# Tfh dysfunction in HIV and Aging

> **NIH NIH R01** · UNIVERSITY OF MIAMI SCHOOL OF MEDICINE · 2023 · $743,891

## Abstract

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...

## Key facts

- **NIH application ID:** 10652325
- **Project number:** 5R01AG068110-04
- **Recipient organization:** UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
- **Principal Investigator:** SURESH PALLIKKUTH
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $743,891
- **Award type:** 5
- **Project period:** 2020-09-30 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10652325

## Citation

> US National Institutes of Health, RePORTER application 10652325, Tfh dysfunction in HIV and Aging (5R01AG068110-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10652325. Licensed CC0.

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