# MultiOMICS to uncover immune and virological mechanisms that drive HIV DNA decay, restore immune homeostasis, and promote HIV specific immunity in PWH receiving cell therapies.

> **NIH NIH P01** · EMORY UNIVERSITY · 2023 · $209,400

## Abstract

ABSTRACT
Immune cell-based therapies have been postulated to be able to induce HIV remission and facilitate antiretroviral
therapy (ART) discontinuation. To date, allogeneic stem cell transplantation (allo-HSCT) with CCR5∆32/∆32
donor cells is the only medical intervention that has been able to cure HIV in up to five reported cases. Allo-
HSCT also results in a dramatic reduction in the HIV reservoir even when using non-mutated CCR5 donor cells.
Passive transfer of autologous CCR5-modified CD4 T cells has emerged as a more affordable, less-risky,
alternative to reinstate an HIV-refractory immune cell milieu. In this proposal we will define the role of the host
environment (including host/non-host metabolites) on virological and immunological outcomes. To this end we
will access PBMCs and plasma, and clinical metadata from three independent study populations: the IciStem
cohort (allo-HSCT) and 2 cohorts of subjects infused with autologous CCR5-modified CD4 T cells. We
hypothesize that a pre-intervention plasma milieu (microbiota associated metabolites and cytokines) allows for
better engraftment of both allo-HSCT and autologous CCR5-modified CD4 T cells which is associated with
reduced HIV reservoir and rejuvenation of CD4 and CD8 memory stem cells (Tscm) and effector cells and innate
cell antiviral responses that limit HIV rebound upon ATI. In aim1 we will identify the impact of the host
environment driving the heterogeneity of virological features including frequencies of cells with intact provirus
integrity of viral sequences, integration sites and translation competence prevalent during long-lasting viral
control pre-intervention and which can impact on the kinetics of viral load rebound and immune reconstitution
post engraftment. In aim 2 we will identify the impact of host environment on the magnitude of host-donor
chimerism, innate immune activation and stem-like CD4+ T-cell associated immune reconstitution. Our
preliminary data show that frequencies of HIV resistant CD4 TSCM are the best predictors of long-term control
of viral load post adoptive transfer of autologous CD4 T cells. Microbial and host metabolites are important
modulators of the differentiation and effector function of innate and adaptive immune cells. Hence selected pro-
inflammatory metabolites could impact on the development of these T cell stem cells and as well HIV resistant
myeloid cells by promoting their activation and differentiation and this will impede on BM engraftment. In aim 3
we will define parallel virological and metabolic mechanisms that are associated with viral control post autologous
CCR5 modified CD4+ T-cell therapy and all-HSCT intervention. The virological features listed above, and the
host and environmental features cited in Aims 1 and 2 will impact on adoptive transfer of autologous HIV resistant
CD4 T cells as they did for BMT. The experimental design includes virology, immunology and multiomic cutting
edge technologies which will be integrated to...

## Key facts

- **NIH application ID:** 10731666
- **Project number:** 1P01AI178376-01
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Javier Martinez-Picado
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $209,400
- **Award type:** 1
- **Project period:** 2023-07-03 → 2028-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10731666

## Citation

> US National Institutes of Health, RePORTER application 10731666, MultiOMICS to uncover immune and virological mechanisms that drive HIV DNA decay, restore immune homeostasis, and promote HIV specific immunity in PWH receiving cell therapies. (1P01AI178376-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10731666. Licensed CC0.

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