# CHEETAH Center for the Structural Biology of HIV Infection, Restriction, and Viral Dynamics

> **NIH NIH U54** · UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH · 2022 · $1,185,192

## Abstract

PROJECT SUMMARY
Although untreated HIV/AIDS infections are fatal, humans nevertheless have an array of powerful innate antiviral responses
that help suppress replication and exert strong selective pressures on the virus during transmission and during viral rebound
following ART interruption. These observations suggest that innate immune responses could be of therapeutic value if we
can understand them better and discover ways to strengthen them. To infect a cell, HIV-1 must run a gauntlet of such innate
immune sensors and restrictions. Studies in Project 2, Cellular Defenses Against HIV, will reconstitute and characterize the
mechanisms of cellular innate immune sensing and restriction of HIV-1 that occur during the first half of the viral life cycle.
Studies in Aim 1 (SERINC Structure, Mechanism, and Antiviral Activity) will build on our recent cryoEM structure of
hSERINC3, and our discoveries that restricting SERINCs are nonspecific phospholipid scramblases and that loss of
phosphatidyl serine (PS) asymmetry elicits antiviral effects. We hypothesize that SERINCs inhibit HIV-1 entry by altering
the natural asymmetry of the virion lipid bilayer. We propose to determine how SERINCs flip lipids, and to test whether
SERINCs exert their antiviral activities by altering PS distribution and disrupting Env conformations.
Studies in Aim 2 (HIV-1 Recognition and Innate Signaling) will leverage our ability to reconstitute cGAS innate immune
sensing of replicating HIV cores in vitro and our discovery that HIV-1 capsid inhibitors can promote innate signaling in
infected myeloid cells. We now propose to determine: 1) how viral core structure and stability affect cGAS-mediated
detection of reverse transcription, 2) how capsid-binding factors such as PQBP1 contribute to cGAS sensing in myeloid
cells, 3) whether and how CA inhibitors can promote cGAS detection of HIV-1, 4) how cell-specific factors regulate cGAS
activity, and 5) how the resulting downstream responses restrict HIV-1 infection.
Studies in Aim 3 (TRIM Restrictions) will follow from our observation that TRIM5 proteins form hexagonal cages around
incoming HIV-1 capsids. Experiments in this Aim are designed to fill fundamental gaps in our understanding of the viral
inhibition and signaling processes that follow this initial TRIM5 recognition step, and to discover how host cofactors
facilitate or modulate TRIM5 restriction.
Studies in Aim 4 (Reconstitution of Other Restrictions) will build on our ability to reconstitute SAMHD1 and APOBEC3G
restriction of replicating HIV-1 cores in vitro, and we now propose to reconstitute MxB restriction. These reconstituted
reactions will be used to fill gaps in our understanding of restriction mechanisms, cofactors, and regulation, and to examine
how capsid inhibitors can enhance MxB activity.

## Key facts

- **NIH application ID:** 10508318
- **Project number:** 1U54AI170856-01
- **Recipient organization:** UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH
- **Principal Investigator:** Owen Pornillos
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $1,185,192
- **Award type:** 1
- **Project period:** 2022-07-11 → 2027-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10508318

## Citation

> US National Institutes of Health, RePORTER application 10508318, CHEETAH Center for the Structural Biology of HIV Infection, Restriction, and Viral Dynamics (1U54AI170856-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10508318. Licensed CC0.

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