# +TIPs as novel host capsid-binding co-factors in early HIV-1 infection

> **NIH NIH R01** · NORTHWESTERN UNIVERSITY · 2024 · $734,072

## Abstract

PROJECT SUMMARY/ABSTRACT
Several aspects of early HIV-1 infection are both unusual and still poorly understood. In particular, HIV-1's
cone-shaped viral core consists of pentamers and hexamers of capsid (CA) protein and is known to be
metastable, undergoing restructuring and CA loss that is driven by and facilitates reverse transcription of the
viral genome. Yet only a relatively small number of host proteins have been both structurally and functionally
well-characterized in terms of how they bind to and influence core stability, and to date their binding strategies
all center around recognition of hexamers. This includes microtubule motor adaptor proteins, which HIV-1
exploits to indirectly engage motor proteins to regulate both capsid stability and transport to the nucleus. Our
recent work was at the forefront in identifying the Kinesin-1 adaptor for HIV-1 as Fasiculation and Elongation
Factor Zeta-1 (FEZ1) and determining that negatively charged amino acids in one of FEZ1's coiled-coil
domains mediate binding to the positively charged central pore of CA hexamers. While the structural basis of
its interactions have yet to be determined, others subsequently found that another coiled-coil domain protein,
Bicaudal D Homolog 2 (BICD2) acts as HIV-1's Dynein adaptor. Independently, we discovered that the
specialized microtubule regulatory protein, Cytoplasmic Linker Protein 170 (CLIP170) binds to HIV-1 cores and
in vitro assembled CA structures in a unique manner that is distinct from currently known co-factors.
Specifically, unlike hexamer-binding co-factors, CLIP170 binds to the extreme ends of wildtype CA assemblies
and also has a unique ability to bind and stabilize CA-R18L mutant assemblies, which form pentamer-rich
rather than hexamer-rich structures. Moreover, CLIP170 binds to the Major Homology Region (MHR) of CA,
which is structurally oriented inward and predicted to be inaccessible to cytosolic co-factors. However, cryoEM
imaging reveals that native HIV-1 cores contain breaks while we reveal unusual pentamer organizations in
R18-derived CA assemblies that create a pore which makes the MHR domain accessible from outside the
capsid. From this, we hypothesize that CLIP170 recognizes the MHR upon exposure by natural breaks in the
CA lattice of native cores or WT CA assemblies, or through previously unrecognized pores that form in R18-
derived assemblies, and functions to then control the HIV-1 metastable state. Furthermore, our data shows
that Dynactin 1 (DCTN1), a key component of the primary Dynein adaptor complex, Dynactin, also functions
independently to negatively regulate the pro-viral functions of CLIP170. We hypothesize that this makes
DCTN1 incompatible with HIV-1's goal of separately engaging motors through its hexamers while using
CLIP170 to regulate core metastability, and that this was an evolutionary driver for HIV-1 to instead use BICD2
to engage Dynein. In this proposal, we employ cutting-edge cryoEM, biochemical and functional...

## Key facts

- **NIH application ID:** 10806242
- **Project number:** 5R01AI172818-02
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Mojgan Hosseini Naghavi
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $734,072
- **Award type:** 5
- **Project period:** 2023-03-09 → 2028-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10806242

## Citation

> US National Institutes of Health, RePORTER application 10806242, +TIPs as novel host capsid-binding co-factors in early HIV-1 infection (5R01AI172818-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10806242. Licensed CC0.

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