A role for an HTLV-1 vaccine?

HTLV-1 is a global infection with 5-20 million infected individuals. Although only a minority of infected individuals develop myelopathy, lymphoproliferative malignancy, or inflammatory disorders, infection is associated with immunosuppression and shorter survival. Transmission of HTLV-1 is through contaminated blood or needles, mother-to-child exposure through breast-feeding, and sexual intercourse. HTLV-1 is a delta retrovirus that expresses immunogenic Gag, Envelope, TAX, and Hbz proteins. Neutralizing antibodies have been identified directed against the surface envelope protein, and cytotoxic T-cell epitopes within TAX have been characterized. Thus far, there have been few investigations of vaccines directed against each of these proteins, with limited responses, thus far. However, with new technologies developed in the last few years, a renewed investigation is warranted in search for a safe and effective HTLV-1 vaccine

Substitution of HIV type 1 Nef with HTLV-1 p12

Human retroviruses, such as HTLV-1 and HIV-1, encode accessory proteins, which regulate viral pathogenesis. The p12 protein of HTLV-1 is encoded from the pX-I open reading frame, and is critical for efficient virus replication in rabbits. Although dispensable for infection, replication, and immortalization of activated lymphocytes in culture, p12 expression is important for infection of quiescent lymphocytes. Similar to HTLV-1 p12, Nef is important for virus infectivity in SIV animal models. We questioned whether p12 could replace Nef in HIV-1, and reconstitute virus replication in culture. We found that p12 could complement for effects of Nef on HIV-1 infection of Magi-CCR5 cells or macrophages

The HTLV-1 hbz antisense gene indirectly promotes tax expression via down-regulation of p30II mRNA

AbstractHuman T-cell leukemia virus type 1 (HTLV-1) basic leucine zipper factor (HBZ) is transcribed from the antisense genomic DNA strand and functions differently in its RNA and protein forms. To distinguish between the roles of hbz mRNA and HBZ protein, we generated mutants in a proviral clone that specifically disrupt the hbz gene product. A proviral clone with a splice acceptor mutation that disrupts expression of the predominant hbz mRNA resulted in lower levels of tax mRNA. Heterologous hbz expression restored Tax activity in cells expressing this mutant clone. In contrast, proviral mutants that disrupt HBZ protein did not affect levels of tax mRNA. Expression of hbz resulted in lower levels of p30II mRNA. Mutation of p30II overcame the effects of the splice acceptor mutation of hbz, and restored tax expression. Thus, there is a complex interplay of viral regulatory proteins controlling levels of HTLV-1 gene expression

The HTLV Receptor Is a Widely Expressed Protein

AbstractThe receptor for human T-cell leukemia virus type 1 (HTLV-1) was found to be expressed on a broad range of cell lines derived from multiple species. Receptor expression was assessed using human immunodeficiency virus type 1 particles, pseudotyped with the HTLV-1 envelope glycoprotein, and expressing luciferase under the control of an SV40 enhancer and promoter. Infection by pseudotyped virus was blocked with neutralizing antibodies to HTLV-1, and infection was dependent on the presence of the cleavage and fusogenic sequences in the envelope protein precursor. Trypsin treatment of susceptible target lymphocytes reduced entry. Entry was partially resistant to ammonium chloride

Splicing factor 3B subunit 1 interacts with HIV Tat and plays a role in viral transcription and reactivation from latency

ABSTRACT The main obstacle to an HIV cure is the transcriptionally inert proviruses that persist in resting CD4 T cells and other reservoirs. None of the current approaches has significantly reduced the size of the viral reservoir. Hence, alternative approaches, such as permanent blocking of viral transcription, to achieve a sustained remission, need urgent attention. To identify cellular factors that may be important for this approach, we sought for host targets that when altered could block HIV transcription and reactivation. Here, we identified splicing factor 3B subunit 1 (SF3B1) as a critical HIV dependency factor required for viral replication. SF3B1 is a splicing factor involved in directing chromatin and nascent gene transcripts to appropriate splice sites. Inhibitors of SF3B1 are currently in development for cancer and have been found to be nontoxic to normal cells compared to malignant cells. Knockdown of SF3B1 abrogated HIV replication in all cell types tested. SF3B1 interacted with viral protein Tat in vitro and in vivo. Genetic or pharmacologic inhibition of SF3B1 prevented Tat-mediated HIV transcription and RNA polymerase II association with the HIV promoter. In addition, an inhibitor of SF3B1 prevented HIV reactivation from latency irrespective of the latency-reversing agent used. The data show that SF3B1 is involved in viral transcription and reactivation from latency and may serve as a therapeutic target in the HIV cure efforts. IMPORTANCE The reason why HIV cannot be cured by current therapy is because of viral persistence in resting T cells. One approach to permanent HIV remission that has received less attention is the so-called “block and lock” approach. The idea behind this approach is that the virus could be permanently disabled in patients if viral genome or surrounding chromatin could be altered to silence the virus, thus enabling patients to stop therapy. In this work, we have identified splicing factor 3B subunit 1 (SF3B1) as a potential target for this approach. SF3B1 interacts with the viral protein Tat, which is critical for viral transcription. Inhibition of SF3B1 prevents HIV transcription and reactivation from latency. Since there are preclinical inhibitors for this protein, our findings could pave the way to silence HIV transcription, potentially leading to prolonged or permanent remission