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The autophagy protein ATG9A promotes HIV-1 infectivity.
Mailler, Elodie; Waheed, Abdul A; Park, Sang-Yoon; Gershlick, David C; Freed, Eric O; Bonifacino, Juan S.
Afiliação
  • Mailler E; Cell Biology and Neurobiology Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, 20892, USA.
  • Waheed AA; HIV Dynamics and Replication Program, National Cancer Institute, National Institutes of Health, Frederick, MD, 21702, USA.
  • Park SY; Cell Biology and Neurobiology Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, 20892, USA.
  • Gershlick DC; Cell Biology and Neurobiology Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, 20892, USA.
  • Freed EO; Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK.
  • Bonifacino JS; HIV Dynamics and Replication Program, National Cancer Institute, National Institutes of Health, Frederick, MD, 21702, USA. efreed@mail.nih.gov.
Retrovirology ; 16(1): 18, 2019 07 03.
Article em En | MEDLINE | ID: mdl-31269971
ABSTRACT

BACKGROUND:

Nef is a multifunctional accessory protein encoded by HIV-1, HIV-2 and SIV that plays critical roles in viral pathogenesis, contributing to viral replication, assembly, budding, infectivity and immune evasion, through engagement of various host cell pathways.

RESULTS:

To gain a better understanding of the role of host proteins in the functions of Nef, we carried out tandem affinity purification-mass spectrometry analysis, and identified over 70 HIV-1 Nef-interacting proteins, including the autophagy-related 9A (ATG9A) protein. ATG9A is a transmembrane component of the machinery for autophagy, a catabolic process in which cytoplasmic components are degraded in lysosomal compartments. Pulldown experiments demonstrated that ATG9A interacts with Nef from not only HIV-1 and but also SIV (cpz, smm and mac). However, expression of HIV-1 Nef had no effect on the levels and localization of ATG9A, and on autophagy, in the host cells. To investigate a possible role for ATG9A in virus replication, we knocked out ATG9A in HeLa cervical carcinoma and Jurkat T cells, and analyzed virus release and infectivity. We observed that ATG9A knockout (KO) had no effect on the release of wild-type (WT) or Nef-defective HIV-1 in these cells. However, the infectivity of WT virus produced from ATG9A-KO HeLa and Jurkat cells was reduced by ~ fourfold and eightfold, respectively, relative to virus produced from WT cells. This reduction in infectivity was independent of the interaction of Nef with ATG9A, and was not due to reduced incorporation of the viral envelope (Env) glycoprotein into the virus. The loss of HIV-1 infectivity was rescued by pseudotyping HIV-1 virions with the vesicular stomatitis virus G glycoprotein.

CONCLUSIONS:

These studies indicate that ATG9A promotes HIV-1 infectivity in an Env-dependent manner. The interaction of Nef with ATG9A, however, is not required for Nef to enhance HIV-1 infectivity. We speculate that ATG9A could promote infectivity by participating in either the removal of a factor that inhibits infectivity or the incorporation of a factor that enhances infectivity of the viral particles. These studies thus identify a novel host cell factor implicated in HIV-1 infectivity, which may be amenable to pharmacologic manipulation for treatment of HIV-1 infection.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Infecções por HIV / Proteínas de Transporte Vesicular / Produtos do Gene nef do Vírus da Imunodeficiência Humana / Proteínas Relacionadas à Autofagia / Interações entre Hospedeiro e Microrganismos / Proteínas de Membrana Tipo de estudo: Prognostic_studies Limite: Humans Idioma: En Revista: Retrovirology Assunto da revista: VIROLOGIA Ano de publicação: 2019 Tipo de documento: Article País de afiliação: Estados Unidos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Infecções por HIV / Proteínas de Transporte Vesicular / Produtos do Gene nef do Vírus da Imunodeficiência Humana / Proteínas Relacionadas à Autofagia / Interações entre Hospedeiro e Microrganismos / Proteínas de Membrana Tipo de estudo: Prognostic_studies Limite: Humans Idioma: En Revista: Retrovirology Assunto da revista: VIROLOGIA Ano de publicação: 2019 Tipo de documento: Article País de afiliação: Estados Unidos