title: Herpesvirus saimiri terminal membrane proteins modulate HIV-1 replication by altering Nef and Tat functions.
abstract: Herpesvirus saimiri (HVS)-transformed human T cells expressing terminal membrane proteins (TMPs) tyrosine kinase interacting protein (Tip) and saimiri transformation associated protein strain C (StpC) are highly permissive for R5 and X4 strains of HIV-1. StpC expression enhances replication of R5 and X4 strains of HIV-1 and induces latent reservoirs of replication competent HIV-1 in cell lines derived from T cells or monocytes. Paradoxically Tip expression restricts replication and cytopathic effects of R5 and X4 strains of HIV-1 in T cells and monocytes post-retrotransposition. Understanding the canonical pathways whereby Tip and StpC alter HIV-1 replication may uncover novel therapeutic approaches to HIV-1 infection. Here we show Tip inhibits Tat-mediated transcriptional activation of the long terminal repeat (LTR). Tip mediated inhibition of Tat transactivation is reversed by Nef. Tip also mediates restriction of late-stage replication of HIV-1 by disrupting Nef interaction with lymphocyte-specific protein-tyrosine kinase (Lck) in lipid rafts. Specifically, in the presence of Tip, Lck does not localize to lipid rafts reducing Nef interaction with Lck within the lipid rafts. Finally, the permissive phenotype conferred by StpC is the result of synergy with Tat during transcriptional activation of the HIV-1 LTR. This transcriptional synergy between StpC and Tat requires Lck and NF-kappaB consensus binding sequences. These findings demonstrate that the HVS TMPs influence transcriptional and post-transcriptional stages in HIV-1 replication. We propose that HVS-encoded TMPs associated with T cell transformation have evolved ability to modulate the replication of competing retroviruses. Gene based approaches utilizing Tip and StpC may provide therapeutic models for treating acute and latent HIV-1 infections, respectively.
authors.affiliation: Department of Microbiology and Immunology, Temple University School of Medicine, Temple University Philadelphia, PA 19140, USA.
authors.forename: Andrea D
authors.initials: AD
authors.lastname: Raymond
authors.forename: Muneer
authors.initials: M
authors.lastname: Hasham
authors.forename: Alexander Y
authors.initials: AY
authors.lastname: Tsygankov
authors.forename: Earl E
authors.initials: EE
authors.lastname: Henderson
mesh_terms: D023241:Antiretroviral Therapy, Highly Active; D015693:Gene Products, nef / Q000502:physiology*; D015696:Gene Products, tat / Q000502:physiology*; D016325:HIV Long Terminal Repeat; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D019169:Jurkat Cells; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000378:metabolism; D021962:Membrane Microdomains / Q000378:metabolism; D016328:NF-kappa B / Q000502:physiology; D010750:Phosphoproteins / Q000502:physiology*; D021381:Protein Transport; D015533:Transcriptional Activation; D014764:Viral Proteins / Q000502:physiology*; D014779:Virus Replication; D054311:nef Gene Products, Human Immunodeficiency Virus; D054322:tat Gene Products, Human Immunodeficiency Virus
chemical_list: D015693:Gene Products, nef; D015696:Gene Products, tat; D016328:NF-kappa B; D010750:Phosphoproteins; D014764:Viral Proteins; D054311:nef Gene Products, Human Immunodeficiency Virus; C514837:nef protein, Human immunodeficiency virus 1; D054322:tat Gene Products, Human Immunodeficiency Virus; C092384:tyrosine kinase interacting protein, Saimiriine herpesvirus 2; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck)