Dataset Information

The tale of the long tail: the cytoplasmic domain of HIV-1 gp41.

ABSTRACT: Envelope glycoproteins (Env) of lentiviruses typically possess unusually long cytoplasmic domains, often 150 amino acids or longer. It is becoming increasingly clear that these sequences contribute a diverse array of functional activities to the life cycle of their viruses. The cytoplasmic domain of gp41 (gp41CD) is required for replication of human immunodeficiency virus type 1 (HIV-1) in most but not all cell types, whereas it is largely dispensable for replication of simian immunodeficiency virus (SIV). Functionally, gp41CD has been shown to regulate rapid clathrin-mediated endocytosis of Env. The resultant low levels of Env expression at the cell surface likely serve as an immune avoidance mechanism to limit accessibility to the humoral immune response. Intracellular trafficking of Env is also regulated by gp41CD through interactions with a variety of cellular proteins. Furthermore, gp41CD has been implicated in the incorporation of Env into virions through an interaction with the virally encoded matrix protein. Most recently, the gp41CDs of HIV-1 and SIV were shown to activate the key cellular-transcription factor NF-?B via the serine/threonine kinase TAK1. Less well understood are the cytotoxicity- and apoptosis-inducing activities of gp41CD as well as potential roles in modulating the actin cytoskeleton and overcoming host cell restrictions. In this review, we summarize what is currently known about the cytoplasmic domains of HIV-1 and SIV and attempt to integrate the wealth of information in terms of defined functional activities.

SUBMITTER: Postler TS

PROVIDER: S-EPMC3536369 | biostudies-literature | 2013 Jan

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

The tale of the long tail: the cytoplasmic domain of HIV-1 gp41.

Postler Thomas S TS Desrosiers Ronald C RC

Journal of virology 20121017 1

Envelope glycoproteins (Env) of lentiviruses typically possess unusually long cytoplasmic domains, often 150 amino acids or longer. It is becoming increasingly clear that these sequences contribute a diverse array of functional activities to the life cycle of their viruses. The cytoplasmic domain of gp41 (gp41CD) is required for replication of human immunodeficiency virus type 1 (HIV-1) in most but not all cell types, whereas it is largely dispensable for replication of simian immunodeficiency v ...[more]

PMID: 23077317

Similar Datasets

Project description:The matrix (MA) domains of HIV-1 precursor Gag (PrGag) proteins direct PrGag proteins to plasma membrane (PM) assembly sites where envelope (Env) protein trimers are incorporated into virus particles. MA targeting to PM sites is facilitated by its binding to phosphatidylinositol-(4,5)-bisphosphate [PI(4,5)P2], and MA binding to cellular RNAs appears to serve a chaperone function that prevents MA from associating with intracellular membranes prior to arrival at the PI(4,5)P2-rich PM. Investigations have shown genetic evidence of an interaction between MA and the cytoplasmic tails (CTs) of Env trimers that contributes to Env incorporation into virions, but demonstrations of direct MA-CT interactions have proven more difficult. In direct binding assays, we show here that MA binds to Env CTs. Using MA mutants, matrix-capsid (MACA) proteins, and MA proteins incubated in the presence of inositol polyphosphate, we show a correlation between MA trimerization and CT binding. RNA ligands with high affinities for MA reduced MA-CT binding levels, suggesting that MA-RNA binding interferes with trimerization and/or directly or indirectly blocks MA-CT binding. Rough-mapping studies indicate that C-terminal CT helices are involved in MA binding and are in agreement with cell culture studies with replication-competent viruses. Our results support a model in which full-length HIV-1 Env trimers are captured in assembling PrGag lattices by virtue of their binding to MA trimers.IMPORTANCE The mechanism by which HIV-1 envelope (Env) protein trimers assemble into virus particles is poorly understood but involves an interaction between Env cytoplasmic tails (CTs) and the matrix (MA) domain of the structural precursor Gag (PrGag) proteins. We show here that direct binding of MA to Env CTs correlates with MA trimerization, suggesting models where MA lattices regulate CT interactions and/or MA-CT trimer-trimer associations increase the avidity of MA-CT binding. We also show that MA binding to RNA ligands impairs MA-CT binding, potentially by interfering with MA trimerization and/or directly or allosterically blocking MA-CT binding sites. Rough mapping implicated CT C-terminal helices in MA binding, in agreement with cell culture studies on MA-CT interactions. Our results indicate that targeting HIV-1 MA-CT interactions may be a promising avenue for antiviral therapy.

Project description:HIV-1 encodes an envelope glycoprotein (Env) that contains a long cytoplasmic tail (CT) harboring trafficking motifs implicated in Env incorporation into virus particles and viral transmission. In most physiologically relevant cell types, the gp41 CT is required for HIV-1 replication, but in the MT-4 T-cell line the gp41 CT is not required for a spreading infection. To help elucidate the role of the gp41 CT in HIV-1 transmission, in this study, we investigated the viral and cellular factors that contribute to the permissivity of MT-4 cells to gp41 CT truncation. We found that the kinetics of HIV-1 production and virus release are faster in MT-4 than in the other T-cell lines tested, but MT-4 cells express equivalent amounts of HIV-1 proteins on a per-cell basis relative to cells not permissive to CT truncation. MT-4 cells express higher levels of plasma-membrane-associated Env than nonpermissive cells, and Env internalization from the plasma membrane is less efficient than that from another T-cell line, SupT1. Paradoxically, despite the high levels of Env on the surface of MT-4 cells, 2-fold less Env is incorporated into virus particles produced from MT-4 than SupT1 cells. Contact-dependent transmission between cocultured 293T and MT-4 cells is higher than in cocultures of 293T with most other T-cell lines tested, indicating that MT-4 cells are highly susceptible to cell-to-cell infection. These data help to clarify the long-standing question of how MT-4 cells overcome the requirement for the HIV-1 gp41 CT and support a role for gp41 CT-dependent trafficking in Env incorporation and cell-to-cell transmission in physiologically relevant cell lines.IMPORTANCE The HIV-1 Env cytoplasmic tail (CT) is required for efficient Env incorporation into nascent particles and viral transmission in primary CD4+ T cells. The MT-4 T-cell line has been reported to support multiple rounds of infection of HIV-1 encoding a gp41 CT truncation. Uncovering the underlying mechanism of MT-4 T-cell line permissivity to gp41 CT truncation would provide key insights into the role of the gp41 CT in HIV-1 transmission. This study reveals that multiple factors contribute to the unique ability of a gp41 CT truncation mutant to spread in cultures of MT-4 cells. The lack of a requirement for the gp41 CT in MT-4 cells is associated with the combined effects of rapid HIV-1 protein production, high levels of cell-surface Env expression, and increased susceptibility to cell-to-cell transmission compared to nonpermissive cells.

Dataset Information

The tale of the long tail: the cytoplasmic domain of HIV-1 gp41.

Publications

The tale of the long tail: the cytoplasmic domain of HIV-1 gp41.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets