Human cyclin T1 expression ameliorates a T-cell-specific transcriptional limitation for HIV in transgenic rats, but is not sufficient for a spreading infection of prototypic R5 HIV-1 strains ex vivo.
BACKGROUND
Cells derived from native rodents have limits at distinct steps of HIV replication. Rat primary CD4 T-cells, but not macrophages, display a profound transcriptional deficit that is ameliorated by transient trans-complementation with the human Tat-interacting protein Cyclin T1 (hCycT1).


RESULTS
Here, we generated transgenic rats that selectively express hCycT1 in CD4 T-cells and macrophages. hCycT1 expression in rat T-cells boosted early HIV gene expression to levels approaching those in infected primary human T-cells. hCycT1 expression was necessary, but not sufficient, to enhance HIV transcription in T-cells from individual transgenic animals, indicating that endogenous cellular factors are critical co-regulators of HIV gene expression in rats. T-cells from hCD4/hCCR5/hCycT1-transgenic rats did not support productive infection of prototypic wild-type R5 HIV-1 strains ex vivo, suggesting one or more significant limitation in the late phase of the replication cycle in this primary rodent cell type. Remarkably, we identify a replication-competent HIV-1 GFP reporter strain (R7/3 YU-2 Env) that displays characteristics of a spreading, primarily cell-to-cell-mediated infection in primary T-cells from hCD4/hCCR5-transgenic rats. Moreover, the replication of this recombinant HIV-1 strain was significantly enhanced by hCycT1 transgenesis. The viral determinants of this so far unique replicative ability are currently unknown.


CONCLUSIONS
Thus, hCycT1 expression is beneficial to de novo HIV infection in a transgenic rat model, but additional genetic manipulations of the host or virus are required to achieve full permissivity.
Michel
Nico
N
Department of Virology, University of Heidelberg, 69120 Heidelberg, Germany. mail@nicomichel.de
Goffinet
Christine
C
Ganter
Kerstin
K
Allespach
Ina
I
Kewalramani
Vineet N
VN
Saifuddin
Mohammed
M
Littman
Dan R
DR
Greene
Warner C
WC
Goldsmith
Mark A
MA
Keppler
Oliver T
OT
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000821:virology*; D002478:Cells, Cultured; D056906:Cyclin T; D016213:Cyclins / Q000378:metabolism*; D015497:HIV-1 / Q000254:growth & development / Q000502:physiology*; D006801:Humans; D008264:Macrophages / Q000821:virology; D051381:Rats; D055647:Rats, Transgenic; D014158:Transcription, Genetic; D014779:Virus Replication
C503684:CCNT1 protein, human; D056906:Cyclin T; D016213:Cyclins