A critical role for the TAR element in promoting efficient human immunodeficiency virus type 1 reverse transcription

Harrich, David; Ulich, Catherine; Gaynor, Richard B.

doi:10.1128/jvi.70.6.4017-4027.1996

Cited by 60 publications

(51 citation statements)

References 60 publications

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“…It has recently been suggested that destabilization of the TAR hairpin reduces the reverse transcription efficiency (27). In our study, destabilization of the 5Ј poly(A) hairpin also resulted in reduced reverse transcription, but we demonstrate that this defect is primarily the result of a reduction in the genomic RNA content of the mutant virions.…”

Section: Discussioncontrasting

confidence: 43%

“…There is now substantial evidence that the R region of HIV-1 RNA molecules contains two critical hairpin structures. Previous studies demonstrated the importance of the TAR stem-loop structure in viral replication (26,27,34,46). In this study, we focused on the adjacent structure, the poly(A) hairpin ( Fig.…”

Section: Discussionmentioning

confidence: 99%

“…The 5Ј TAR element is essential for Tat-mediated activation of viral transcription (reviewed in ref-erences 23 and 32). Furthermore, the 5Ј and/or 3Ј TAR elements may have additional roles in viral replication (34), and a function in reverse transcription was recently proposed (27). In contrast, little is known on the function of the 5Ј and 3Ј poly(A) hairpin motifs.…”

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confidence: 99%

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A conserved hairpin motif in the R-U5 region of the human immunodeficiency virus type 1 RNA genome is essential for replication

Das

Klaver

Klasens

et al. 1997

J Virol

119

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The untranslated leader region of the human immunodeficiency virus (HIV) RNA genome contains multiple hairpin motifs. The repeat region of the leader, which is reiterated at the 3 end of the RNA molecule, encodes the well-known TAR hairpin and a second hairpin structure with the polyadenylation signal AAUAAA in the single-stranded loop [the poly(A) hairpin]. The fact that this poly(A) stem-loop structure and its thermodynamic stability are well conserved among HIV and simian immunodeficiency virus isolates, despite considerable divergence in sequence, suggests a biological function for this RNA motif in viral replication. Consistent with this idea, we demonstrate that mutations that alter the stability of the stem region or delete the upper part of the hairpin do severely inhibit replication of HIV type 1. Whereas destabilizing mutations in either the leftor right-hand side of the base-paired stem interfere with virus replication, the double mutant, which allows the formation of new base pairs, replicates more rapidly than the two individual virus mutants. Upon prolonged culturing of viruses with an altered hairpin stability, revertant viruses were obtained with additional mutations that restore the thermodynamic stability of the poly(A) hairpin. Transient transfection experiments demonstrated that transcription of the proviral genomes, translation of the viral mRNAs, and reverse transcription of the genomic RNAs are not affected by mutation of the 5 poly(A) hairpin. We show that the genomic RNA content of the virions is reduced by destabilization of this poly(A) hairpin but not by stabilization or truncation of this structure. These results suggest that the formation of the poly(A) hairpin structure at the 5 end of the genomic RNA molecule is necessary for packaging of viral genomes into virions and/or stability of the virion RNA.

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Section: Discussioncontrasting

confidence: 43%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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A conserved hairpin motif in the R-U5 region of the human immunodeficiency virus type 1 RNA genome is essential for replication

Das

Klaver

Klasens

et al. 1997

J Virol

119

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“…An intact TAR element is also critical for the regulation of reverse transcription of the HIV-1 genome [39]. It was interesting to investigate whether Tat was also involved in regulating this process.…”

Section: Tat As Hiv-1 Transcription Factormentioning

confidence: 99%

Multiple effects of HIV‐1 trans‐activator protein on the pathogenesis of HIV‐1 infection

Huigen

Kamp²,

Nottet

2004

Eur J Clin Investigation

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The HIV-1 trans-activator (Tat) protein is proposed as an important factor in the complex HIV-induced pathogenesis of AIDS. In this paper, multiple effects of this viral protein are described. Originally discovered as an intracellular activator of HIV-1 transcription, Tat was found to regulate viral reverse transcription as well. Trans-activator was found to be secreted by HIV-infected cells and taken up by neighbouring cells. In this way, Tat is able to affect both infected and uninfected cells. Intracellularly, Tat can deregulate the expression of several heterologous cellular and viral genes. Extracellular Tat can contribute to the spreading of HIV-1 and immunosuppression of uninfected cells. Finally, there is evidence that exogenous Tat is involved in AIDS-associated pathologies such as Kaposi's sarcoma and HIV-associated dementia. These capacities together accelerate the progression towards AIDS and make Tat an interesting candidate as a constituent of an anti-AIDS vaccine.

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“…Precisely how these RNA interactions function in RTN is not known, but RNA stem-loop structures are associated with pausing by RT and by RNA polymerase II during synthesis [14,[18][19][20], which makes it somewhat surprising that mutations in the A-rich loop which prevent kissing-loop base pairing result in decreased initiation efficiency and reduced virus replication kinetics [17]. Likewise, subtle changes in RNA sequences upstream of the PBS inhibit proviral DNA synthesis [21][22][23][24][25], but the precise role of these sequences in RTN is also unknown.…”

Section: Introductionmentioning

confidence: 99%

Mechanistic aspects of HIV‐1 reverse transcription initiation

Harrich

Hooker

2002

Reviews in Medical Virology

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During reverse transcription, the positive-strand HIV-1 RNA genome is converted into a double-stranded DNA copy which can be permanently integrated into the host cell genome. Recent analyses show that HIV-1 reverse transcription is a highly regulated process. The initiation reaction can be distinguished from a subsequent elongation reaction carried out by a reverse transcription complex composed of (at least) heterodimeric reverse transcriptase, cellular tRNA(lys3) and HIV-1 genomic RNA sequences. In addition, viral factors including Tat, Nef, Vif, Vpr, IN and NCp7, cellular proteins, and TAR RNA and other RNA stem-loop structures appear to influence this complex and contribute to the efficiency of the initiation reaction. As viral resistance to many antiretroviral compounds is a continuing problem, understanding the ways in which these factors influence the reverse transcription complex will likely lead to novel antiretroviral strategies.

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A critical role for the TAR element in promoting efficient human immunodeficiency virus type 1 reverse transcription

Cited by 60 publications

References 60 publications

A conserved hairpin motif in the R-U5 region of the human immunodeficiency virus type 1 RNA genome is essential for replication

A conserved hairpin motif in the R-U5 region of the human immunodeficiency virus type 1 RNA genome is essential for replication

Multiple effects of HIV‐1 trans‐activator protein on the pathogenesis of HIV‐1 infection

Mechanistic aspects of HIV‐1 reverse transcription initiation

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