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HIV-1 and interferons: who's interfering with whom?

Nature Reviews Microbiology volume 13, pages 403–413 (2015)Cite this article

Subjects

Key Points

  • Interferon-α (IFNα) treatment of cultured primary CD4+ T cells and macrophages potently inhibits HIV-1 replication.

  • IFNα treatment upregulates the expression of the currently identified HIV-1 and SIV restriction factors — APOBEC3G (apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-like 3G), TRIM5α (tripartite motif-containing protein 5α), tetherin and SAMHD1 (SAM and HD domain-containing protein 1) — and of the known HIV-1 resistance factors myxovirus resistance 2 (MX2), schlafen 11 (SLFN11) and IFN-induced transmembrane (IFITM) proteins.

  • An intact type I IFN system seems to be crucial for the control of acute lentiviral infection, and IFN treatment suppresses initial SIV infection of macaques.

  • IFNα treatment of patients infected with HIV-1 decreases viral load.

  • In pathogenic, but not in non-pathogenic, non-human primate lentiviral models, there is evidence of persistent IFN signalling.

  • CD4+ T cells of patients chronically infected with HIV-1 show evidence of persistent upregulation of IFN-stimulated genes.

  • Understanding the relationship between HIV-1 infection and the IFN system will yield valuable insights into HIV-1 pathogenesis and will aid the future development of therapeutics.

Abstract

The ability of interferons (IFNs) to inhibit HIV-1 replication in cell culture models has long been recognized, and the therapeutic administration of IFNα to HIV-1-infected patients who are not receiving antiretroviral therapy produces a clear but transient decrease in plasma viral load. Conversely, studies of chronic HIV-1 infection in humans and SIV-infected animal models of AIDS show positive correlations between elevated plasma levels of IFNs, increased expression of IFN-stimulated genes (ISGs), biomarkers of inflammation and disease progression. In this Review, we discuss the evidence that IFNs can control HIV-1 replication in vivo and debate the controversial role of IFNs in promoting the pathological sequelae of chronic HIV-1 infection.

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Figure 1: Induction of ISG expression.
Figure 2: Intracellular sensing of HIV-1 infection.
Figure 3: HIV-1 restriction and resistance factors.
Figure 4: The effect of IFNα treatment on plasma HIV-1 viral load.

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Acknowledgements

The authors are funded by grants and fellowships from the UK Medical Research Council, the European Commission, the Wellcome Trust, the US National Institutes of Health, and the Department of Health via a UK National Institute for Health Research comprehensive Biomedical Research Centre award to Guy's and St. Thomas' National Health Service (NHS) Foundation Trust in partnership with King's College London and King's College Hospital NHS Foundation Trust.

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  1. Department of Infectious Diseases, King's College London, 2nd Floor, Borough Wing, Guy's Hospital, London Bridge, London, SE1 9RT, UK

    Tomas Doyle, Caroline Goujon & Michael H. Malim

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  1. Tomas Doyle
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  2. Caroline Goujon
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Correspondence to Michael H. Malim.

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FURTHER INFORMATION

Interferome v2.01

PowerPoint slides

Glossary

Retrovirus

A positive-sense single-stranded RNA virus of the family Retroviridae. These viruses replicate via a DNA intermediate that is synthesized by the reverse transcriptase enzyme. Retroviruses integrate their DNA into the host cell chromosome.

Lentivirus

A particular genus of retroviruses that are primarily characterized by infections with long clinical incubation periods, often years to decades. Lentiviruses infect primate and non-primate hosts.

Set-point plasma viral load

The semi-stable plasma level of HIV-1 RNA that is reached after the period of acute HIV-1 infection in most patients, in the absence of antiretroviral therapy.

Pattern recognition receptors

(PRRs). Germ line-encoded receptors that recognize the pathogen-associated molecular patterns which characterize pathogenic microorganisms.

Pathogen-associated molecular patterns

(PAMPs). Biomolecules of diverse nature (ranging from lipopolysaccharides to forms of nucleic acids) that are characteristic of pathogenic microorganisms.

Apoptosis

A mode of programmed cell death that leads to the elimination of the cell without the release of inflammatory mediators.

Plasmacytoid dendritic cells

(pDCs). DCs that are specialized in the detection of microbial pathogens and the production of interferon-α (IFNα). pDCs are thought to be particularly important for HIV-1 sensing.

Monocyte-derived dendritic cells

(MDDCs). DCs that have been derived by inducing their differentiation from primary monocytes in vitro.

Monocyte-derived macrophages

(MDMs). Macrophages that have been derived by inducing their differentiation from primary monocytes in vitro.

Reverse-transcription complexes

(RTCs). Complexes of viral nucleic acid, viral proteins (for example, reverse transcriptase) and cellular proteins that mediate viral DNA synthesis. RTCs are derived from viral capsids following virus entry into the cytoplasm during infection.

Pyroptosis

A mode of programmed cell death that leads to the release of mediators of inflammation and that is often triggered by recognition of pathogenic microorganisms.

Lymphoid aggregate cultures

Cultures composed of small blocks of lymphoid tissue usually derived from the tonsils or the spleen. This experimental system is used in an attempt to replicate the spatial organization and cytokine milieu of in vivo lymphoid tissue.

Humanized mice

Mice that congenitally lack T cells, B cells and natural killer cells, and that are transplanted with human haematopoietic stem cells, leading to the reconstitution of a human-derived immune system.

Nuclear pore complexes

Large protein complexes that form the channels in the nuclear envelope which allow the transport of molecules between the nucleus and the cytoplasm.

Pegylated

Covalently conjugated to polyethylene glycol (PEG). This alters the pharmacokinetic behaviour of a drug, allowing the dosing frequency to be reduced in the case of interferon-α (IFNα).

Transmitted/founder viruses

(T/F viruses). Viruses that are responsible for the establishment of initial HIV-1 infection and from which the viral population seen in later infection is thought to be derived.

Highly active antiretroviral therapy

(HAART). A combination of antiretroviral drugs used to suppress HIV replication.

Kaposi sarcoma

A common tumour associated with advanced HIV-1 infection. The tumour is caused by human herpesvirus 8 (HHV8) and presents as a purplish-brown vascular lesion either on the skin or in internal organs.

HIV-1 eradication

Clearance of replication-competent HIV-1 from the body of an infected person. Achieving this goal is generally thought to require the inhibition of any ongoing HIV-1 replication during conventional antiretroviral therapy and the elimination of infected cells harbouring latent (or transcriptionally inactive) but replication-competent HIV-1. The term reservoir is generally used to denote the pool of latently infected cells.

Microbial translocation

The emergence of microorganisms and microbial products into the portal and systemic circulation from the gut, owing to compromise of the host gastrointestinal immune system.

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Doyle, T., Goujon, C. & Malim, M. HIV-1 and interferons: who's interfering with whom?. Nat Rev Microbiol 13, 403–413 (2015). https://doi.org/10.1038/nrmicro3449

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