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Generation of HIV latency during thymopoiesis

Nature Medicine volume 7, pages 459–464 (2001)Cite this article

Abstract

The use of combination antiretroviral therapy results in a substantial reduction in viremia, a rebound of CD4+ T cells and increased survival for HIV-infected individuals. However, this treatment does not result in the total eradication of HIV. Rather, the virus is thought to remain latent in a subset of cells, where it avoids elimination by the immune system. In this state the virus is capable of reactivation of productive infection following cessation of therapy. These latently infected cells are very few in number and it has thus been difficult to determine their origin and to study the molecular nature of the latent viral genome. HIV replication is linked to cellular gene transcription and requires target cell activation. Therefore, should an activated, infected cell become transcriptionally inactive prior to cytopathic effects, the viral genome might be maintained in a latent state. We used the SCID-hu (Thy/Liv) mouse model to establish that activation-inducible HIV can be generated at high frequency during thymopoiesis, a process where previously activated cells mature towards quiescence. Moreover, we showed that these cells can be exported into the periphery where the virus remains latent until T-cell receptor stimulation, indicating that the thymus might be a source of latent HIV in humans.

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Figure 1: Activation status of thymocyte subsets.
Figure 2: Latent HIV in mature thymocytes from SCID-hu mice.
Figure 3: Molecular analysis of latent HIV in SCID-hu thymocytes and the effect of cytokines on reactivation.
Figure 4: HIV latency in the periphery.

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Acknowledgements

We thank I.S.Y. Chen and T.M. Folks for critical reviews of this manuscript and G. Bristol, R. Cortado and A. Kacena for technical assistance. This work was supported by NIH grants #AI 36554 and AI 36059, and the UCLA CFAR. J.A.Z. is an Elizabeth Glaser scientist supported by the Pediatric AIDS Foundation. S.G.K. is a recipient of the UCLA Center for Clinical AIDS Research and Education HIV Pathogenesis Institutional Training Grant.

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Authors and Affiliations

  1. Department of Microbiology and Molecular Genetics, University of California at Los Angeles, Los Angeles, California, USA

    David G. Brooks, Deirdre D. Scripture-Adams & Jerome A. Zack

  2. Department of Medicine and AIDS Institute, School of Medicine, University of California at Los Angeles, Los Angeles, California, USA

    Scott G. Kitchen & Jerome A. Zack

  3. Department of Biostatistics, School of Public Health, University of California at Los Angeles, Los Angeles, California, USA

    Christina M. R. Kitchen

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  1. David G. Brooks
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Correspondence to Jerome A. Zack.

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Brooks, D., Kitchen, S., Kitchen, C. et al. Generation of HIV latency during thymopoiesis. Nat Med 7, 459–464 (2001). https://doi.org/10.1038/86531

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