Abstract
It has recently been established that both acute human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) infections are accompanied by a dramatic and selective loss of memory CD4+ T cells predominantly from the mucosal surfaces. The mechanism underlying this depletion of memory CD4+ T cells (that is, T-helper cells specific to previously encountered pathogens) has not been defined. Using highly sensitive, quantitative polymerase chain reaction together with precise sorting of different subsets of CD4+ T cells in various tissues, we show that this loss is explained by a massive infection of memory CD4+ T cells by the virus. Specifically, 30–60% of CD4+ memory T cells throughout the body are infected by SIV at the peak of infection, and most of these infected cells disappear within four days. Furthermore, our data demonstrate that the depletion of memory CD4+ T cells occurs to a similar extent in all tissues. As a consequence, over one-half of all memory CD4+ T cells in SIV-infected macaques are destroyed directly by viral infection during the acute phase—an insult that certainly heralds subsequent immunodeficiency. Our findings point to the importance of reducing the cell-associated viral load during acute infection through therapeutic or vaccination strategies.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 51 print issues and online access
$199.00 per year
only $3.90 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Veazey, R. S. et al. Gastrointestinal tract as a major site of CD4+ T cell depletion and viral replication in SIV infection. Science 280, 427–431 (1998)
Mattapallil, J. J., Smit-McBride, Z., McChesney, M. & Dandekar, S. Intestinal intraepithelial lymphocytes are primed for γ-interferon and MIP-1β expression and display antiviral cytotoxic activity despite severe CD4+ T-cell depletion in primary simian immunodeficiency virus infection. J. Virol. 72, 6421–6429 (1998)
Brenchley, J. M. et al. CD4+ T cell depletion during all stages of HIV disease occurs predominantly in the gastrointestinal tract. J. Exp. Med. 200, 749–759 (2004)
Veazey, R. S. et al. Dynamics of CCR5 expression by CD4+ T cells in lymphoid tissues during simian immunodeficiency virus infection. J. Virol. 74, 11001–11007 (2000)
Veazey, R. S. et al. Identifying the target cell in primary simian immunodeficiency virus (SIV) infection: highly activated memory CD4+ T cells are rapidly eliminated in early SIV infection in vivo . J. Virol. 74, 57–64 (2000)
Mattapallil, J. J., Letvin, N. L. & Roederer, M. T-cell dynamics during acute SIV infection. AIDS 18, 13–23 (2004)
Douek, D. C. et al. HIV preferentially infects HIV-specific CD4+ T cells. Nature 417, 95–98 (2002)
Haase, A. T. et al. Quantitative image analysis of HIV-1 infection in lymphoid tissue. Science 274, 985–989 (1996)
Haase, A. T. Population biology of HIV-1 infection: viral and CD4+ T cell demographics and dynamics in lymphatic tissues. Annu. Rev. Immunol. 17, 625–656 (1999)
Lassen, K., Han, Y., Zhou, Y., Siliciano, J. & Siliciano, R. F. The multifactorial nature of HIV-1 latency. Trends Mol. Med. 10, 525–531 (2004)
Chen, Z., Zhou, P., Ho, D. D., Landau, N. R. & Marx, P. A. Genetically divergent strains of simian immunodeficiency virus use CCR5 as a coreceptor for entry. J. Virol. 71, 2705–2714 (1997)
Marcon, L. et al. Utilization of C–C chemokine receptor 5 by the envelope glycoproteins of a pathogenic simian immunodeficiency virus, SIVmac239. J. Virol. 71, 2522–2527 (1997)
Jung, A. et al. Multiply infected spleen cells in HIV patients. Nature 418, 144 (2002)
Gratton, S., Cheynier, R., Dumaurier, M. J., Oksenhendler, E. & Wain-Hobson, S. Highly restricted spread of HIV-1 and multiply infected cells within splenic germinal centers. Proc. Natl Acad. Sci. USA 97, 14566–14571 (2000)
Nishimura, Y. et al. Highly pathogenic SHIVs and SIVs target different CD4+ T cell subsets in rhesus monkeys, explaining their divergent clinical courses. Proc. Natl Acad. Sci. USA 101, 12324–12329 (2004)
Mengozzi, M. et al. Naive CD4 T cells inhibit CD28-costimulated R5-tropic HIV replication in memory CD4 T cells. Proc. Natl Acad. Sci. USA 98, 11644–11649 (2001)
Zhang, Z. et al. Sexual transmission and propagation of SIV and HIV in resting and activated CD4+ T cells. Science 286, 1353–1357 (1999)
Zhang, Z. Q. et al. Roles of substrate availability and infection of resting and activated CD4+ T cells in transmission and acute simian immunodeficiency virus infection. Proc. Natl Acad. Sci. USA 101, 5640–5645 (2004)
Endo, Y. et al. Short- and long-term clinical outcomes in rhesus monkeys inoculated with a highly pathogenic chimeric simian/human immunodeficiency virus. J. Virol. 74, 6935–6945 (2000)
Pitcher, C. J. et al. Development and homeostasis of T cell memory in rhesus macaque. J. Immunol. 168, 29–43 (2002)
Lifson, J. D. et al. Role of CD8+ lymphocytes in control of simian immunodeficiency virus infection and resistance to rechallenge after transient early antiretroviral treatment. J. Virol. 75, 10187–10199 (2001)
Livak, K. J. & Schmittgen, T. D. Analysis of relative gene expression data using real-time quantitative PCR and the ΔΔCT Method. Methods 25, 402–408 (2001)
Mori, K., Ringler, D. J., Kodama, T. & Desrosiers, R. C. Complex determinants of macrophage tropism in env of simian immunodeficiency virus. J. Virol. 66, 2067–2075 (1992)
Folks, T. M. et al. Biological and biochemical characterization of a cloned Leu-3- cell surviving infection with the acquired immune deficiency syndrome retrovirus. J. Exp. Med. 164, 280–290 (1986)
Folks, T. et al. Characterization of a continuous T-cell line susceptible to the cytopathic effects of the acquired immunodeficiency syndrome (AIDS)-associated retrovirus. Proc. Natl Acad. Sci. USA 82, 4539–4543 (1985)
Acknowledgements
We thank R. Koup for critical comments on the manuscript; S. Perfetto, J. Yu, R. Nguyen, D. Ambrozak and other members of the VRC Laboratory of Immunology for advice and technical help; M. St Claire for assistance with the animals; and S. Rao, V. Dang and J.-P. Todd for their assistance during the course of this study.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare that they have no competing financial interests.
Rights and permissions
About this article
Cite this article
Mattapallil, J., Douek, D., Hill, B. et al. Massive infection and loss of memory CD4+ T cells in multiple tissues during acute SIV infection. Nature 434, 1093–1097 (2005). https://doi.org/10.1038/nature03501
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/nature03501
This article is cited by
-
Intestinal endothelial cells increase HIV infection and latency in resting and activated CD4 + T cells, particularly affecting CCR6 + CD4 + T cells
Retrovirology (2023)
-
Direct intranodal tonsil vaccination with modified vaccinia Ankara vaccine protects macaques from highly pathogenic SIVmac251
Nature Communications (2023)
-
Early treatment regimens achieve sustained virologic remission in infant macaques infected with SIV at birth
Nature Communications (2022)
-
Periods of Homelessness Linked to Higher VACS Index Among HIV-Positive People Who Use Drugs
AIDS and Behavior (2022)
-
Quantitative PET imaging of the CD4 pool in nonhuman primates
European Journal of Nuclear Medicine and Molecular Imaging (2022)
Comments
By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.
