Activation of virus uptake through induction of macropinocytosis with a novel polymerizing peptide
Sarah I Daniels1, Erin E Soule, Katharine S Davidoff
1110 Center Dr., Bldg 10, Rm. 6N106, MSC 1868, NIH, Bethesda MD 20892-1868, USA. dadavis@helix.nih.gov.
Abstract:
A 27-aa peptide (P27) was previously shown to decrease the accumulation of human immunodeficiency virus type 1 (HIV-1) in the supernatant of chronically infected cells; however, the mechanism was not understood. Here, we show that P27 prevents virus accumulation by inducing macropinocytosis (MPC). Treatment of HIV-1- and human T-cell lymphotropic virus type 1 (HTLV-1)-infected cells with 2-10 μM P27 caused cell membrane ruffling and uptake of virus and polymerized forms of the peptide into large vacuoles. As demonstrated by electron microscopy, activation of MPC did not require virus or cells infected with virus, as P27 initiated its own uptake in the absence of virus. Inhibitors of MPC, Cytochalasin D and amiloride, decreased P27-mediated uptake of soluble dextran and inhibited P27-induced virus uptake by >60%, which provides further evidence that P27 induces MPC. In CD4(+) HeLa cells, HIV-1 infection was enhanced by P27 up to 4-fold, and P27 increased infection at concentrations as low as 20 nM. The 5-aa C-terminal domain of P27 was necessary for virus uptake and may be responsible for the polymerization of P27 into fibrils. These forms of P27 may play a key role in triggering MPC, making this peptide a useful tool for studying virus uptake and infection, as well as MPC of other macromolecules.
Insights
A novel peptide, P27, triggers macropinocytosis (MPC), a cellular uptake process, to prevent human immunodeficiency virus type 1 (HIV-1) accumulation. This peptide
Area of Science:
- Virology
- Cell Biology
- Biochemistry
Background:
- A 27-amino acid peptide (P27) was previously observed to reduce human immunodeficiency virus type 1 (HIV-1) accumulation in infected cells.
- The mechanism behind P27's antiviral activity remained unclear.
Purpose of the Study:
- To elucidate the mechanism by which P27 reduces HIV-1 accumulation.
- To investigate P27's role in cellular uptake processes.
Main Methods:
- Treatment of HIV-1 and HTLV-1 infected cells with P27.
- Electron microscopy to observe cellular changes.
- Utilizing MPC inhibitors (Cytochalasin D, amiloride) to assess P27's effect.
- Investigating the role of P27's C-terminal domain.
Main Results:
- P27 induces macropinocytosis (MPC), leading to the uptake of virus and peptide into vacuoles.
- P27-induced MPC occurs independently of viral infection.
- MPC inhibitors significantly reduced P27-mediated virus uptake.
- P27 enhanced HIV-1 infection in CD4+ HeLa cells at low concentrations.
- The C-terminal domain of P27 is crucial for virus uptake and peptide polymerization.
Conclusions:
- P27 functions by inducing macropinocytosis, a cellular uptake mechanism.
- P27's ability to trigger MPC, potentially through polymerization, offers a new avenue for studying viral entry and cellular processes.
- The peptide serves as a valuable tool for investigating both virus uptake and MPC of other macromolecules.
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