Study on the molecular interactions of HIV-1 with the endomembrane system of the host cells

• Grant number: 14/25812-0
• Support Opportunities: Regular Research Grants
• Duration: June 01, 2015 - November 30, 2017
• Field of knowledge: Biological Sciences - Morphology - Cytology and Cell Biology
• Principal Investigator: Luis Lamberti Pinto da Silva
• Grantee: Luis Lamberti Pinto da Silva
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil

Abstract

The HIV promotes its replication and evades defense mechanisms by manipulating various cellular machineries including the ones that regulate protein trafficking in the endomembrane system. As other enveloped viruses, the HIV utilizes cell membranes as platforms for virion assembly and the targeting of its surface glycoproteins (Env) to these assembly sites are highly controlled. The envelope complex (Env) and Gag are the two main structural proteins of HIV, being responsible for mediating host cell entry and virion assembly/maturation, respectively. Despite its importance in infection, the mechanisms by which Env and Gag are targeted to viral assembly sites remain incompletely understood. This study aims to elucidate the intracellular transport routes followed by newly-synthesized Env complexes and to investigate the possible co-targeting of Env and Gag to HIV-1 assembly sites. Specifically, we will investigate the role of the adaptor protein complexes (AP-1 to AP-5) and clathrin in the correct incorporation of Env and production of infectious virus particles. The accessory protein Nef also mediates the interactions of HIV with the host endomembrane system. Nef serves as an adaptor that physically binds to sorting machinery and modulates the surface expression of a number of proteins involved in immune responses, such as CD4 and MHC-I molecules. It is well established that Nef downregulates CD4 and MHC-I by inducing the targeting of these proteins to lysosomes, but the molecular mechanisms involved are not completely understood. Here, we will investigate the role of the ESCRT proteins, Alix and the AP complexes in this activity of Nef. The identification of cellular factors used by HIV to manipulate the endomembrane system of the host cell and the molecular dissection of the interactions between the cellular and viral factors regulating these processes, may potentially serve as basis for novel strategies to interfere with HIV pathogenesis. (AU)

Scientific publications

(5)

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

TAVARES, LUCAS A.; DA SILVA, EULALIA M. L.; DA SILVA-JANUARIO, MARA E.; JANUARIO, YUNAN C.; DE CAVALHO, JULIANNE V.; CZERNISZ, ERIKA S.; MARDONES, GONZALO A.; DASILVA, LUIS L. P.. CD4 downregulation by the HIV-1 protein Nef reveals distinct roles for the gamma 1 and gamma 2 subunits of the AP-1 complex in protein trafficking. Journal of Cell Science, v. 130, n. 2, p. 429-443, JAN 15 2017. (09/54014-7, 14/02438-6, 14/25812-0)

GONZALEZ, ALEXIS E.; MUNOZ, VANESSA C.; CAVIERES, VIVIANA A.; BUSTAMANTE, HIANARA A.; CORNEJO, VICTOR-HUGO; JANUARIO, YUNAN C.; GONZALEZ, IBETH; HETZ, CLAUDIO; DASILVA, LUIS L.; ROJAS-FERNANDEZ, ALEJANDRO; et al. Autophagosomes cooperate in the degradation of intracellular C-terminal fragments of the amyloid precursor protein via the MVB/lysosomal pathway. FASEB JOURNAL, v. 31, n. 6, p. 2446-2459, JUN 2017. (14/25812-0)

TAVARES, LUCAS A.; DASILVA, LUIS L. P.. Monitoring the Targeting of Cathepsin D to the Lysosome by Metabolic Labeling and Pulse-chase Analysis. BIO-PROTOCOL, v. 7, n. 21, NOV 5 2017. (16/18207-9, 14/25812-0)

BARBOSA, NATALIA S.; MENDONCA, LEILA R.; DIAS, MARCOS V. S.; PONTELLI, MARJORIE C.; DA SILVA, ELAINE Z. M.; CRIADO, MIRIA F.; DA SILVA-JANUARIO, MARA E.; SCHINDLER, MICHAEL; JAMUR, MARIA C.; OLIVER, CONSTANCE; et al. ESCRT machinery components are required for Orthobunyavirus particle production in Golgi compartments. PLOS PATHOGENS, v. 14, n. 5, MAY 2018. (09/54014-7, 14/02438-6, 14/25812-0)

PEREIRA, ESTELA A.; DASILVA, LUIS L. P.. HIV-1 Nef: Taking Control of Protein Trafficking. TRAFFIC, v. 17, n. 9, p. 976-996, SEP 2016. (14/02438-6, 14/25812-0)