Tfh dysfunction in HIV and Aging

Project: Research project

Project Details

Description

With effective ART, HIV infected persons can achieve a near normal life span but have increasing incidence of comorbidities and co-infections that occur earlier, are more frequent than the general population. Underlying inflammation is considered to be a major factor for comorbidities, but less well appreciated is the associated immune deficiency that persist even after durable virologic control, putting people living with HIV (PWH) at greater risk for influenza, for which flu vaccinations are recommended. Besides decreasing risk for influenza infection, flu vaccines can serve as probes for testing host immune competence an approach used in this proposal and in a previous project (AI108472) for assessing immunity in PWH and we could classify participants as vaccine responders (VR) and vaccine non-responders (VNR). We observed that aging and HIV had a negative effect on vaccine response. In studying mechanisms of immune defects in VNR, we identified quantitative and qualitative defects in peripheral T follicular helper cells (pTfh), which are a subset of CD4 T cells that are essential for vaccine-induced antibody (Ab) responses. The pTfh displayed a skewed polarization away from a favorable IL-21 secreting phenotype towards a detrimental IL-2 secreting Th1 phenotype, coupled with abundance of inflammatory markers, resulting in failure of pTfh to provide B cells with the helper signals required for Ab secretion. Our central hypothesis is that skewed polarization of pTfh away from a favorable IL-21 secreting phenotype towards one of IL-2 and inflammation is detrimental, worsens with age or HIV but is amenable to change by ex-vivo and in-vivo manipulation. We will recruit HIV negative and virally suppressed HIV+ populations to address key questions on Ab response following seasonal influenza vaccination. The project has 3 aims: Aim 1 will investigate cell-intrinsic properties of pTfh cells that influence their function in the context of age, HIV infection and the generation of memory B cells. Aim 2 will investigate VNR to define mechanism of pTfh dysfunction via study of cellular and molecular interactions affecting pTfh function and will test in-vitro interventions to reverse the pTfh dysfunction. Aim 3 will test whether administering high dose flu vaccine improves immune response in VNR from all groups and will investigate the immune mechanisms affected. In this project we will evaluate immune cell populations of interest using a combination of technologies including multi-parameter flow cytometry, single cell RNA sequencing, repertoire sequencing, monoclonal Ab generation and cell co- cultures to gain high resolution datasets. Our approach will obtain a snapshot of immune perturbation of pTfh cells in aging and HIV infection. In vitro studies with purified cell subsets will allow for mechanistic evaluation of the immune system. These studies are feasible, given our expertise in the technologies described, access to desired population and resources for bioinformatics and data integration. We expect to provide novel insights into immune perturbations that will help in strategizing vaccine approaches in aging populations.
StatusActive
Effective start/end date5/1/214/30/22

Funding

  • National Institute on Aging: $760,092.00

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