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

Jacob Couturier, Aaron F. Orozco, Hongbing Liu, Sona Budhiraja, Edward B. Siwak, Pramod N. Nehete, K. Jagannadha Sastry, Andrew P. Rice, Dorothy E. Lewis

Research output: Contribution to journalArticle

4 Scopus citations

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.

Original languageEnglish (US)
Article number22
JournalVirology Journal
Volume16
Issue number1
DOIs
StatePublished - Feb 20 2019

Keywords

  • Cyclin T1
  • Flow cytometry
  • HIV latency
  • HIV replication
  • HIV reservoirs
  • Memory CD4 T cells
  • P-TEFb

ASJC Scopus subject areas

  • Virology
  • Infectious Diseases

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