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  • Review Article
  • Published:

Understanding HIV-1 latency provides clues for the eradication of long-term reservoirs

Nature Reviews Microbiology volume 7, pages 798–812 (2009)Cite this article

Key Points

  • Latent HIV-1 reservoirs are established early during primary infection in CD4+ T cells and constitute a major barrier to HIV-1 eradication, even in the presence of highly active antiretroviral therapy.

  • Resting CD4+ T cells represent an extremely restrictive environment for HIV-1 replication. By contrast, immune activation in CD4+ T cells provides an optimal environment for robust HIV-1 replication.

  • Most factors involved in the maintenance of HIV-1 latency operate at the transcriptional level; examples include the chromosome environment at the site of integration and the availability of viral and host transcription factors.

  • HIV-1 integration and expression can be restrained or enhanced by different host cell factors, such as inhibitor of nuclear factor-κB α-subunit (IκBα), COMMD1 (copper metabolism (Murr1) domain-containing protein 1), APOBEC3G (apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like 3G), lens epithelium-derived growth factor (LEDGF) and emerin.

  • Both cellular and viral microRNAs could be involved in maintaining HIV-1 latency or in controlling low ongoing viral replication. HIV-1 modifies the miRNA expression profile of the host cell and, in addition, has developed strategies to overcome the cellular miRNA restriction machinery.

  • The existence of cellular elements that restrict retroviral replication and actively inhibit the viral transcriptional machinery provides a new paradigm for HIV-1 latency. As a result, latency should not be considered a merely passive process but rather an active process that is tightly regulated by cellular and viral factors.

  • New insights into the molecular mechanisms of HIV-1 latency have led to the characterization of targets that are useful for designing new drugs. In particular, attractive possibilities for specific drug development include the modification of chromatin conformation through histone deacetylase inhibitors and the activation of kinase pathways that lead to the activation of transcription factors.

Abstract

HIV-1 can infect both activated and resting, non-dividing cells, following which the viral genome can be permanently integrated into a host cell chromosome. Latent HIV-1 reservoirs are established early during primary infection and constitute a major barrier to eradication, even in the presence of highly active antiretroviral therapy. This Review analyses the molecular mechanisms that are necessary for the establishment of HIV-1 latency and their relationships with different cellular and anatomical reservoirs, and discusses the current treatment strategies for targeting viral persistence in reservoirs, their main limitations and future perspectives.

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Figure 1: HIV-1 life cycle and viral latency.
Figure 2: HIV-1 replication in different cellular environments.
Figure 3: Influence of provirus integration site and orientation into the host cell genome on HIV-1 replication efficiency.
Figure 4: Epigenetic modifications that regulate chromatin accessibility and influence HIV-1 latency.
Figure 5: The microRNA pathway can modulate both cellular and viral gene expression.
Figure 6: Sources of viral replication in patients infected with HIV-1 and strategies to control residual viraemia.

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Acknowledgements

We thank P. Perez-Romero, M. J. McConnell, S. Moreno and A. Alcamí for helpful suggestions. The research of our laboratory is supported by grants from the European Union (EUROPRISE), the Instituto de Salud Carlos III (RETIC RD06/0006 and the Intrasalud programme), the Comunidad de Madrid (VIRHOST Network) and FIPSE (Fundación para la investigación y prevención del SIDA en España).

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  1. AIDS Immunopathology Unit, National Centre of Microbiology, Instituto de Salud Carlos III, Majadahonda, 28220, Madrid, Spain

    Mayte Coiras, María Rosa López-Huertas, Mayte Pérez-Olmeda & José Alcamí

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Glossary

Highly active antiretroviral therapy

A combination of three or more potent anti-HIV-1 drugs that reduces viral load below detection limits by standard techniques.

Reservoir

A cell type or anatomical site in which a replication-competent virus persists for much longer than it does in the main pool of productive infected cells, thereby sustaining the infection. Integrated proviral genomes and cells that persistently replicate HIV-1 in the presence of highly active antiretroviral therapy can be considered viral reservoirs.

Provirus

Viral genomic double-stranded cDNA that has permanently integrated into the host cell genome and that acts as a template for the synthesis of viral RNAs.

Direct repeats

Two or more identical or nearly identical repeats of specific nucleotide sequences that are in the same direction in the DNA molecule.

Blunt end

The end of a double-stranded DNA molecule that terminates in paired bases, rather than with uneven ends, such that one strand overhangs.

Enhancer element

A DNA consensus site, usually located 5′ from the basal gene promoter, that is bound to by specific transcription factors to increase the rate of transcription of the gene that it controls. An enhancer element may be placed thousands of bases upstream or downstream of the transcription initiation site of this gene.

Tat

A regulatory HIV-1 protein that is essential for viral transcript elongation through its interaction with the Tat response element and several host factors, such as the positive transcription elongation factor b.

Rev

A regulatory HIV-1 protein that controls the nuclear export of viral mRNA species through its interaction with the Rev response element that is found in unspliced or incompletly spliced HIV-1 RNAs.

Naive T cell

A mature T cell from the acquired immune system that has not yet made contact with its cognate antigen and that therefore lacks both activation and memory markers on the cell surface.

Memory T cell

A T cell that persists for a long time after its exposure to a specific foreign antigen and that can be promptly expanded to effector T cells after contact with the same antigen to initiate a faster and stronger immune response.

Retroviral restriction factor

A component of the innate immune system that aids the survival of a host cell after retroviral infection by interfering with viral replication at different steps of the viral life cycle.

Elite controller

A patient infected with HIV whose immune system can limit viral RNA to below 50 copies per ml for at least 12 months in the absence of highly active antiretroviral therapy.

Gut-associated lymphoid tissue

The intestinal mucosa-associated lymphoid tissue that constitutes 70% of the whole immune system and may be the main site of HIV-1 activity, despite the use of highly active antiretrovial therapy.

Transcriptional interference

Interruption of RNA transcription that is caused by adjacent active promoters owing to the competition for transcription factors or the collision of RNA polymerase II elongation complexes.

Basal transcription machinery

The complex that regulates the initiation and elongation of transcription by binding to a core promoter that is located ∼50 bp upstream of the transcription initiation site and contains the highly conserved TATA box. The complex consists of RNA polymerase II and several transcription factors and co-activators.

Predominant plasma clone

The main plasma clone of infected cells that is responsible for most of the residual viraemia in patients on highly active antiretroviral therapy. This clone is replication competent and shows a specific sequence for each patient that cannot be easily found in the patient's activated or resting CD4+ T cells.

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Coiras, M., López-Huertas, M., Pérez-Olmeda, M. et al. Understanding HIV-1 latency provides clues for the eradication of long-term reservoirs. Nat Rev Microbiol 7, 798–812 (2009). https://doi.org/10.1038/nrmicro2223

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