# Exploring the features of HIV exceptional elite controllers in humanized mice

> **NIH NIH R21** · COLORADO STATE UNIVERSITY · 2021 · $244,399

## Abstract

Project Summary/Abstract:
Newer insights into long-term natural control of HIV infection in the absence of ART will inform efforts to induce
a functional cure or “remission.” Recent work has identified a subset of HIV elite controllers (EC) who are
considered “exceptional” (EEC) with decades of virologic control without immunologic decline. Multiple
mechanisms likely contribute to control in EECs, including a potent and sustained CD8+ T cell response.
However, it is unclear whether EECs can maintain this status indefinitely, whether they have any ongoing viral
activity and benefit from initiation of ART (or are harmed by withdrawal of ART), or whether they spontaneously
cleared viral reservoirs. Whether such individuals may represent a true model of durable HIV control or, in some
cases, a functional cure are important questions needing further investigation. Leveraging the largest elite
controller cohort in the USA, the UCSF SCOPE cohort, our recent work focused on the question: is there a
subset of ECs that might serve as a model for long-term ART-free HIV remission? Using the new intact proviral
DNA assay (IPDA) to detect intact proviruses as well as sensitive antibody and T-cell immune-assays, we
identified a small subset of 21 exceptional ECs with ultra-low reservoir size. Recent analyses using a combination
of IPDA and FLIP-seq suggested that some ECs have ultralow levels of intact proviruses existing in a deeply
latent state making their detection difficult. Therefore, novel virological assays to detect ultralow levels of latent
HIV and immunological analyses to evaluate the role of CD8+ T cell control need to be employed to further our
understanding of EECs. Towards this goal, we propose to employ our new ultrasensitive in vivo humanized
mouse viral outgrowth assay (hmVOA) model for latent viral detection. This model also provides a unique in vivo
setting to examine the role of immune control since CD4+ T cells from the EEC can be tested for viral outgrowth
in the presence or absence of autologous CD8+ T cells believed to mediate control which is otherwise not
possible to evaluate in a human setting. While full comprehension of EECs is a complex undertaking, here we
propose to start with simpler initial goals to:
1. Determine whether intact HIV can be recovered (via viral outgrowth) from exceptional elite controllers not
currently on ART and elite controllers on long-term ART using the humanized mouse viral outgrowth (hmVOA)
assay
2. Ascertain if the predominant viral control in EEC is indeed mediated by CD8+ T cells and assess if this control
can also provide resistance to a potential new HIV exposure (superinfection) in vivo.
Results from here will help in furthering our understanding of the latent virus and the role of strong cell-mediated
virus control in EECs.

## Key facts

- **NIH application ID:** 10326905
- **Project number:** 1R21AI162248-01A1
- **Recipient organization:** COLORADO STATE UNIVERSITY
- **Principal Investigator:** Ramesh Akkina
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $244,399
- **Award type:** 1
- **Project period:** 2021-08-20 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10326905

## Citation

> US National Institutes of Health, RePORTER application 10326905, Exploring the features of HIV exceptional elite controllers in humanized mice (1R21AI162248-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10326905. Licensed CC0.

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