title: Stable Phenotypic Changes of the Host T Cells Are Essential to the Long-Term Stability of Latent HIV-1 Infection.
abstract: The extreme stability of the latent HIV-1 reservoir in the CD4(+) memory T cell population prevents viral eradication with current antiretroviral therapy. It has been demonstrated that homeostatic T cell proliferation and clonal expansion of latently infected T cells due to viral integration into specific genes contribute to this extraordinary reservoir stability. Nevertheless, given the constant exposure of the memory T cell population to specific antigen or bystander activation, this reservoir stability seems remarkable, unless it is assumed that latent HIV-1 resides exclusively in memory T cells that recognize rare antigens. Another explanation for the stability of the reservoir could be that the latent HIV-1 reservoir is associated with an unresponsive T cell phenotype. We demonstrate here that host cells of latent HIV-1 infection events were functionally altered in ways that are consistent with the idea of an anergic, unresponsive T cell phenotype. Manipulations that induced or mimicked an anergic T cell state promoted latent HIV-1 infection. Kinome analysis data reflected this altered host cell phenotype at a system-wide level and revealed how the stable kinase activity changes networked to stabilize latent HIV-1 infection. Protein-protein interaction networks generated from kinome data could further be used to guide targeted genetic or pharmacological manipulations that alter the stability of latent HIV-1 infection. In summary, our data demonstrate that stable changes to the signal transduction and transcription factor network of latently HIV-1 infected host cells are essential to the ability of HIV-1 to establish and maintain latent HIV-1 infection status.
  
  
  OBJECTIVE
  The extreme stability of the latent HIV-1 reservoir allows the infection to persist for the lifetime of a patient, despite completely suppressive antiretroviral therapy. This extreme reservoir stability is somewhat surprising, since the latently HIV-1 infected CD4(+) memory T cells that form the structural basis of the viral reservoir should be exposed to cognate antigen over time. Antigen exposure would trigger a recall response and should deplete the reservoir, likely over a relatively short period. Our data demonstrate that stable and system-wide phenotypic changes to host cells are a prerequisite for the establishment and maintenance of latent HIV-1 infection events. The changes observed are consistent with an unresponsive, anergy-like T cell phenotype of latently HIV-1 infected host cells. An anergy-like, unresponsive state of the host cells of latent HIV-1 infection events would explain the stability of the HIV-1 reservoir in the face of continuous antigen exposure.
authors: Department of Medicine, The University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors: Lillian
authors: L
authors: Seu
authors: Department of Medicine, The University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors: Steffanie
authors: S
authors: Sabbaj
authors: Department of Medicine, The University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors: Alexandra
authors: A
authors: Duverger
authors: Department of Medicine, The University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors: Frederic
authors: F
authors: Wagner
authors: Department of Radiation Oncology, The University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors: Joshua C
authors: JC
authors: Anderson
authors: Department of Medicine, The University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors: Elizabeth
authors: E
authors: Davies
authors: Department of Medicine, The University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors: Frank
authors: F
authors: Wolschendorf
authors: Department of Radiation Oncology, The University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors: Christopher D
authors: CD
authors: Willey
authors: Department of Medicine, The University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors: Michael S
authors: MS
authors: Saag
authors: Department of Medicine, The University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors: Paul
authors: P
authors: Goepfert
authors: Department of Medicine, The University of Alabama at Birmingham, Birmingham, Alabama, USA okutsch@uab.edu.
authors: Olaf
authors: O
authors: Kutsch
mesh_terms: D000328:Adult; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000821:virology*; D017635:Clonal Anergy; D015658:HIV Infections / Q000276:immunology* / Q000821:virology*; D015497:HIV-1 / Q000276:immunology* / Q000502:physiology*; D006801:Humans; D060066:Protein Interaction Maps; D011494:Protein Kinases / Q000378:metabolism; D017735:Virus Latency
chemical_list: D011494:Protein Kinases