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Exploring the features of HIV exceptional elite controllers in humanized mice

Award Number: R21AI162248
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/20/2021
PERIOD OF PERFORMANCE END DATE: 07/31/2024

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Exploring the features of HIV exceptional elite controllers in humanized mice - 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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = -$1,405 )
2025	2022	COLORADO STATE UNIVERSITY	601 S HOWES ST	FORT COLLINS	CO	80521	LARIMER	USA	Allergy and Infectious Diseases Research	000	2	2/11/2025	NON-COMPETING CONTINUATION	-$1,405
														Subtotal = -$1,405

Issue Date FY: 2022 ( Subtotal = $193,399 )
2022	2022	COLORADO STATE UNIVERSITY	601 S HOWES ST	FORT COLLINS	CO	80521	LARIMER	USA	Allergy and Infectious Diseases Research	000	2	7/15/2022	NON-COMPETING CONTINUATION	$193,399
														Subtotal = $193,399

Issue Date FY: 2021 ( Subtotal = $244,399 )
2021	2021	COLORADO STATE UNIVERSITY	601 S HOWES ST	FORT COLLINS	CO	80521	LARIMER	USA	Allergy and Infectious Diseases Research	000	1	8/20/2021	NEW	$244,399
														Subtotal = $244,399

Grand Total All Awards = $436,393

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Exploring the features of HIV exceptional elite controllers in humanized mice

Award Number: R21AI162248

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 08/20/2021

PERIOD OF PERFORMANCE END DATE: 07/31/2024

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