# Identification of the Initial Targets of Transmission

> **NIH NIH R37** · NORTHWESTERN UNIVERSITY · 2022 · $910,732

## Abstract

Program Director/Principal Investigator (Last, First, Middle): Hope, Thomas J.
Recent advances in HIV Prevention science include the demonstration of PreP efficacy of the long acting
injectable Cabotegravir and broadly neutralizing antibodies against sensitive strains. Likewise, there have
been advances in HIV vaccine science with novel immunogens, adjuvants, and delivery strategies that are
increasing the immune responses to the virus and their ability to prevent systemic infection. However, the
fine tuning of these preventative interventions and our ability to increase their potency require a better
understanding of the mechanisms of HIV sexual transmission. The primary focus of this project has been
on 1) developing and optimizing methods allowing the identification of the first cells infected after a
mucosal challenge; 2) the characterization of the expanding foci of infection, and 3) the definition of the
cascade of events that takes place during the eclipse phase as the virus disseminates before detectable
viremia. This project has uniquely impacted and advanced our understanding of the detailed natural history
of the virus in the first 4 days after mucosal challenge. This success is a consequence of the innovative
approach of beacon-guided necropsy where a signal is generated by the presence of infected cells. The
first version of this technique utilized luciferase expressed by a replication defective dual-reporter vector.
However, we have developed the next generation of this approach, which uses 64Cu labeled FAB2 probes
specific for the SIV envelope protein and PET/CT as next generation beacon-guided necropsy. This
approach is highly sensitive and efficient allowing the unbiased identification of multiple foci within the
same animal at the whole-body level including the characterization of the interactions of the virus with host
innate and inflammatory responses. The study of small foci of infection during the eclipse phase after
transmission reveals a complex crosstalk between different infected cells and local tissue environment,
which can vary in different areas and tissues within the same animal. This and other observations reveal
target cell susceptibility, rather than the “tropism” of the viral envelope, is the key driver of early infection. It
is clear that the local anatomy and physiology of virus exposed mucosal tissue has a major impact on the
natural history of the virus during the eclipse phase. Through the interrogation of small tissue blocks
containing replication foci, we will define the who, where, and when of early mucosal infection, including
which cells are generating virus specific alarms and which cells are responding to these alarms. This will
be accomplished by incorporating new approaches for the identification of cells migrating into the infected
tissue site, restriction of cell mobilization, the disruption of pathways involved in innate and inflammatory
responses, and short and long term responses within the inf...

## Key facts

- **NIH application ID:** 10368220
- **Project number:** 4R37AI094595-11
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Thomas Hope
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $910,732
- **Award type:** 4C
- **Project period:** 2022-07-01 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10368220

## Citation

> US National Institutes of Health, RePORTER application 10368220, Identification of the Initial Targets of Transmission (4R37AI094595-11). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10368220. Licensed CC0.

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