting conditions.
Project description:Recently, several neutralizing anti-HIV antibodies have been isolated from memory B cells of HIV-infected individuals. However, despite extensive evidence of B-cell dysfunction in HIV disease, little is known about the cells from which these rare HIV-specific antibodies originate. Accordingly, HIV envelope gp140 and CD4 or co-receptor (CoR) binding site (bs) mutant probes were used to evaluate HIV-specific responses in the peripheral blood B cells of individuals at various stages of infection. In contrast to non-HIV responses, HIV-specific responses against gp140 were enriched within abnormal B cells, namely activated and exhausted memory subsets, which are largely absent in the blood of uninfected individuals. Responses against the CoRbs (a poorly-neutralizing epitope) arose early whereas those against the CD4bs (a well-characterized neutralizing epitope) were delayed and infrequent. Enrichment of the HIV-specific response within resting memory B cells, the predominant subset in uninfected individuals, did occur in certain infected individuals who maintained low levels of plasma viremia and immune activation with or without antiretroviral therapy. These findings were corroborated by transcriptional profiles. Taken together, our findings provide valuable insight into virus-specific B-cell responses in HIV infection and demonstrate that memory B-cell abnormalities may contribute to the ineffectiveness of the antibody response in infected individuals.
Project description:Recently, several neutralizing anti-HIV antibodies have been isolated from memory B cells of HIV-infected individuals. However, despite extensive evidence of B-cell dysfunction in HIV disease, little is known about the cells from which these rare HIV-specific antibodies originate. Accordingly, HIV envelope gp140 and CD4 or co-receptor (CoR) binding site (bs) mutant probes were used to evaluate HIV-specific responses in the peripheral blood B cells of individuals at various stages of infection. In contrast to non-HIV responses, HIV-specific responses against gp140 were enriched within abnormal B cells, namely activated and exhausted memory subsets, which are largely absent in the blood of uninfected individuals. Responses against the CoRbs (a poorly-neutralizing epitope) arose early whereas those against the CD4bs (a well-characterized neutralizing epitope) were delayed and infrequent. Enrichment of the HIV-specific response within resting memory B cells, the predominant subset in uninfected individuals, did occur in certain infected individuals who maintained low levels of plasma viremia and immune activation with or without antiretroviral therapy. These findings were corroborated by transcriptional profiles. Taken together, our findings provide valuable insight into virus-specific B-cell responses in HIV infection and demonstrate that memory B-cell abnormalities may contribute to the ineffectiveness of the antibody response in infected individuals. HIV-specific responses against gp140 were enriched within abnormal B cells, namely activated (AM) and exhausted (tissue-like; TLM) memory subsets, which are largely absent in the blood of uninfected individuals. These responses are highest during the early stage of HIV infection, significantly decreased following the initiation of antiretroviral therapy (ART), and most importantly, enriched in normal resting memory B cells (RM) when HIV viremia and immune activation are controlled either naturally or as a result of ART. These HIV-specific B cells (AM and TLM) and resting memory B cells (RM) were sorted from peripheral blood mononuclear cells (PBMCs) of 6 HIV infected individuals. In addition, gp140-specific IgG+ B cells were sorted from individuals with either a strong (n= 6) or weak (n= 6) pro-resting memory profile. TaqMan gene expression assay was performed on these HIV-specific B cells and B cell subset. The array consisted of 29 genes.
Project description:Systemic and local (oral mucosal) immune responses in acutely infected HIV individuals before the initiation of HAART have not been well characterized. Protein microarrays were used to analyze saliva and plasma from HIV infected and HIV uninfected subjects to identify new biomarkers for HIV disease progression and pathogenesis. A 507 protein microarray was employed to provide a broad view of cytokines and chemokines in saliva and plasma in acutely HIV infected subjects as compared to uninfected subjects. A custom array derived from the initial results was refined to highlight those molecules with significant change relative to control subjects indicating the potential for biological impact.
Project description:A 507 protein microarray was employed to provide a broad view of cytokines and chemokines in saliva and plasma in acutely HIV infected subjects as compared to uninfected subjects. A 40 cytokine custom array derived from the initial results was refined to highlight those molecules with significant change relative to control subjects indicating the potential for biological impact. Systemic and local (oral mucosal) immune responses in acutely infected HIV individuals before the initiation of HAART have not been well characterized. Protein microarrays were used to analyze saliva and plasma from HIV infected and HIV uninfected subjects to identify new biomarkers for HIV disease progression and pathogenesis.
Project description:Persistent exposure to antigen leads to T cell exhaustion and immunologic dysfunction. We examined the immune exhaustion markers TIGIT and PD-1 in HIV-infected and healthy individuals and the relationship with cytotoxic CD8+ T lymphocyte (CTL) activity. Frequencies of TIGIT but not PD-1 positively correlated with CTL activity in HIV-aviremic and healthy individuals; however, there was no correlation in HIV-viremic individuals. Transcriptome analyses revealed upregulation of genes associated with antiviral immunity in TIGIT+ versus TIGIT-CD8+ T cells. Our data suggest that TIGIT+CD8+ T cells do not necessarily represent a state of immune exhaustion and maintain an intrinsic cytotoxicity in HIV-infected individuals.
Project description:Systemic and local (oral mucosal) immune responses in acutely infected HIV individuals before the initiation of HAART have not been well characterized. Protein microarrays were used to analyze saliva and plasma from HIV infected and HIV uninfected subjects to identify new biomarkers for HIV disease progression and pathogenesis.
Project description:In an effort to identify mechanisms governing HIV-1 permissiveness in gut-homing Th17 cells, we analyzed the transcriptome of CCR6+ versus CCR6- T-cells exposed to the gut-homing inducer retinoic acid (RA) and performed functional validations in colon biopsies of HIV-infected individuals receiving ART (HIV+ART). Together, our results identify mTOR as a druggable key regulator of HIV permissiveness in gut-homing CCR6+ T-cells.
Project description:HIV â??controllersâ?? are individuals infected with the human immunodeficiency virus, type I (HIV) who maintain long-term control of viremia without antiviral therapy and who usually do not develop the acquired immune deficiency syndrome (AIDS). In this study, we have used oligonucleotide expression arrays to characterize the mucosal immune responses of these subjects in relation to untreated HIV+ individuals with high viral loads and progressive disease (â??non-controllersâ??). Recto-sigmoid biopsies were analyzed from 9 controllers and 11 non-controllers. All of the genes identified to be significantly different were more highly expressed in the non-controllers. Many of these genes are involved in immunity and defence. These results underscore the importance of the sustained inflammatory response that attends progressive HIV disease. Keywords: Recto-sigmoid biopsy profiles from HIV infected individuals We analyzed a series of 20 HEEBO arrays on which were hybed RNA amplified from the recto-sigmoid biopsies of HIV infected individuals that either have progressive disease or can maintain long term control of viremia.