# Roles of Macropinocytosis in HIV-1 infection of CD4+ T Cells

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2022 · $652,522

## Abstract

Title: Roles of Macropinocytosis in HIV-1 infection of CD4+ T Cells
Project Summary:
Host cell entry is the first step in the replication cycle of HIV-1, the causative agent of AIDS. Although receptor
binding of viral Env glycoprotein and subsequent virus-cell fusion during the virus entry process have been
described in detail, subcellular locations of these events remain to be determined. In particular, despite the
importance of CD4+ T lymphocytes as a natural host cell type for HIV-1, the contribution of virion endocytosis
to HIV-1 infection of CD4+ T cells remains poorly understood. Previous studies of HIV-1 entry into T cells have
largely focused on clathrin-mediated endocytosis and cell surface fusion. However, our team recently
discovered that primary CD4+ T cells engage in robust macropinocytosis, a large-scale, clathrin-independent
form of endocytosis. Importantly, our preliminary data indicate that pharmacological inhibition of
macropinocytosis blocks both internalization of HIV-1 particles and productive infection in primary human
CD4+ T cells. In contrast, the same treatment does not affect HIV infection of a commonly used CD4+ T cell
line. These results suggest that the macropinocytic entry is a hitherto overlooked mode of HIV-1 entry that
contributes to infection of primary human CD4+ T cells. Interestingly, our preliminary study also showed that
inhibition of macropinocytosis after completion of virus internalization also blocks expression of virus-encoded
genes, suggesting that macropinocytosis has another later role in productive HIV infection, which is separable
from virus internalization. In the current application, we propose to determine the roles of macropinocytosis in
productive infection of primary CD4+ T cells. Our long-term goal is to fully describe cellular mechanisms that
promote HIV-1 infection and to use the obtained knowledge for developing antiviral strategies. Our central
hypothesis in this application is that macropinocytosis in primary human CD4+ T cells contributes to productive
infection as a major HIV-1 entry pathway and as a cellular function necessary for maintaining a permissive
environment for the virus. To test this hypothesis, we plan to determine: 1) the extent to which macropinocytic
internalization contributes to productive HIV entry into primary human CD4+ T cells; 2) the roles played by
Env-receptor interactions in promoting HIV-1 macropinocytosis; 3) the influence of macropinosome
environment on HIV-1 entry; and 4) the nature of post-internalization macropinocytosis function that promotes
productive infection. The outcomes of the experiments outlined in this proposal will likely fill the knowledge gap
in our understanding of HIV-1 entry, a fundamental aspect of the HIV-1 replication cycle, and help us develop
or improve antiviral strategies that target virus entry and establishment of productive infection in CD4+ T cells.

## Key facts

- **NIH application ID:** 10412160
- **Project number:** 1R01AI165381-01A1
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** PHILIP D KING
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $652,522
- **Award type:** 1
- **Project period:** 2022-06-23 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10412160

## Citation

> US National Institutes of Health, RePORTER application 10412160, Roles of Macropinocytosis in HIV-1 infection of CD4+ T Cells (1R01AI165381-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10412160. Licensed CC0.

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