# ?Resetting immune homeostasis: a non-invasive approach towards HIV eradication

> **NIH NIH U01** · CASE WESTERN RESERVE UNIVERSITY · 2020 · $667,065

## Abstract

The Berlin patient who received allogeneic transplantation of bone marrow cells from an allogeneic donor who
carried a mutation that rendered progeny cells resistant to HIV infection has shown that eradication of HIV is a
realistic though difficult goal to reach. This strategy highlighted the positive impact of replacing the immune
system of the infected host by cells that cannot be infected by HIV. Our group and others have used strategies
less invasive than bone marrow transplantation to achieve the goal of replacing CD4 T cells that are
susceptible to HIV infection by cells that are resistant to HIV infection. We have shown in single-arm studies
that infusion of CCR5 modified autologous CD4 T cells leads to increased CD4 T cell numbers, down
regulation of pro-inflammatory responses in cells of the innate and adaptive immune systems, and
enhancement of HIV-specific T cell function; we showed in all subjects who received the modified cells a half
log to 3 log10 decrease in total and integrated HIV DNA. This decline in HIV reservoir was associated with the
expansion and long term persistence of a novel T cell subset (TSCM) that has features of stemness as these
cells persisted for over 3 years and gave rise to progeny in all memory T cell subsets. Herein we propose a
two arm double blinded controlled clinical trial designed to understand the role of ex vivo induced CCR5
modification (By Zn-finger nuclease) on the restoration of T cell homeostasis and function and the decay of HIV
persistence in blood and lymphoid tissues . We will test the hypothesis that immune reconstitution with cells
that are resistant to HIV infection results in a global improvement of immune homeostasis by downregulating
the inflammation that drives immune senescence and triggers immune dysfunction and leads to the restoration
of adaptive immunity that can control and eliminate residual HIV infected cells. One group of subjects (n=20)
will be infused with CCR5 modified cells that are resistant to HIV infection while the other (n=10) will receive
unmodified cells; both unmodified and modified cells will be expanded ex vivo using the same manufacturing
procedures. In Aim 1 we will first test the hypothesis that subjects infused with CCR5-deleted cells will show
dramatic decay of the replication competent HIV reservoir and then mechanistically confirm that this is related
to CCR5 modification and not to ex vivo expansion alone by comparing this decay to changes in this reservoir
seen in subjects infused with non-modified CD4 T cells. In Aim 2 we will test the hypothesis that this decay in
HIV reservoir will be a consequence of expansion and persistence of an HIV resistant stem-cell-like subset of T
cells (TSCM). In Aim 3 we will test the hypothesis that CD4 TSCM will restore immune homeostasis by
reducing the pro-inflammatory milieu that prevails in cART-treated HIV-infected subjects which will result (Aim
4) in the restoration of an immune function capable of eliminating the ...

## Key facts

- **NIH application ID:** 9996534
- **Project number:** 5U01AI131295-04
- **Recipient organization:** CASE WESTERN RESERVE UNIVERSITY
- **Principal Investigator:** Rafick Pierre Sekaly
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $667,065
- **Award type:** 5
- **Project period:** 2017-08-09 → 2020-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9996534

## Citation

> US National Institutes of Health, RePORTER application 9996534, ?Resetting immune homeostasis: a non-invasive approach towards HIV eradication (5U01AI131295-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9996534. Licensed CC0.

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