Human retroviral antisense mRNAs are retained in the nuclei of infected cells for viral persistence

Proc Natl Acad Sci U S A. 2021 Apr 27;118(17):e2014783118. doi: 10.1073/pnas.2014783118.


Human retroviruses, including human T cell leukemia virus type 1 (HTLV-1) and HIV type 1 (HIV-1), encode an antisense gene in the negative strand of the provirus. Besides coding for proteins, the messenger RNAs (mRNAs) of retroviral antisense genes have also been found to regulate transcription directly. Thus, it has been proposed that retroviruses likely localize their antisense mRNAs to the nucleus in order to regulate nuclear events; however, this opposes the coding function of retroviral antisense mRNAs that requires a cytoplasmic localization for protein translation. Here, we provide direct evidence that retroviral antisense mRNAs are localized predominantly in the nuclei of infected cells. The retroviral 3' LTR induces inefficient polyadenylation and nuclear retention of antisense mRNA. We further reveal that retroviral antisense RNAs retained in the nucleus associate with chromatin and have transcriptional regulatory function. While HTLV-1 antisense mRNA is recruited to the promoter of C-C chemokine receptor type 4 (CCR4) and enhances transcription from it to support the proliferation of HTLV-1-infected cells, HIV-1 antisense mRNA is recruited to the viral LTR and inhibits sense mRNA expression to maintain the latency of HIV-1 infection. In summary, retroviral antisense mRNAs are retained in nucleus, act like long noncoding RNAs instead of mRNAs, and contribute to viral persistence.

Keywords: ASP; HBZ; HIV-1; HTLV-1; RNA-FISH.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Basic-Leucine Zipper Transcription Factors / genetics
  • Basic-Leucine Zipper Transcription Factors / metabolism
  • Cell Line
  • Cell Nucleus / metabolism
  • Gene Expression / genetics
  • Gene Expression Regulation, Viral / genetics
  • HIV-1 / genetics*
  • Human Immunodeficiency Virus Proteins / genetics
  • Human Immunodeficiency Virus Proteins / metabolism
  • Human T-lymphotropic virus 1 / genetics*
  • Humans
  • Primary Cell Culture
  • Promoter Regions, Genetic / genetics
  • Proviruses / genetics
  • RNA, Antisense / genetics
  • RNA, Antisense / metabolism
  • RNA, Messenger / metabolism
  • RNA, Viral / genetics
  • Retroviridae Proteins / genetics
  • Retroviridae Proteins / metabolism
  • Terminal Repeat Sequences / genetics
  • Transcription, Genetic / genetics
  • Viral Envelope Proteins / genetics
  • Viral Envelope Proteins / metabolism
  • Viral Proteins / metabolism
  • Virus Latency / genetics*
  • Virus Replication / genetics


  • ASP protein, HIV-1
  • Basic-Leucine Zipper Transcription Factors
  • HBZ protein, human T-cell leukemia virus type I
  • Human Immunodeficiency Virus Proteins
  • RNA, Antisense
  • RNA, Messenger
  • RNA, Viral
  • Retroviridae Proteins
  • Viral Envelope Proteins
  • Viral Proteins