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  • Review Article
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Nuclear landscape of HIV-1 infection and integration

Nature Reviews Microbiology volume 15, pages 69–82 (2017)Cite this article

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A Corrigendum to this article was published on 01 April 2017

This article has been updated

Key Points

  • The Import of viral DNA into the cell nucleus is the first step in the nuclear portion of the viral life cycle. The process is determined by the activity of different proteins, among which viral capsid protein and its cellular partners RANBP2, transportin 3 (TNPO3) and especially cleavage and polyadenylation specificity factor 6 (CPSF6) have important roles. This step precedes viral integration and affects the selection of the integration site.

  • HIV-1 integrase has a pivotal role in the integration of viral DNA into the cellular genome. It carries out two enzymatic reactions: 3′-end processing of the viral DNA and the strand transfer reaction to stably insert the viral genome into cellular chromatin.

  • Integrase tetramers associate with nascent viral DNA to form the functional integrase–viral DNA complex (or intasome). The intasome associates with different cellular factors, which enable the correct positioning of the pre-integration complex in the nuclear space and in relation to cellular chromatin.

  • The structure of chromatin, its underlying DNA sequence and cellular factors, especially lens-epithelium-derived growth factor (LEDGF) and CPSF6, have important roles in facilitating the integration of viral DNA into the cellular genome. In the 3D nuclear space, the viral genome is preferentially positioned in the outer shell of the nucleus in close proximity to the nuclear pore.

  • The functional importance of integration into the correct place in the cellular genome is reflected by the fact that the transcriptional fate of the provirus largely depends on the chromatin setting and on the surrounding nuclear environment. If integrated into permissive regions of chromatin, the viral genome proceeds immediately to transcription, whereas if integration occurs in less-accessible regions, viral transcription becomes silenced, which probably contributes to the formation of latent viral reservoirs.

  • Targeting HIV-1 integration is one of the most compelling therapeutic tasks: drugs that target the integrase of HIV-1, such as raltegravir or its variants, or those that interfere with the integrase–LEDGF interaction are already in clinical use or are being extensively tested. Gene-editing approaches aim to excise the viral genome, which can be achieved either by endonuclease activity or through the use of CRISPR–Cas technology.

Abstract

To complete its life cycle, HIV-1 enters the nucleus of the host cell as reverse-transcribed viral DNA. The nucleus is a complex environment, in which chromatin is organized to support different structural and functional aspects of cell physiology. As such, it represents a challenge for an incoming viral genome, which needs to be integrated into cellular DNA to ensure productive infection. Integration of the viral genome into host DNA depends on the enzymatic activity of HIV-1 integrase and involves different cellular factors that influence the selection of integration sites. The selection of integration site has functional consequences for viral transcription, which usually follows the integration event. However, in resting CD4+ T cells, the viral genome can be silenced for long periods of time, which leads to the generation of a latent reservoir of quiescent integrated HIV-1 DNA. Integration represents the only nuclear event in the viral life cycle that can be pharmacologically targeted with current therapies, and the aspects that connect HIV-1 nuclear entry to HIV-1 integration and viral transcription are only beginning to be elucidated.

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Figure 1: An overview of the life cycle of HIV-1.
Figure 2: Nuclear entry and the selection of integration site.
Figure 3: Integrase and the integration mechanism.
Figure 4: HIV-1 integration at the nuclear periphery.
Figure 5: Connecting integration and transcription.

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Change history

  • 27 February 2017

    In the first paragraph of the section 'Sequence specificity and chromatin determinants', at the end of the sixth sentence an incorrect reference is cited. In the following sentence accurate information is now provided in regard to what was done in the original study. These sentences should read as follows: “A recent study of approximately 1 million integration sites in infected HEK293 cells showed that 75% of integrations occurred in active, RNA pol II-dependent transcriptional units that had numerous introns; when corrected for their relative length, no selection of intronic over exonic sequences was observed79. Analysis of transcriptional units that were grouped based on their number of introns revealed that integration density correlates strongly with the levels of splicing, and that the cellular protein LEDGF is required for targeting highly spliced transcriptional units, through its direct interaction with numerous splicing factors79.” The authors apologize to the readers for any misunderstanding caused.

  • 01 April 2017

    Nature Reviews Microbiology 15, 69–82 (2017) In the first paragraph of the section 'Sequence specificity and chromatin determinants', at the end of the sixth sentence an incorrect reference is cited. In the following sentence accurate information is now provided in regard to what was done in the original study.

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Acknowledgements

M.L. is funded by grants from the German Centre for Infectious Research (Deutsche Zentrum fur Infektion Forschung, DZIF) and by the Hector Foundation for AIDS and Cancer Research.

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Authors and Affiliations

  1. Department of Infectious Diseases, Integrative Virology, University Hospital Heidelberg and German Center for Infection Research (DZIF), Im Neuenheimer Feld 324, 69120, Heidelberg, Germany

    Marina Lusic

  2. Howard Hughes Medical Institute; Department of Medicine, Johns Hopkins University School of Medicine,

    Robert F. Siliciano

  3. Department of Medicine, Johns Hopkins University School of Medicine, Room 879, Edward D. Miller Research Building, 733 North Broadway, Baltimore, 21205, Maryland, USA

    Robert F. Siliciano

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  1. Marina Lusic
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Correspondence to Marina Lusic.

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PowerPoint slides

Glossary

Viral envelope glycoproteins

Surface proteoglycan proteins that are products of the env gene. The env gene encodes glycoprotein 160 (gp160), which forms a homotrimer and is cleaved into gp120 and gp41 by host cell proteases. The outer glycoprotein gp120 and the transmembrane protein gp41 are embedded in the viral envelope, which forms the outermost layer of the virion.

Viral core

A viral component that contains the viral capsule protein p24, which surrounds two single strands of HIV-1 RNA, bound to the nucleocapsid protein p7 and late assembly protein p6. It also contains enzymes that are needed for the replication of HIV-1, such as reverse transcriptase, protease, ribonuclease and integrase, and numerous cellular proteins.

Central polypurine tract

A specific structural element that is involved in viral DNA structure and nuclear entry. It is formed during the second-strand DNA synthesis of reverse transcription as a central 99-nucleotide-long plus-strand overlap in the linear DNA molecule; it is located centrally in the genome, in the integrase open reading frame, and acts as a cis determinant of lentiviral DNA nuclear import.

Two-long terminal repeat circles

(2-LTR circles). Unintegrated, circular molecules of viral DNA that contain two adjacent LTR promoter regions. They are considered byproducts of integration, and their quantification by PCR-based methods is used as an indicator of the efficiency of nuclear import.

Nuclear-localization signal

(NLS). A motif that is present in proteins that are imported into the nucleus by importins and adaptor proteins, which interact with the nuclear pore complex.

Phe-Gly repeats

(FG repeats). Phenylalanine-rich and glycine-rich domains found in nucleoporins that facilitate the transport of cargo through the channel of the nuclear pore complex (NPC).

Zinc-finger domains

Protein structural domains that can coordinate one or more zinc atoms to act as binding partners for a wide variety of substrates, including DNA.

Nucleosomes

The building blocks of chromatin, which are composed of an octameric histone core around which 147 bp of DNA are wrapped (in 1.65 turns of a left-handed superhelix).

Euchromatin

A loosely packed form of chromatin (DNA, RNA and histones) that is usually enriched in genes that are often being actively transcribed. Most of the genome is euchromatic (predicted at approximately 90%), whereas the rest is heterochromatic, that is, tightly packed and not actively transcribing. Euchromatin is often referred to as open chromatin.

SWI/SNF chromatin remodelling complex

A complex that remodels nucleosomes using the hydrolysis of ATP to regulate the accessibility of DNA to the transcription machinery.

Promyelocytic leukaemia bodies

(PML bodies). Nuclear structures the main component of which is the promyelocytic leukaemia protein (or TRIM19). Several different protein components as well as various functions, such as transcription, apoptosis, senescence DNA damage response and antiviral defence, are associated with these bodies.

CpG islands

Regions that have a high frequency of CpG sites, usually connected with the promoter regions of genes.

Cre recombinase

A tyrosine recombinase enzyme that catalyses a site-specific recombination event between two DNA recognition sites; these sites consist of 13 bp palindromic sequences that flank an 8 bp spacer region. The unique and specific recombination system of the enzyme is used to manipulate genes and chromosomes in several applications.

Zinc-finger nucleases

(ZFNs). Artificial restriction enzymes that are created through the fusion of a zinc-finger DNA-binding domain and a DNA-cleavage domain. These enzymes facilitate targeted editing of the genome by creating double-strand breaks in the DNA at a specific (desired) location.

Transcription activator-like effector nucleases

(TALENs). Restriction nucleases that are engineered to cut specific DNA sequences.

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Lusic, M., Siliciano, R. Nuclear landscape of HIV-1 infection and integration. Nat Rev Microbiol 15, 69–82 (2017). https://doi.org/10.1038/nrmicro.2016.162

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