HIV-1 regulation of latency in the monocyte- macrophage lineage ...
Molecular control of HIV - 1 postintegration latency: implications for therapeutic strategies
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INVITED SPEAKER PRESENTATION Open Access Molecular control of HIV - 1 postintegration latency: implications for therapeutic strategies Carine Van Lint From 17th International Symposium on HIV and Emerging Infectious Diseases (ISHEID) Marseille, France. 23-25 May 2012 The current antiretroviral therapy HAART is effective and life-prolonging but does not eradicate HIV-1 from infected patients. A reduction of HIV-1 RNA levels in the plasma in HAART-treated individuals to less than 50 copies/ml is frequently achieved but residual viremia per- sists as detected by ultrasensitive assays. The sources of this persistent viremia are still not fully understood but could arise from ongoing cycles of residual viral replica- tion and/or from the reactivation of viral expression from latently-infected cells. These latently-infected cells con- tain stably-integrated, transcriptionally-silent but replica- tion-competent proviruses, thereby representing latent reservoirs of HIV-1. They are a permanent source for virus reactivation and could be responsible for the rebound of plasma viral load observed after HAART interruption. HIV-1 transcriptional repression is crucial to the estab- lishment and maintenance of postintegration latency. Several elements contribute to HIV-1 transcriptional repression including: 1) the site of integration and mechanisms of transcriptional interference, 2) the absence of crucial inducible host transcription factors, 3) the pre- sence of transcriptional repressors, 4) the nucleosomal organization of the HIV-1 promoter, 5) the epigenetic control of the HIV-1 promoter (histone posttranslational modifications, such as acetylation and methylation, and DNA methylation), 6) the sequestration in an inactive form of the cellular positive transcription elongation factor b (P-TEFb), composed of cyclin-dependent kinase 9 (CDK9) and human cyclin T1, 7) the absence of the viral transactivator Tat, which promotes transcription via recruitment to the HIV-1 promoter of P-TEFb, histone- modifying enzymes and ATP-dependent chromatin-remo- deling complexes required for nucleosomal disruption and transcriptional processivity. The involvement of these elements in postintegration latency depends on the status of activation and differentiation of the heterogeneous CD4 + T cell populations hosting the HIV-1 reservoirs. Further understanding of the epigenetic and non- epigenetic mechanisms regulating HIV-1 latency and reactivation from latency should help devise novel stra- tegies to eliminate latent HIV-1 infection or to restrict the latent pool to a size bearable by the host immune system. Published: 25 May 2012 doi:10.1186/1742-4690-9-S1-I10 Cite this article as: Van Lint: Molecular control of HIV - 1 postintegration latency: implications for therapeutic strategies. Retrovirology 2012 9(Suppl 1):I10. Submit your next manuscript to BioMed Central and take full advantage of: • Convenient online submission • Thorough peer review • No space constraints or color figure charges • Immediate publication on acceptance • Inclusion in PubMed, CAS, Scopus and Google Scholar • Research which is freely available for redistribution Submit your manuscript at www.biomedcentral.com/submit Gosselies Campus, Charleroi, Belgium Van Lint Retrovirology 2012, 9(Suppl 1):I10 http://www.retrovirology.com/content/9/S1/I10 © 2012 Van Lint; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Transcript of Molecular control of HIV - 1 postintegration latency: implications for therapeutic strategies
INVITED SPEAKER PRESENTATION Open Access
Molecular control of HIV - 1 postintegrationlatency: implications for therapeutic strategiesCarine Van Lint
From 17th International Symposium on HIV and Emerging Infectious Diseases (ISHEID)Marseille, France. 23-25 May 2012
The current antiretroviral therapy HAART is effectiveand life-prolonging but does not eradicate HIV-1 frominfected patients. A reduction of HIV-1 RNA levels inthe plasma in HAART-treated individuals to less than 50copies/ml is frequently achieved but residual viremia per-sists as detected by ultrasensitive assays. The sources ofthis persistent viremia are still not fully understood butcould arise from ongoing cycles of residual viral replica-tion and/or from the reactivation of viral expression fromlatently-infected cells. These latently-infected cells con-tain stably-integrated, transcriptionally-silent but replica-tion-competent proviruses, thereby representing latentreservoirs of HIV-1. They are a permanent source forvirus reactivation and could be responsible for therebound of plasma viral load observed after HAARTinterruption.HIV-1 transcriptional repression is crucial to the estab-
lishment and maintenance of postintegration latency.Several elements contribute to HIV-1 transcriptionalrepression including: 1) the site of integration andmechanisms of transcriptional interference, 2) the absenceof crucial inducible host transcription factors, 3) the pre-sence of transcriptional repressors, 4) the nucleosomalorganization of the HIV-1 promoter, 5) the epigeneticcontrol of the HIV-1 promoter (histone posttranslationalmodifications, such as acetylation and methylation, andDNA methylation), 6) the sequestration in an inactiveform of the cellular positive transcription elongation factorb (P-TEFb), composed of cyclin-dependent kinase 9(CDK9) and human cyclin T1, 7) the absence of the viraltransactivator Tat, which promotes transcription viarecruitment to the HIV-1 promoter of P-TEFb, histone-modifying enzymes and ATP-dependent chromatin-remo-deling complexes required for nucleosomal disruption andtranscriptional processivity. The involvement of these
elements in postintegration latency depends on the statusof activation and differentiation of the heterogeneousCD4+ T cell populations hosting the HIV-1 reservoirs.Further understanding of the epigenetic and non-
epigenetic mechanisms regulating HIV-1 latency andreactivation from latency should help devise novel stra-tegies to eliminate latent HIV-1 infection or to restrictthe latent pool to a size bearable by the host immunesystem.
Published: 25 May 2012
doi:10.1186/1742-4690-9-S1-I10Cite this article as: Van Lint: Molecular control of HIV - 1postintegration latency: implications for therapeutic strategies.Retrovirology 2012 9(Suppl 1):I10.
Submit your next manuscript to BioMed Centraland take full advantage of:
• Convenient online submission
• Thorough peer review
• No space constraints or color figure charges
• Immediate publication on acceptance
• Inclusion in PubMed, CAS, Scopus and Google Scholar
• Research which is freely available for redistribution
Submit your manuscript at www.biomedcentral.com/submit
Gosselies Campus, Charleroi, Belgium
Van Lint Retrovirology 2012, 9(Suppl 1):I10http://www.retrovirology.com/content/9/S1/I10
© 2012 Van Lint; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative CommonsAttribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction inany medium, provided the original work is properly cited.
