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Comparative Study
. 2004 Aug 17;101(33):12324-9.
doi: 10.1073/pnas.0404620101. Epub 2004 Aug 5.

Highly pathogenic SHIVs and SIVs target different CD4+ T cell subsets in rhesus monkeys, explaining their divergent clinical courses

Yoshiaki Nishimura  1 , Tatsuhiko Igarashi, Olivia K Donau, Alicia Buckler-White, Charles Buckler, Bernard A P Lafont, Robert M Goeken, Simoy Goldstein, Vanessa M Hirsch, Malcolm A Martin
Affiliations
Comparative Study

Highly pathogenic SHIVs and SIVs target different CD4+ T cell subsets in rhesus monkeys, explaining their divergent clinical courses

Yoshiaki Nishimura et al. Proc Natl Acad Sci U S A. .

Abstract

In contrast to simian immunodeficiency viruses (SIVs), which induce immunodeficiency over a 1- to 3-year period, highly pathogenic simian-human immunodeficiency viruses (SHIVs) cause a complete, irreversible, and systemic depletion of CD4(+) T lymphocytes in rhesus monkeys within weeks of infection. By using small-molecule competitors specific for CCR5 and CXCR4 in ex vivo assays, we found that highly pathogenic SHIV(DH12R) exclusively uses CXCR4 for infection of rhesus peripheral blood mononuclear cells, whereas SIV(mac239) and SIV(smE543) use CCR5 for entry into the same cells. During the period of peak virus production in SHIV(DH12R)- or SHIV(89.6P)-infected rhesus monkeys, massive elimination of CXCR4(+) naïve CD4(+) T cells occurred. In contrast, circulating CCR5(+) memory CD4(+) T cells were selectively depleted in rapidly progressing SIV-infected monkeys. At the time of their death, two SIV rapid progressors had experienced a nearly complete loss of the memory CD4(+) T cell subset from the blood and mesenteric lymph nodes. Thus, pathogenic SHIVs and SIVs target different subsets of CD4(+) T cells in vivo, with the pattern of CD4(+) T lymphocyte depletion being inextricably linked to chemokine receptor use. In the context of developing an effective prophylactic vaccine, which must potently control virus replication during the primary infection, regimens that suppress SHIVs might not protect monkeys against SIV or humans against HIV-1.

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Figures

Fig. 1.
Fig. 1.
Coreceptor use by SIVs (A–C) and SHIVDH12R-CL-7 (D). SIVsmE543–3, SIVmac239, SIVmac316, and SHIVDH12R-CL-7 were spinoculated onto rhesus PBMCs in the presence of the indicated amounts of chemokine receptor inhibitors. The reverse transcriptase activity released into the medium on day 5 after infection was determined in the absence (dashed line) or presence of inhibitor.
Fig. 2.
Fig. 2.
Expression of memory/naïve markers and CCR5/CXCR4 on uninfected rhesus monkey CD4+ T lymphocytes. (a–c) Cells from a representative uninfected macaque were initially gated by flow cytometry on CD4 and were then analyzed for CD28/CD95 (a), CD45RA/CD11a (b), or CCR5/CXCR4 (c) expression. The percentage of total cells within each sector is indicated. The bar graphs depict the fraction of: (i) CD4+ naïve and memory cells in 45 (a) and 26 (b) uninfected macaques or (ii) CD4+CXCR4+ and CD4+CCR5+ lymphocytes in 30 uninfected animals (c). (d) Chemokine expression on CD4+ naïve and memory cells was determined by initially gating on CD95lowCD28high, CD95highCD28low, or CD95highCD28high cells and then by analyzing for CXCR4 or CCR5. The boxes show the gates used to quantitate CXCR4 and CCR5 cells based on the staining with isotype matched control mAbs.
Fig. 3.
Fig. 3.
SHIVs preferentially target the depletion of CD4+ CXCR4+ naïve cells, whereas SIV induces the loss of CD4+ CCR5+ memory cells during the first 10 weeks of infection. (a) SHIVDH12R, SHIV89.6P, and SIVsmE543 all replicate to high levels in rhesus monkeys, but only the SHIVs induce a rapid and complete loss of CD4+ T lymphocytes. (b and c) EDTA-treated samples of blood, collected at the indicated times from SIV- or SHIV-infected animals, were gated on CD4+ T cells and analyzed for the indicated surface markers, which distinguish naïve and memory (b) or CCR5+ and CXCR4+ (c) cells. The percentage of total cells within each sector is indicated.
Fig. 4.
Fig. 4.
At the time of death, two SIV-infected monkeys had lost virtually all of their CD4+ memory T cells from the blood and lymph nodes. EDTA-treated blood samples or mesenteric lymph node suspensions, collected before death from macaques RHCK2K and RHCK2F, were gated on CD4+ T cells and stained for the indicated surface markers that distinguish naïve and memory cells. The percentages are indicated for each CD4+ T cell subset.
Fig. 5.
Fig. 5.
Changes in the levels of naïve (a), memory (a), CXCR4+ (b), and CCR5+ (b) CD4+ T cells in rhesus monkeys inoculated with SHIVs and SIVs at week 0 and week 6 after infection. The significance of differences between each paired group was analyzed by using the Mann–Whitney U test.
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References

    1. Igarashi, T., Endo, Y., Englund, G., Sadjadpour, R., Matano, T., Buckler, C., Buckler-White, A., Plishka, R., Theodore, T., Shibata, R. & Martin, M. (1999) Proc. Natl. Acad. Sci. USA 96, 14049–14054. - PMC - PubMed
    1. Joag, S. V., Li, Z., Foresman, L., Stephens, E. B., Zhao, L.-J., Adany, I., Pinson, D. M., McClure, H. M. & Narayan, O. (1996) J. Virol. 70, 3189–3197. - PMC - PubMed
    1. Reimann, K. A., Li, J. T., Veazey, R., Halloran, M., Park, I.-W., Karlsson, G. B., Sodroski, J. & Letvin, N. L. (1996) J. Virol. 70, 6922–6928. - PMC - PubMed
    1. Amara, R. R., Villinger, F., Altman, J. D., Lydy, S. L., O'Neil, S. P., Staprans, S. I., Montefiori, D. C., Xu, Y., Herndon, J. G., Wyatt, L. S., et al. (2001) Science 292, 69–74. - PubMed
    1. Barouch, D. H., Santra, S., Schmitz, J. E., Kuroda, M. J., Fu, T.-M., Wagner, W., Bilska, M., Craiu, A., Zheng, X. X., Krivulka, G. R., et al. (2000) Science 290, 486–492. - PubMed

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