UNIGE document Doctoral Thesis
previous document  unige:31889  next document
add to browser collection
Title

HIV-1 innate immune detection and evasion

Author
Directors
Defense Thèse de doctorat : Univ. Genève, 2013 - Sc. 4610 - 2013/10/16
Abstract Dendritic cells are important sentinels of the innate immune system that present antigen to the adaptive immune system, initiating the host immune response. Dendritic cells can be infected by HIV-1, but, in the absence of productive infection dendritic cells facilitate virus transfer to highly permissive CD4+ T cells. HIV-1 is sensitive to the antiviral state induced by type I interferon but the virus is able to evade detection by pattern recognition receptors (PRR) and thereby avoids the induction of a robust immune response. To understand the interactions between HIV-1 and the innate immune system we focused on two host factors (TRIM5 and SAMHD1). TRIM5 is a restriction factor that binds the retroviral capsid lattice and blocks viral replication. We showed that TRIM5 is also a signal transducer in the type I interferon pathway. Using a newly developed method to knockdown genes of interest in monocyte derived dendritic cells (MDDCs), we demonstrated that TRIM5 knockdown cells produce less type I interferon in response to LPS, which in turn leads to a weaker antiviral state in the TRIM5 knockdown cells, as compared to the control cells. The induction of inflammatory mRNA level and secreted proteins was also reduced in TRIM5 knockdown. Challenge with capsid variants that are restricted by TRIM5 stimulated the production of inflammatory cytokines, demonstrating that TRIM5 is a pattern recognition receptor specific for the retroviral capsid. SIVMAC/HIV-2 accessory protein Vpx acts as an adaptor with DCAF1 to target the host protein SAMHD1 for ubiquitination and proteasomal degradation. Disruption of SAMHD1 in myeloid and resting T cells leads to an increase in the intracellular nucleotide pool, permitting reverse transcription to take place that it would otherwise be blocked in the presence of SAMHD1. We showed that Vpx rescues HIV-1 from it mature MDDCs but it does not rescue SIVMAC or HIV-2. This rescue of HIV-1 is independent of DCAF1 and the increase of the intracellular nucleotide pool. When compared to the effect of treating cells with exogenous nucleosides to artificially increase the intracellular nucleotide pool, Vpx increases nuclear import and integration of the HIV-1 genome in mature dendritic cells and monocytes. Taken together the data obtained in these two projects clarifies the interaction between HIV-1 and the innate immune system. The first project elucidates how retroviruses are detected by the innate immune system. The second project sheds light on the mechanisms that HIV-1 and other retroviruses use to evade detection by the innate immune system and the associated activation of effectors that block viral replication.
Keywords HIV-1Innate immunityRestriction factors
Identifiers
URN: urn:nbn:ch:unige-318897
Full text
Thesis (7.1 MB) - public document Free access
Structures
Citation
(ISO format)
REINHARD, Christian. HIV-1 innate immune detection and evasion. Université de Genève. Thèse, 2013. https://archive-ouverte.unige.ch/unige:31889

318 hits

436 downloads

Update

Deposited on : 2013-12-09

Export document
Format :
Citation style :