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Animal models for HIV/AIDS research

Nature Reviews Microbiology volume 10, pages 852–867 (2012)Cite this article

Subjects

Key Points

  • Animal models are essential for testing antiretroviral drugs to treat HIV infection of humans and for acquiring the basic scientific knowledge that will ultimately be needed to develop a safe and effective vaccine against HIV-1.

  • Owing to the narrow host range of HIV, HIV-1 infection of mice that have been reconstituted with a human immune system (humanized mice) and simian immunodeficiency virus (SIV) infection of macaques are used as surrogate models for studying HIV-1 infection of humans.

  • There is no single animal model for AIDS, but rather a collection of host species and viruses that can be used depending on the question to be addressed.

  • A number of humanized mouse models have been developed using different genetic backgrounds and engraftment with various human tissues. Whereas humanized mice make it possible to model HIV-1 infection of human cells in vivo and to design studies using genetically identical animals, these models are limited in their ability to replicate the effects of HIV-1 on non-haematopoietic tissues and to recreate basic features of HIV-1 disease in humans.

  • Infection of Asian macaques with certain SIV or simian–human immunodeficiency virus (SHIV) recombinants results in gradual CD4+ T cell depletion and progression to AIDS, similar to HIV infection of humans. Thus, SIV and SHIV infection of macaques are currently the best, most widely accepted models for AIDS research.

  • Genetic differences between macaque species, and in some cases between geographically distinct populations of the same species, can dramatically affect the outcome of SIV and SHIV infections and are important considerations in the use of these models.

  • There is now considerable interest in engineering HIV-1 to overcome the barriers to HIV-1 replication in macaques. These barriers are imposed by the apolipoprotein B-editing catalytic subunit-like 3 (APOBEC3) proteins, by tripartite-motif-containing protein 5 (TRIM5) variants and by tetherin, all of which are HIV restriction factors. The development of minimally modified simian-tropic strains of HIV-1 that can reproducibly cause disease in macaques might eventually allow direct efficacy testing of antiretroviral drugs and vaccines in non-human primates.

Abstract

The AIDS pandemic continues to present us with unique scientific and public health challenges. Although the development of effective antiretroviral therapy has been a major triumph, the emergence of drug resistance requires active management of treatment regimens and the continued development of new antiretroviral drugs. Moreover, despite nearly 30 years of intensive investigation, we still lack the basic scientific knowledge necessary to produce a safe and effective vaccine against HIV-1. Animal models offer obvious advantages in the study of HIV/AIDS, allowing for a more invasive investigation of the disease and for preclinical testing of drugs and vaccines. Advances in humanized mouse models, non-human primate immunogenetics and recombinant challenge viruses have greatly increased the number and sophistication of available mouse and simian models. Understanding the advantages and limitations of each of these models is essential for the design of animal studies to guide the development of vaccines and antiretroviral therapies for the prevention and treatment of HIV-1 infection.

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Figure 1: 'Humanized' mouse models used in HIV-1 research.
Figure 2: Macaque species commonly used in AIDS research, and their geographical ranges.
Figure 3: Restriction factor polymorphism and the effects on viral replication in macaques.
Figure 4: Derivation of common simian immunodeficiency virus and simian–human immunodeficiency virus strains.

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Acknowledgements

The authors are grateful to P. Bieniasz and R. Desrosiers for critically reviewing this manuscript. The authors also thank P. Marx for sharing the data included in table 1, and A. Halper-Stromberg and R. Liberatore for help with figure 1 and lessons in mouse anatomy. The authors acknowledge and regret that a number of important studies are not cited owing to space constraints. T.H. is supported by US Department of Health and Human Services Public Health Service (PHS) grants AI078788 and AI093255. D.T.E. is supported by PHS grants AI087498, AI095098, AI098485 and RR000168/OD011103, and is an Elizabeth Glaser Scientist of the Elizabeth Glaser Pediatric AIDS Foundation.

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Authors and Affiliations

  1. Aaron Diamond AIDS Research Center, The Rockefeller University, 455 First Avenue, New York, 10016, New York, USA

    Theodora Hatziioannou

  2. Department of Microbiology and Immunobiology, Harvard Medical School, New England Primate Research Center, 1 Pine Hill Drive, Southborough, 01772, Massachusetts, USA

    David T. Evans

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  1. Theodora Hatziioannou
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  2. David T. Evans
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Glossary

ESCRT

(Endosomal sorting complex required for transport). A conserved cellular machinery for the sorting of ubiquitylated cargo proteins into vesicles and the subsequent scission of the membrane neck. The recruitment of ESCRT proteins through retroviral late domains is essential for viral budding.

Proviruses

The DNA forms of retroviral genomes that are integrated into host chromosomal DNA.

Haematopoietic (CD34+) progenitor stem cells

A population of multipotent cells that can differentiate into any type of blood cell, including the major cell lineages of the immune system. These cells are typically defined by the cell surface marker CD34.

Natural killer cells

Cytotoxic lymphocytes that do not express the B cell or T cell receptor and are capable of responding to virus-infected cells or tumour cells without prior antigenic stimulation.

Passive immunization

The transfer of immunoglobulins.

Complement

A system of >25 serum proteins that is activated by a number of triggers responding to foreign antigen on the surface of a cell; complement activation results in a proteolytic cascade leading to cell lysis or enhanced phagocytosis.

Gut-associated lymphoid tissue

(GALT). Secondary lymphoid tissue associated with the digestive tract, including the Peyer's patches, mesenteric lymph nodes and the appendix. For the purpose of this Review, the GALT also refers to effector sites of the lamina propria and intestinal epithelium that are rich in memory lymphocytes which support HIV and simian immunodeficiency virus (SIV) replication.

Central memory CD4+ T cells

Antigen-experienced resting T cells that express cell surface receptors which are required for homing to secondary lymphoid organs. These cells are generally long-lived and can serve as the precursors for effector T cells during recall responses.

Effector memory CD4+ T cells

Terminally differentiated T cells that lack lymph node-homing receptors but express receptors that enable the cells to home to inflamed tissues. Effector memory T cells can exert immediate effector functions without the need for further differentiation.

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Hatziioannou, T., Evans, D. Animal models for HIV/AIDS research. Nat Rev Microbiol 10, 852–867 (2012). https://doi.org/10.1038/nrmicro2911

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