Narute, PS and Smithgall, TE
(2012)
Nef alleles from all major HIV-1 clades activate Src-family kinases and enhance HIV-1 replication in an inhibitor-sensitive manner.
PLoS ONE, 7 (2).
Abstract
The HIV-1 accessory factor Nef is essential for high-titer viral replication and AIDS progression. Nef function requires interaction with many host cell proteins, including specific members of the Src kinase family. Here we explored whether Src-family kinase activation is a conserved property of Nef alleles from a wide range of primary HIV-1 isolates and their sensitivity to selective pharmacological inhibitors. Representative Nef proteins from the major HIV-1 subtypes A1, A2, B, C, F1, F2, G, H, J and K strongly activated Hck and Lyn as well as c-Src to a lesser extent, demonstrating for the first time that Src-family kinase activation is a highly conserved property of primary M-group HIV-1 Nef isolates. Recently, we identified 4-amino substituted diphenylfuropyrimidines (DFPs) that selectively inhibit Nef-dependent activation of Src-family kinases as well as HIV replication. To determine whether DFP compounds exhibit broad-spectrum Nef-dependent antiretroviral activity against HIV-1, we first constructed chimeric forms of the HIV-1 strain NL4-3 expressing each of the primary Nef alleles. The infectivity and replication of these Nef chimeras was indistinguishable from that of wild-type virus in two distinct cell lines (U87MG astroglial cells and CEM-T4 lymphoblasts). Importantly, the 4-aminopropanol and 4-aminobutanol derivatives of DFP potently inhibited the replication of all chimeric forms of HIV-1 in both U87MG and CEM-T4 cells in a Nef-dependent manner. The antiretroviral effects of these compounds correlated with inhibition of Nef-dependent activation of endogenous Src-family kinases in the HIV-infected cells. Our results demonstrate that the activation of Hck, Lyn and c-Src by Nef is highly conserved among all major clades of HIV-1 and that selective targeting of this pathway uniformly inhibits HIV-1 replication. © 2012 Narute, Smithgall.
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Details
| Item Type: |
Article
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| Status: |
Published |
| Creators/Authors: |
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| Contributors: |
| Contribution | Contributors Name | Email | Pitt Username | ORCID  |
|---|
| Editor | Vartanian, Jean-Pierre | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED |
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| Date: |
29 February 2012 |
| Date Type: |
Publication |
| Journal or Publication Title: |
PLoS ONE |
| Volume: |
7 |
| Number: |
2 |
| DOI or Unique Handle: |
10.1371/journal.pone.0032561 |
| Schools and Programs: |
School of Public Health > Infectious Diseases and Microbiology
School of Medicine > Microbiology and Molecular Genetics |
| Refereed: |
Yes |
| MeSH Headings: |
Alleles; Amino Acid Sequence; Anti-HIV Agents--pharmacology; Cell Line, Tumor; Dimerization; HIV Infections; HIV-1--genetics; Humans; Molecular Conformation; Molecular Sequence Data; Proto-Oncogene Proteins c-hck--metabolism; Sequence Analysis, DNA; Sequence Homology, Amino Acid; Species Specificity; Virus Replication; nef Gene Products, Human Immunodeficiency Virus--genetics; nef Gene Products, Human Immunodeficiency Virus--metabolism; src-Family Kinases--metabolism |
| Other ID: |
NLM PMC3290594 |
| PubMed Central ID: |
PMC3290594 |
| PubMed ID: |
22393415 |
| Date Deposited: |
13 Sep 2012 18:06 |
| Last Modified: |
26 Jan 2019 10:55 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/14146 |
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