Abstract
Development of a small animal model to study HIV replication and pathogenesis has been hampered by the failure of the virus to replicate in non-primate cells. Most studies aimed at achieving replication in murine cells have been limited to fibroblast cell lines, but generating an appropriate model requires overcoming blocks to viral replication in primary T cells. We have studied HIV-1 replication in CD4+ T cells from human CD4/ CCR5/Cyclin T1 transgenic mice. Expression of hCD4 and hCCR5 in mouse CD4+ T cells enabled efficient entry of R5 strain HIV-1. In mouse T cells, HIV-1 underwent reverse transcription and nuclear import as efficiently as in human T cells. In contrast, chromosomal integration of HIV-1 proviral DNA was inefficient in activated mouse T cells. This process was greatly enhanced by providing a secondary T cell receptor (TCR) signal after HIV-1 infection, especially between 12 to 24 h post infection. This effect was specific for primary mouse T cells. The pathways involved in HIV replication appear to be PKCθ−, CARMA1-, and WASp-independent. Treatment with Cyclosporin A (CsA) further relieved the pre-integration block. However, transcription of HIV-1 RNA was still reduced in mouse CD4+ T cells despite expression of the hCyclin T1 transgene. Additional post-transcriptional defects were observed at the levels of Gag expression, Gag processing, Gag release and virus infectivity. Together, these post-integration defects resulted in a dramatically reduced yield of infectious virus (300–500 fold) after a single cycle of HIV-1 replication. This study implies the existence of host factors, in addition to those already identified, that are critical for HIV-1 replication in mouse cells. This study also highlights the differences between primary T cells and cell lines regarding pre-integration steps in the HIV-1 replication cycle.
Highlights
A small animal model for HIV infection and pathogenesis would be invaluable for basic research as well as for vaccine development
The xenotransplant models include severe combined immunodeficiency (SCID) mice transplanted with human fetal thymus or liver cells (SCID-Hu (Thy/Liv)), SCID mice transplanted with human peripheral blood lymphocytes (Hu-PBL-SCID) and Rag2/2cc2/2 mice reconstituted with human CD34+ stem cells [1,2]
We found that viral entry, reverse transcription, and nuclear import of HIV-1 are as efficient in primary mouse T cells as in human T cells
Summary
A small animal model for HIV infection and pathogenesis would be invaluable for basic research as well as for vaccine development. The xenotransplant models include severe combined immunodeficiency (SCID) mice transplanted with human fetal thymus or liver cells (SCID-Hu (Thy/Liv)), SCID mice transplanted with human peripheral blood lymphocytes (Hu-PBL-SCID) and Rag2/2cc2/2 mice reconstituted with human CD34+ stem cells [1,2]. These mice have been useful for in vivo HIV-1 pathogenesis studies, as they have aspects of the human immune system, each model has its limitations. Cells from rats transgenic for human CD4 and human CCR5 were susceptible to HIV-1 entry [5,6] In this rat model, primary macrophages and microglia supported some productive HIV-1 replication. Rat T cells were unable to support virus spreading due to putative post-transcriptional blocks [5]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
