# Targeting virus-specific CAR T cells to lymphoid follicles to achieve durable HIV suppression

> **NIH NIH R01** · UNIVERSITY OF MINNESOTA · 2020 · $725,949

## Abstract

Abstract
Virus-specific CD8 T cells exert potent antiviral activity against HIV-1 and SIV both in vitro and in
vivo. Nevertheless, despite abundant CD8 T cell responses in HIV-1-infected humans and SIV-
infected macaques, they are unable to fully suppress virus replication. This is likely due to the
majority of HIV-1 and SIV replication occurring in CD4+ T cells concentrated within B-cell follicles
in secondary lymphoid tissues; where virus-specific CD8 T cells are relatively few in number. In
fact, we found that in vivo effector virus-specific CD8 T cell to target SIV RNA+ cell ratios (E:T)
were over 40-fold lower inside compared to outside of B cell follicles in lymphoid tissues during SIV
infection in rhesus macaques. These findings indicate that B cell follicles are an immune privileged
site in which low levels of virus-specific CD8 T cells permit ongoing viral replication. Furthermore,
we found that the majority of virus-specific CD8 T cells fail to express the follicular homing
molecule CXCR5, likely explaining low levels of virus-specific CD8 T cells localizing to and
surveilling B cell follicles. Taken together these data suggest that the inability of HIV- and SIV-
specific CD8 T cells to fully suppress virus replication may be due to a deficiency of virus-specific
CD8 T cells in B-cell follicles. These findings have led us to our central hypothesis that
targeting HIV-specific T cells to B cell follicles will lead to durable remission of HIV
infection. In support of this hypothesis we have shown, in SIV-infected rhesus macaques, that
increased levels of virus-specific CD8 T cells in B cell follicles is associated with lower viral loads.
To test this hypothesis, we propose to evaluate a T cell immunotherapy product that targets virus-
specific CD8 T cells to B cell follicles. We are calling this product CD4-MBL-CAR/CXCR5 T cell
immunotherapy. Our long-term goal is to develop an intervention that will lead to durable remission
of HIV infection. To test this central hypothesis, we propose the following two specific aims. 1) To
determine the in vivo localization, persistence and antiviral efficacy of autologous CD4-MBL-
CAR/CXCR5 T cells infused into antiretroviral drug (ART) suppressed rhesus macaques before
and after treatment interruption. 2) To determine whether preconditioning with CD20 antibodies
(instead of cyclophosphamide) improves the abundance, persistence, or antiviral efficacy of
autologous CAR/CXCR5-transduced CD8 T cells infused into ART suppressed rhesus macaques
before and after treatment interruption. Our proposed studies targeting virus-specific CAR T cells
to follicles will have a broad impact on the field by providing insights into cell trafficking,
persistence, and pre-conditioning regimens for immunotherapy approaches. Most importantly,
these studies could result in an effective strategy to induce long-term sustained remission of HIV.

## Key facts

- **NIH application ID:** 9821737
- **Project number:** 5R01AI143380-02
- **Recipient organization:** UNIVERSITY OF MINNESOTA
- **Principal Investigator:** PAMELA J SKINNER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $725,949
- **Award type:** 5
- **Project period:** 2018-11-13 → 2023-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9821737

## Citation

> US National Institutes of Health, RePORTER application 9821737, Targeting virus-specific CAR T cells to lymphoid follicles to achieve durable HIV suppression (5R01AI143380-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9821737. Licensed CC0.

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