Regulation of cyclin T1 during HIV replication and latency establishment in human memory CD4 T cells

Virology Journal

K. Jagannadha Sastry¹  Sona Budhiraja²  Andrew P. Rice²  Edward B. Siwak²  Hongbing Liu²  Pramod N. Nehete³  Jacob Couturier⁴  Dorothy E. Lewis⁴  Aaron F. Orozco⁴ 

[1] Department of Immunology, The University of Texas MD Anderson Cancer Center;Department of Molecular Virology & Microbiology, Baylor College of Medicine;Department of Veterinary Sciences, The University of Texas MD Anderson Cancer Center;Division of Infectious Diseases, Department of Internal Medicine, University of Texas Health Science Center at Houston;

关键词: Cyclin T1;    Flow cytometry;    HIV latency;    HIV replication;    HIV reservoirs;    Memory CD4 T cells;   

DOI  :  10.1186/s12985-019-1128-6

来源: DOAJ

【 摘 要 】

Abstract Background The regulatory cyclin, Cyclin T1 (CycT1), is a host factor essential for HIV-1 replication in CD4 T cells and macrophages. The importance of CycT1 and the Positive Transcription Elongation Factor b (P-TEFb) complex for HIV replication is well-established, but regulation of CycT1 expression and protein levels during HIV replication and latency establishment in CD4 T cells is less characterized. Methods To better define the regulation of CycT1 levels during HIV replication in CD4 T cells, multiparameter flow cytometry was utilized to study the interaction between HIV replication (intracellular p24) and CycT1 of human peripheral blood memory CD4 T cells infected with HIV in vitro. CycT1 was further examined in CD4 T cells of human lymph nodes. Results In activated (CD3+CD28 costimulation) uninfected blood memory CD4 T cells, CycT1 was most significantly upregulated in maximally activated (CD69+CD25+ and HLA.DR+CD38+) cells. In memory CD4 T cells infected with HIV in vitro, two distinct infected populations of p24+CycT1+ and p24+CycT1- cells were observed during 7 days infection, suggestive of different phases of productive HIV replication and subsequent latency establishment. Intriguingly, p24+CycT1- cells were the predominant infected population in activated CD4 T cells, raising the possibility that productively infected cells may transition into latency subsequent to CycT1 downregulation. Additionally, when comparing infected p24+ cells to bystander uninfected p24- cells (after bulk HIV infections), HIV replication significantly increased T cell activation (CD69, CD25, HLA.DR, CD38, and Ki67) without concomitantly increasing CycT1 protein levels, possibly due to hijacking of P-TEFb by the viral Tat protein. Lastly, CycT1 was constitutively expressed at higher levels in lymph node CD4 T cells compared to blood T cells, potentially enhancing latency generation in lymphoid tissues. Conclusions CycT1 is most highly upregulated in maximally activated memory CD4 T cells as expected, but may become less associated with T cell activation during HIV replication. The progression into latency may further be predicated by substantial generation of p24+CycT1- cells during HIV replication.

【 授权许可】

Unknown