# Role of HIV-1 capsid in innate sensing of viral nucleic acids

> **NIH NIH F31** · WASHINGTON UNIVERSITY · 2022 · $32,704

## Abstract

Abstract
 Despite the development of dozens of drugs since the start of the HIV/AIDS epidemic, the emergence of
drug resistance and lack of a vaccine or cure necessitate the development of new antiretroviral compounds. The
HIV-1 capsid (CA) protein plays essential roles throughout the viral replication cycle. After an immature HIV-1
virion buds from a host cell, the structural Gag polyprotein undergoes proteolytic cleavage and rearrangement.
The retroviral core is formed when rings of CA, held together by intra- and inter-subunit interactions, arrange into
a conical lattice around the viral genomic RNA (gRNA) and enzymes. Since many CA-CA interactions are
required to form a stable lattice, CA is genetically fragile and a favorable drug target. In fact, compounds that
successfully target CA assembly and stability have recently been developed as part of long-acting drug regimens
and show great promise clinically.
 Following their release into the cytoplasm of target cells, HIV-1 cores undergo an uncoating process in
which CA subunits are shed from the core. It is now evident that proper uncoating is crucial for subsequent steps
in virus replication, including reverse transcription, nuclear entry, and integration. We have recently
demonstrated that destabilization of the CA lattice through mutations and CA-targeting compounds increases
the propensity to form aberrant virus particles. In these particles, the gRNA and enzymes are localized between
the CA lattice and viral envelope. Interestingly, this phenotype has striking similarities with the eccentric virions
that are generated by inhibition of integrase (IN)-gRNA interactions. We have shown that the lack of protection
by the CA lattice in both circumstances results in premature loss of gRNA and IN in a proteasome-independent
manner. However, the mechanism by which IN and gRNA are degraded upon loss of CA protection remains
unclear. Furthermore, recent studies have implicated that CA may shield viral nucleic acids from the host sensor
proteins that initiate antiviral responses. I hypothesize that tampering with the stability of the HIV-1 CA lattice will
result in premature exposure and sensing of viral nucleic acids in infected cells. Here, I propose to determine
how prematurely exposed viral ribonucleoprotein complexes (vRNPs) are degraded in target cells (Aim 1). I plan
to determine if altered CA stability elicits a more robust innate immune response against HIV-1 and the
mechanism by which viral nucleic acids are sensed (Aim 2). Together, the results of these experiments will
contribute to a better understanding of the proposed role of CA in virus replication and evasion of innate immune
sensing.

## Key facts

- **NIH application ID:** 10481252
- **Project number:** 1F31AI167695-01A1
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Jenna Eschbach
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $32,704
- **Award type:** 1
- **Project period:** 2022-09-01 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10481252

## Citation

> US National Institutes of Health, RePORTER application 10481252, Role of HIV-1 capsid in innate sensing of viral nucleic acids (1F31AI167695-01A1). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10481252. Licensed CC0.

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