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Study of viral and cellular factors involved in traffic of the gp41 glycoprotein of HIV-1

Grant number: 13/13878-4
Support type:Scholarships in Brazil - Scientific Initiation
Effective date (Start): October 01, 2013
Effective date (End): September 30, 2014
Field of knowledge:Biological Sciences - Morphology
Principal Investigator:Luis Lamberti Pinto da Silva
Grantee:Mara Elisama da Silva Januário
Home Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil

Abstract

The Human Immunodeficiency Virus Type 1 (HIV-1) causes the progressive debilitation of the immune system in infected individuals, leading to the Acquired Immunodeficiency Syndrome (AIDS), a disease that currently affects over 30 million people in the world. Infection by HIV-1 begins with the fusion of the viral envelope with the host cell plasma membrane that allows entry of the capsid containing the viral genomic RNA into the cytoplasm. This membrane fusion event is mediated by a complex of envelope glycoproteins named Env. During viral replication, these glycoproteins are synthesized in the endoplasmic reticulum as a precursor, gp160, which is processed by host proteases on its itinerary within the secretory pathway. Processing of gp160 results in two glycoproteins: the surface glycoprotein (gp120) and the transmembrane glycoprotein (gp41), which remain associated by non-covalent interactions. The gp41 subunit anchors the gp41/gp120 complex to membranes and contain the necessary information for sorting in its cytosolic tail (CT). The correct incorporation of Env on nascent virions is essential for the production infectious virus particles. Both the plasma membrane and endosomal compartments have been identified as sites of viral assembly. However, the mechanisms that control the targeting of Env to these sites are only partially understood. This project aims characterize targeting signals in the CT of gp41 and identify components of the protein trafficking machinery involved in this process. In particular, we will map the AP-1 binding sites, present in gp41 CT and test the involvement of AP-1, the GTPase Arf-1 and clatrin in the transport of gp41. This study will help to clarify the roles suggested for clathrin adapters in the intracellular trafficking of Env, and will contribute to a better understanding of a process of fundamental importance in HIV-1 replication cycle.