# Evolutionary potential of HIV-1 capsid: mechanisms and consequences

> **NIH NIH R01** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2024 · $560,076

## Abstract

PROJECT SUMMARY
The viral capsid, a cone-shaped protein shell, plays multiple roles during HIV-1 replication and has emerged
as a promising antiviral target. It has been widely accepted that structural and functional constraints limit the
mutational tolerance of the capsid. However, there is growing appreciation that HIV-1 accommodates
phenotypic variability in nearly every capsid-mediated function without compromising viral replicative fitness.
These observations raise the possibility that the capability of HIV-1 capsid to adapt is likely underestimated
and substantial. The evolutionary potential of HIV-1 capsid has direct implications for drug resistance and
serves as the molecular basis for host factor utilization and evasion. In this application, building upon our
previous and preliminary studies, we propose to study the mechanisms and consequences of HIV-1 capsid
variability using a multi-pronged strategy with special focus on the use of large-scale genetic approaches. In
Aim 1, high-throughput mutational analysis of HIV-1 capsid will be conducted to generate comprehensive
resistance profiles of various capsid inhibitors. We will also explore how combinatorial use of different types
of capsid inhibitors can improve antiviral activity through synergistic interactions and/or by restricting
resistance pathways. In Aim 2, to elucidate how HIV-1 exploits multiple host factors via highly charged pores
at the center of each CA multimer, we will study the requirement for these cellular factors in capsid stability
and other post-entry steps among diverse lentiviruses. Additionally, deep mutational scanning and detailed
phenotyping will be applied to the central pore of HIV-1 capsid. In Aim 3, leveraging the availability of HIV-1
variants with varying uncoating kinetics, we will study the role of the capsid in shielding viral DNA from innate
sensors in the context of cell-to-cell transmission of HIV-1. Second, to determine how the impacts of the
capsid on viral DNA sensing can define the fate of viral infection, we will develop novel experimental assays
that enable quantification of viral latency and competitions in a co-culture system. These studies will increase
our understanding of the molecular basis for capsid-mediated functions. New findings will provide valuable
insights into the evolutionary potential of HIV-1 capsid and may be harnessed to aid in the discovery and
design of novel capsid targeting antivirals.

## Key facts

- **NIH application ID:** 10865019
- **Project number:** 5R01AI100720-12
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Masahiro Yamashita
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $560,076
- **Award type:** 5
- **Project period:** 2012-04-01 → 2028-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10865019

## Citation

> US National Institutes of Health, RePORTER application 10865019, Evolutionary potential of HIV-1 capsid: mechanisms and consequences (5R01AI100720-12). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10865019. Licensed CC0.

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