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  • Review Article
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The structural biology of HIV-1: mechanistic and therapeutic insights

Nature Reviews Microbiology volume 10, pages 279–290 (2012)Cite this article

Subjects

Key Points

  • HIV-1 replication relies on the proper functioning of specific viral proteins, three of which — protease, integrase, and reverse transcriptase with associated RNase H activity — are enzymes. Antiviral drugs that inhibit protease, integrase and reverse transcriptase (specifically, DNA polymerase) activities are approved for treating patients with AIDS. The highly active antiretroviral therapy (HAART) regimens use cocktails of three inhibitors to suppress HIV-1 replication and the outgrowth of drug-resistant virus strains.

  • Replication of HIV-1 depends on a plethora of functional interactions between its proteins and those of the host. Certain other cellular proteins, referred to as restriction factors, counteract viral growth. TRIM5α, APOBEC3G, tetherin and SAMHD1 are examples of such restriction factors.

  • In addition to enzyme active sites, critical viral protein–host protein interactions define targets for therapeutic intervention. Drugs can block interactions between the viral and host proteins that are needed for replication, as is the case for the approved entry inhibitor maraviroc, or they can enhance the effects of cellular restriction factors.

  • Neutralization of the viral envelope glycoprotein gp120 by the adaptive immune system underscores the development strategies for AIDS vaccines.

  • Structural biology studies yield three-dimensional glimpses of protein function at near atomic resolution. Such approaches form the cornerstone of modern efforts for the development of antiviral drugs and vaccines.

Abstract

Three-dimensional molecular structures can provide detailed information on biological mechanisms and, for cases in which the molecular function affects human health, can significantly aid in the development of therapeutic interventions. For almost 25 years, key components of the lentivirus HIV-1, including the envelope glycoproteins, the capsid and the replication enzymes reverse transcriptase, integrase and protease, have been scrutinized to near atomic-scale resolution. Moreover, structural analyses of the interactions between viral and host cell components have yielded key insights into the mechanisms of viral entry, chromosomal integration, transcription and egress from cells. Here, we review recent advances in HIV-1 structural biology, focusing on the molecular mechanisms of viral replication and on the development of new therapeutics.

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Figure 1: Schematic overview of the HIV-1 replication cycle.
Figure 2: Binding of CD4 and a CD4-mimicking antibody to the gp120 core.
Figure 3: HIV-1 capsid structures.
Figure 4: Structural analyses of HIV-1 reverse transcriptase function and its inhibition by small molecules.
Figure 5: Retroviral intasome structures and mechanism of integrase catalysis.
Figure 6: Higher-order Tat and Rev structures.
Figure 7: Virus–cell interactions and HIV-1 budding.

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Acknowledgements

The authors thank M. Yeager for sharing coordinates of the HIV-1 capsid model. This work was supported by grants AI070042 from the US National Institutes of Health (A.E.) and G1000917 from the UK Medical Research Council (P.C.). The opinions voiced herein in no way reflect those of these funding agencies. The authors apologize to colleagues whose work could not be cited or discussed owing to space limitations.

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Authors and Affiliations

  1. Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston, 02215, Massachusetts, USA

    Alan Engelman

  2. Cancer Research UK London Research Institute, Clare Hall Laboratories, South Mimms, EN6 3LD, Hertfordshire, UK

    Peter Cherepanov

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DATABASES

Protein Data Bank

1RTD

2XDE

2X7L

2ZD1

3H47

3JWD

3KLE

3LPH

3MIA

3NGB

3OBU

3OS2

3OY9

3P05

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Peter Cherepanov's homepage

Approved HIV drugs

Glossary

Zoonotic

Pertaining to a disease: an infection that can transfer between animals and humans.

CD4+ T cells

A subpopulation of T cells that express the CD4 receptor. These cells aid in immune responses and are therefore also referred to as T helper cells.

Cryo-electron tomography

A technique in which a specimen, embedded in vitreous ice, is imaged from multiple angles using electron microscopy. The resulting images are then combined to reconstruct the three-dimensional structure of the specimen.

Fullerene

A closed-shell molecule consisting of hexagonal and pentameric rings of carbon.

NMR

A spectroscopy technique that takes advantage of magnetic properties of nuclei. Applied to structural biology, NMR affords the determination of macromolecular structures by measuring interproton distances.

Single-particle electron cryo-microscopy

A technique that averages multiple images obtained from transmission electron microscopy of homogeneous particles at cryogenic temperatures.

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Engelman, A., Cherepanov, P. The structural biology of HIV-1: mechanistic and therapeutic insights. Nat Rev Microbiol 10, 279–290 (2012). https://doi.org/10.1038/nrmicro2747

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