YEARS

2000-2005

AUTHORS

Ashley T. Haase

TITLE

PATHOGENESIS OF MUCOSAL TRANSMISSION/ACUTE SIV INFECTION

ABSTRACT

Description (from applicant's abstract): The principal aim is to use rhesus macaques infected intravaginally with SIV as a model for HIV-1 transmission and a foundation of designing and evaluating vaccine candidates. Virus-cell relationships will be defined by in situ hybridization and PCR-based techniques and the cellular immune response will be identified and quantified. The proposal involves a consortium of investigators headed by Ashley Haase and includes Christopher Miller, David Watkins and Steven Wolinsky. In aim 1, two competing hypotheses will be tested following transmission: SIV replication is confined to the portal of entry for a sufficient time to allow an anamnestic immune defense to prevent dissemination vs. transmission leads to unimpeded spread in DCs and/or macrophages beyond the site of entry. In aim 2, they will examine the hypothesis that latently or chronically infected cells arise quickly after transmission. In aim 3, they will test the hypothesis that the balance between virus reproduction and the scope and breadth of the immune response determines the success or failure of establishing a persistent infection.

FUNDED PUBLICATIONS

  • Lymphoid tissue structure and HIV-1 infection: life or death for T cells.
  • Premature induction of an immunosuppressive regulatory T cell response during acute simian immunodeficiency virus infection.
  • Propagation and dissemination of infection after vaginal transmission of simian immunodeficiency virus.
  • A period of transient viremia and occult infection precedes persistent viremia and antiviral immune responses during multiple low-dose intravaginal simian immunodeficiency virus inoculations.
  • Detection of macaque perforin expression and release by flow cytometry, immunohistochemistry, ELISA, and ELISpot.
  • Targeting early infection to prevent HIV-1 mucosal transmission
  • CD8+ T-lymphocyte response to major immunodominant epitopes after vaginal exposure to simian immunodeficiency virus: too late and too little.
  • Antifibrotic therapy in simian immunodeficiency virus infection preserves CD4+ T-cell populations and improves immune reconstitution with antiretroviral therapy.
  • Transmission, acute HIV-1 infection and the quest for strategies to prevent infection
  • Visualizing antigen-specific and infected cells in situ predicts outcomes in early viral infection.
  • Global genomic analysis reveals rapid control of a robust innate response in SIV-infected sooty mangabeys.
  • Cumulative mechanisms of lymphoid tissue fibrosis and T cell depletion in HIV-1 and SIV infections.
  • Target cells in vaginal HIV transmission.
  • Simian immunodeficiency virus-induced lymphatic tissue fibrosis is mediated by transforming growth factor beta 1-positive regulatory T cells and begins in early infection.
  • Lymphoid tissue damage in HIV-1 infection depletes naïve T cells and limits T cell reconstitution after antiretroviral therapy.
  • Critical role of CD4 T cells in maintaining lymphoid tissue structure for immune cell homeostasis and reconstitution.
  • Transmission, acute HIV-1 infection and the quest for strategies to prevent infection.
  • A technique to simultaneously visualize virus-specific CD8+ T cells and virus-infected cells in situ.
  • Perforin expression in the gastrointestinal mucosa is limited to acute simian immunodeficiency virus infection.
  • Roles of substrate availability and infection of resting and activated CD4+ T cells in transmission and acute simian immunodeficiency virus infection.
  • Regulation of Src-family protein tyrosine kinase transcription during lymphocyte ontogeny.
  • Use of a replication-defective vector to track cells initially infected by SIV in vivo: infected mononuclear cells rapidly appear in the draining lymph node after intradermal inoculation of rhesus monkeys.
  • Determination of simian immunodeficiency virus production by infected activated and resting cells.
  • Simian immunodeficiency virus-induced intestinal cell apoptosis is the underlying mechanism of the regenerative enteropathy of early infection.
  • The role of collagen deposition in depleting CD4+ T cells and limiting reconstitution in HIV-1 and SIV infections through damage to the secondary lymphoid organ niche.
  • Targeting early infection to prevent HIV-1 mucosal transmission.
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