The trans-activator gene of HTLV-III is essential for virus replication

Abstract

Studies of the genomic structure of human T-lymphotropic virus type III (HTLV-III) and related viruses, implicated as the causal agent of acquired immune deficiency syndrome (AIDS), have identified a sixth open reading frame in addition to the five previously known within the genome (gag, pol, sor, env and 3'orf). This gene, called tat-III, lies between the sor and env genes and is able to mediate activation, in a trans configuration, of the genes linked to HTLV-III long terminal repeat (LTR) sequences. We now present evidence that the product of tat-III is an absolute requirement for virus expression. We show that derivatives of a biologically competent molecular clone of HTLV-III, in which the tat-III gene is deleted or the normal splicing abrogated, failed to produce or expressed unusually low levels of virus, respectively, when transfected into T-cell cultures. The capacity of these tat-III-defective genomes was transiently restored by co-transfection of a plasmid clone containing a functional tat-III gene or by introducing the TAT-III protein itself. As HTLV-III and related viruses are the presumed causal agents of AIDS and associated conditions, the observation that tat-III is critical for HTLV-III replication has important clinical implications, and suggests that specific inhibition of the activity of tat-III could be a novel and effective therapeutic approach to the treatment of AIDS.

Comparative study of Tat vaccine regimens in Mauritian cynomolgus and Indian rhesus macaques: Influence of Mauritian MHC haplotypes on susceptibility/resistance to SHIV89.6P infection

“…Among target HIV antigens for vaccine development is Tat, the potent transcriptional transactivator of HIV gene expression. Tat is produced early after infection [1,2] and is indispensable for viral replication, transmission, and AIDS pathogenesis [3][4][5][6]. Release of Tat from infected cells and its uptake by infected and uninfected cells is critical to the biology of the virus [5,[7][8][9][10].…”

Long-term protection against SHIV89.6P replication in HIV-1 Tat vaccinated cynomolgus monkeys

“…Tat is a key viral regulatory protein of human immunodeficiency virus (HIV) produced very early after infection even prior to provirus integration [1][2][3]. Tat is essential for viral replication, transmission and disease progression [1,[4][5][6][7].…”

IκB-α Represses the Transcriptional Activity of the HIV-1 Tat Transactivator by Promoting Its Nuclear Export

“…The evidence that NF-B is dispensable for the transcriptional activation of HIV-1 raises the question of whether I B-␣ represses other transcription factors, which differ from NF-B and are required for HIV-1 expression. To test this possibility, we have analyzed the functional and physical interactions of I B-␣ with the HIV-1 Tat transactivator, which is indispensable for viral replication (41,42). Here, we report that I B-␣ binds to Tat and promotes its nuclear export to the cytoplasm.…”