Rapid Evolution of HIV-1 to Functional CD8+ T Cell Responses in Humanized BLT Mice

Sci Transl Med 18 July 2012:
Vol. 4, Issue 143, p. 143ra98
Sci. Transl. Med. DOI: 10.1126/scitranslmed.3003984

• Research Article

HIV

Rapid Evolution of HIV-1 to Functional CD8⁺ T Cell Responses in Humanized BLT Mice

1. Timothy E. Dudek¹,
2. Daniel C. No¹,
3. Edward Seung²,
4. Vladimir D. Vrbanac²,
5. Lena Fadda¹,
6. Priyasma Bhoumik¹,
7. Christian L. Boutwell¹,
8. Karen A. Power¹,
9. Adrianne D. Gladden¹,
10. Laura Battis¹,
11. Elizabeth F. Mellors¹,
12. Trevor R. Tivey²,
13. Xiaojiang Gao³,
14. Marcus Altfeld¹,
15. Andrew D. Luster²,
16. Andrew M. Tager² and
17. Todd M. Allen¹,*

+ Author Affiliations

1. ¹Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard, Charlestown, MA 02129, USA.
2. ²Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA.
3. ³Cancer and Immunology Program, Laboratory of Experimental Immunology, Science Applications International Corporation-Frederick, National Cancer Institute-Frederick, Frederick, MD 20882, USA.

1. ↵*To whom correspondence should be addressed. E-mail: tallen2@partners.org

Abstract

The development of mouse/human chimeras through the engraftment of human immune cells and tissues into immunodeficient mice, including the recently described humanized BLT (bone marrow, liver, thymus) mouse model, holds great promise to facilitate the in vivo study of human immune responses. However, little data exist regarding the extent to which cellular immune responses in humanized mice accurately reflect those seen in humans. We infected humanized BLT mice with HIV-1 as a model pathogen and characterized HIV-1–specific immune responses and viral evolution during the acute phase of infection. HIV-1–specific CD8⁺ T cell responses in these mice were found to closely resemble those in humans in terms of their specificity, kinetics, and immunodominance. Viral sequence evolution also revealed rapid and highly reproducible escape from these responses, mirroring the adaptations to host immune pressures observed during natural HIV-1 infection. Moreover, mice expressing the protective HLA-B*57 allele exhibited enhanced control of viral replication and restricted the same CD8⁺ T cell responses to conserved regions of HIV-1 Gag that are critical to its control of HIV-1 in humans. These data reveal that the humanized BLT mouse model appears to accurately recapitulate human pathogen–specific cellular immunity and the fundamental immunological mechanisms required to control a model human pathogen, aspects critical to the use of a small-animal model for human pathogens.

• Copyright © 2012, American Association for the Advancement of Science

Citation: T. E. Dudek, D. C. No, E. Seung, V. D. Vrbanac, L. Fadda, P. Bhoumik, C. L. Boutwell, K. A. Power, A. D. Gladden, L. Battis, E. F. Mellors, T. R. Tivey, X. Gao, M. Altfeld, A. D. Luster, A. M. Tager, T. M. Allen, Rapid Evolution of HIV-1 to Functional CD8⁺ T Cell Responses in Humanized BLT Mice. Sci. Transl. Med. 4, 143ra98 (2012).

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