Aviad Levin, Zvi Hayouka, Assaf Friedler and Abraham Loyter

Aviad Levin

Department of Biological Chemistry, The Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Safra Campus, Givat Ram, Jerusalem 91904, Israel

Zvi Hayouka

Institute of Chemistry, The Hebrew University of Jerusalem, Safra Campus, Givat Ram, Jerusalem 91904, Israel

Assaf Friedler

Institute of Chemistry, The Hebrew University of Jerusalem, Safra Campus, Givat Ram, Jerusalem 91904, Israel

Abraham Loyter

Corresponding author: loyter@cc.huji.ac.il
Department of Biological Chemistry, The Alexander Silberman Institute of Life Sciences

Unlike other retroviruses, Human immunodeficiency virus type-1 (HIV-1) can infect terminally differentiated cells, due to the ability of its pre-integration complex (PIC) to translocate via the host nuclear pore complex (NPC). The PIC Nuclear import has been suggested to be mediated by the viral integrase protein (IN), via either the importin α or transportin 3 (TNPO3/transportin-SR2) pathways.

We show that in virus-infected cells, IN interacts with both importin α and TNPO3, simultaneously or separately, suggesting a multiple use of nuclear import pathways. Disruption of either the IN-importin α or IN-TNPO3 complexes in virus-infected cells by specific cell-permeable-peptides resulted in inhibition of IN and viral cDNA nuclear import. Here we show that peptides which disrupt either one of these complexes block virus infection, indicating involvement of both pathways in efficient viral replication. Formation of IN-importin α and IN-TNPO3 complexes has also been observed in IN-transfected cultured cells. Using specific peptides, we demonstrate that in transfected cells but not in virus infected cells the importin α pathway overrides that of TNPO3. The IN-importin α and IN-TNPO3 complexes were not observed in virus-infected Rev-expressing cells, indicating the Rev protein's ability to disrupt both complexes.