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

Abstract

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.

Latency Reversing Agents: Kick and Kill of HTLV-1?

“…Interestingly, studies combining predictions with experimental validation in a large patient cohort ( n = 432) showed that despite Tax being the immunodominant protein, CD8 + T-cells specific to the antisense protein HTLV-1 basic leucine zipper (HBZ) are the most effective CD8 + T-cells [ 54 ]. However, antigen presentation of HBZ is impaired, possibly due to nuclear retention of HBZ [ 55 , 56 ]. Thus, latency reversal may also be achieved by enhancing antigen presentation of HBZ, a topic that is very interesting, but not discussed within this review.…”

HIV UTR, LTR, and Epigenetic Immunity

“…Recent studies reveal that the 3′LTR serves as the 5′LTR in the DNA negative strand, and transcribes an antisense ncRNA named ASP (the ncRNA codes the antisense protein ASP) [ 84 , 85 ]. The ASP regulates the HIV latency by RNA:DNA base pairing to 5′LTR with Watson–Crick and Hoogsteen specificity.…”

HTLV-1's Foxy Strategy for Survival and Transmission

“…When HBZ is expressed by its native promoter, the 3 ′ LTR, HBZ mRNA is mainly present in the nucleus, but it resides in the cytoplasm when expressed by the exogenous strong promoter. The difference between the HBZ mRNAs in these two scenarios is the length of the poly A tail: poor polyadenylation is the cause of the nuclear localization of HBZ mRNA (48). HBZ mRNA expressed by the 3 ′ LTR can promote the proliferation of T cells, whereas HBZ mRNA expressed by a strong promoter did not promote T-cell proliferation, indicating that nuclear localization is involved in this function.…”