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The Future of HIV-1 Therapeutics pp 121–145Cite as

Targeting HIV Transcription: The Quest for a Functional Cure

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Part of the book series: Current Topics in Microbiology and Immunology ((CT MICROBIOLOGY,volume 389))

Abstract

HIV Transcription and Tat Protein. HIV Tat protein (A), bound to the TAR RNA stem–loop structure, binds to the P-TEFb complex (B), activating transcriptional elongation by RNA polymerase (C). The illustration also shows HIV Rev (D) bound to the Rev-response element and CRM1 (E), a cellular protein involved in transport through the nuclear pore

Antiretroviral therapy (ART) potently suppresses HIV-1 replication, but the virus persists in quiescent infected CD4+T cells as a latent integrated provirus, and patients must indefinitely remain on therapy. If ART is terminated, these integrated proviruses can reactivate, driving new rounds of infection. A functional cure for HIV requires eliminating low-level ongoing viral replication that persists in certain tissue sanctuaries and preventing viral reactivation. The HIV Tat protein plays an essential role in HIV transcription by recruiting the kinase activity of the P-TEFb complex to the viral mRNA’s stem–bulge–loop structure, TAR, activating transcriptional elongation. Because the Tat-mediated transactivation cascade is critical for robust HIV replication, the Tat/TAR/P-TEFb complex is one of the most attractive targets for drug development. Importantly, compounds that interfere with transcription could impair viral reactivation, low-level ongoing replication, and replenishment of the latent reservoir, thereby reducing the size of the latent reservoir pool. Here, we discuss the potential importance of transcriptional inhibitors in the treatment of latent HIV-1 disease and review recent findings on targeting Tat, TAR, and P-TEFb individually or as part of a complex. Finally, we discuss the impact of extracellular Tat in HIV-associated neurocognitive disorders and cancers.

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Abbreviations

ART:

Antiretroviral therapy

HIV:

Human immunodeficiency virus

ARVs:

Antiretrovirals

LTR:

5′ long-terminal repeat

RNAPII:

RNA polymerase II

TAR:

Transactivation response element

PCAF:

p300/CBP-associated factor

P-TEFb:

Positive transcription elongation factor b

CDK9:

Cyclin-dependent kinase 9

CTD:

C-terminal domain

HDAC:

Histone deacetylase

HAT:

Histone acetyl transferase

HAND:

HIV-associated neurocognitive disorders

BBB:

Blood–brain barrier

MCP-1:

Chemoattractant protein-1

PBMC:

Peripheral blood mononuclear cell

TI:

Therapeutic index

IC50 :

Half-maximal inhibitory concentration

NMR:

Nuclear magnetic resonance

MAE:

Michael acceptor electrophile

CC50 :

Half-maximal cytotoxic concentration

dCA:

didehydro-cortistatin A

RT:

Reverse transcriptase

SPMG:

Sulfated polymannuroguluronate

AIDS:

Acquired immune deficiency syndrome

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  1. Department of Infectious Diseases, The Scripps Research Institute, Jupiter, FL, 33458, USA

    Guillaume Mousseau, Sonia Mediouni & Susana T. Valente

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  1. Guillaume Mousseau
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  2. Sonia Mediouni
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  3. Susana T. Valente
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  1. Departments of Molecular and Experimental Medicine and Immunology and Microbial Science (MEM 131), The Scripps Research Institute, La Jolla, California, USA

    Bruce E. Torbett

  2. Department of Integrative Structural and Computational Biology, and RCSB Protein Data Bank, The Scripps Research Institute, La Jolla, California, USA

    David S. Goodsell

  3. Department of Pathology, University of California, San Diego, La Jolla, California, USA

    Douglas D. Richman

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Mousseau, G., Mediouni, S., Valente, S.T. (2015). Targeting HIV Transcription: The Quest for a Functional Cure. In: Torbett, B., Goodsell, D., Richman, D. (eds) The Future of HIV-1 Therapeutics. Current Topics in Microbiology and Immunology, vol 389. Springer, Cham. https://doi.org/10.1007/82_2015_435

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