# Role of cell polarity regulators in HIV spreading

> **NIH NIH R01** · UNIV OF MASSACHUSETTS MED SCH WORCESTER · 2020 · $532,811

## Abstract

ABSTRACT
HIV-1-infected T cells can form stable conjugates with non-infected T cells in a process known as “virological
synapse” formation. This process is reminiscent of the formation of an “immunological synapse”, during which
CD4+ T cells rapidly polarize the actin cytoskeleton, the microtubule-organizing center (MTOC), and cytokine-
containing vesicles towards antigen-presenting cells. The polarization of CD4+ T cells during immunological
synapse formation depends on the RHO family GTPase CDC42, a molecular switch that has a key role in the
establishment of polarity in eukaryotic cells.
 We have now observed that CDC42 is critical for the efficient spreading of HIV-1 in several T cell lines
and in primary cells. However, our data also imply that CDC42 is dispensable for the completion of a single
cycle of replication. Together, our observations implicate CDC42 in the cell-to-cell transmission of HIV-1.
 CDC42 stimulates the formation of membrane extensions, such as filopodia, through effectors that
mediate the polarization of the actin cytoskeleton, and HIV-1 can exploit filopodial bridges to spread from cell
to cell. Thus, our data let us to propose a working model in which CDC42 is crucial for the formation of
intercellular extensions that facilitate the transfer of HIV-1 between CD4+ T cells. In support of this model, we
have observed that CDC42 is required for the formation of HIV-1-induced membrane extensions by MOLT-3
cells. An alternative working model is that CDC42 is required for the polarized trafficking of HIV-1 virion
components to the virologic synapse.
 We propose to directly examine the roles of CDC42 in HIV-1 cell-to-cell transmission and virological
synapse formation, and to determine whether HIV-1 regulates the activity of CDC42. We also propose to
examine the roles of CDC42 effectors that regulate localized actin assembly and polarized trafficking in HIV-1
spreading. Among these effectors are F-BAR proteins that connect to actin polymerization machinery, as does
the F-BAR protein PACSIN2, which we have recently implicated in the cell-to-cell transmission of HIV-1.
Notably, our preliminary results indicate that certain CDC42 effectors, including the CDC42-regulated actin
polymerase FMNL1 and a putative CDC42 effector that controls polarized exocytosis, have crucial roles in
HIV-1 replication.
 The proposed studies have the potential to yield fundamental new insights into the mechanism of an
important but poorly understood mode of HIV-1 transmission. Of particular significance would be the
identification of a kinase downstream of CDC42 as being critical for HIV-1 spreading, since protein kinases
constitute one of the most important groups of drug targets.

## Key facts

- **NIH application ID:** 10013784
- **Project number:** 1R01AI147869-01A1
- **Recipient organization:** UNIV OF MASSACHUSETTS MED SCH WORCESTER
- **Principal Investigator:** HEINRICH GOTTLINGER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $532,811
- **Award type:** 1
- **Project period:** 2020-01-01 → 2024-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10013784

## Citation

> US National Institutes of Health, RePORTER application 10013784, Role of cell polarity regulators in HIV spreading (1R01AI147869-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10013784. Licensed CC0.

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