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Chapter 6 : Human Immunodeficiency Virus Type 1 Tat and Rev as Potential Targets for Drug Development

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Human Immunodeficiency Virus Type 1 Tat and Rev as Potential Targets for Drug Development, Page 1 of 2

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Abstract:

This chapter discusses the potential of HIV Tat, Rev, and their cellular cofactors as drug targets. Tat interacts with numerous transcriptional regulatory factors and presumably by virtue of its interaction with transcription activation response (TAR) RNA, recruits these factors to the human immunodeficiency virus type 1 (HIV-1) promoter. Thus, HIV-1 transcription directed from the viral long terminal repeat (LTR) is balanced by the actions of kinases and phosphatases, and both can be potential targets for drug development. Tat promotes the elongation of viral transcripts by increasing the occupancy time of CDK9/cyclin T1 on the HIV-1 LTR. Small-molecule inhibitors of Tat-TAR RNA interaction, small-molecule inhibitors of CDKs such as CDK9 or CDK2, and inhibitors that disrupt the interaction of Tat with additional host cell factors such as p300/CREB binding protein-associated factor (PCAF) and/or inhibit cellular activities of the host cell factors could all be viable anti-HIV drug candidates. Both Tat and TAR RNA are essential for activated HIV-1 transcription, and were thus the first candidates to be considered for drug design that targeted HIV-1 transcription. Antiviral development against HIV-1 regulatory proteins Tat and Rev represents a conceptual work in progress. In the arena of inhibiting Tat and Rev cellular cofactors, the concerns over host toxicity have not been fully resolved. Future efforts are needed to address the two major challenges of mechanistic specificity and functional toxicity.

Citation: Nekhai S, Jeang K. 2009. Human Immunodeficiency Virus Type 1 Tat and Rev as Potential Targets for Drug Development, p 97-111. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch6

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Figures

Image of Figure 1.
Figure 1.

Illustration of activation of HIV-1 transcription by Tat. Tat cofactors including TAR RNA that were targeted for development of specific inhibitors are indicated.

Citation: Nekhai S, Jeang K. 2009. Human Immunodeficiency Virus Type 1 Tat and Rev as Potential Targets for Drug Development, p 97-111. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch6
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Image of Figure 2.
Figure 2.

Diagrams of Rev and RRE. (A) Schematic representation of the different protein motifs in the Rev protein; (B) secondary structure of the RRE RNA that is the target for Rev function.

Citation: Nekhai S, Jeang K. 2009. Human Immunodeficiency Virus Type 1 Tat and Rev as Potential Targets for Drug Development, p 97-111. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch6
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Image of Figure 3.
Figure 3.

Cartoon of Rev function in exporting unspliced HIV-1 RNAs. Different steps of Rev activity are indicated as potential points for inhibition of function.

Citation: Nekhai S, Jeang K. 2009. Human Immunodeficiency Virus Type 1 Tat and Rev as Potential Targets for Drug Development, p 97-111. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch6
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Tables

Generic image for table
Table 1.

Small-molecule inhibitors of Tat-TAR RNA interaction

Citation: Nekhai S, Jeang K. 2009. Human Immunodeficiency Virus Type 1 Tat and Rev as Potential Targets for Drug Development, p 97-111. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch6
Generic image for table
Table 2.

Inhibitors of CDK9, cyclin T1, and CDK2

Citation: Nekhai S, Jeang K. 2009. Human Immunodeficiency Virus Type 1 Tat and Rev as Potential Targets for Drug Development, p 97-111. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch6
Generic image for table
Table 3.

Inhibitors of Tat-binding cofactors

Citation: Nekhai S, Jeang K. 2009. Human Immunodeficiency Virus Type 1 Tat and Rev as Potential Targets for Drug Development, p 97-111. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch6
Generic image for table
Table 4.

Cellular proteins proposed to interact directly with Rev

Citation: Nekhai S, Jeang K. 2009. Human Immunodeficiency Virus Type 1 Tat and Rev as Potential Targets for Drug Development, p 97-111. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch6
Generic image for table
Table 5.

Selected inhibitors of Rev function

Citation: Nekhai S, Jeang K. 2009. Human Immunodeficiency Virus Type 1 Tat and Rev as Potential Targets for Drug Development, p 97-111. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch6

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