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Suppression of CCR5- but not CXCR4-tropic HIV-1 in lymphoid tissue by human herpesvirus 6

Nature Medicine volume 7, pages 1232–1235 (2001)Cite this article

Abstract

HIV-1 infects target cells via a receptor complex formed by CD4 and a chemokine receptor, primarily CCR5 or CXCR4 (ref. 1). Commonly, HIV-1 transmission is mediated by CCR5-tropic variants, also designated slow/low, non-syncytia-inducer or macrophage-tropic, which dominate the early stages of HIV-1 infection and frequently persist during the entire course of the disease2,3,4,5,6,7,8,9. In contrast, HIV-1 variants that use CXCR4 are typically detected at the later stages, and are associated with a rapid decline in CD4+ T cells and progression to AIDS (refs. 2,7–11). Disease progression is also associated with the emergence of concurrent infections that may affect the course of HIV disease by unknown mechanisms. A lymphotropic agent frequently reactivated in HIV-infected patients is human herpesvirus 6 (HHV-6), which has been proposed as a cofactor in AIDS progression12. Here we show that in human lymphoid tissue ex vivo13,14,15, HHV-6 affects HIV-1 infection in a coreceptor-dependent manner, suppressing CCR5-tropic but not CXCR4-tropic HIV-1 replication, as shown with both uncloned viral isolates and isogenic molecular chimeras. Furthermore, we demonstrate that HHV-6 increases the production of the CCR5 ligand RANTES ('regulated upon activation, normal T-cell expressed and secreted'), the most potent HIV-inhibitory CC chemokine16, and that exogenous RANTES mimics the effects of HHV-6 on HIV-1, providing a mechanism for the selective blockade of CCR5-tropic HIV-1. Our data suggest that HHV-6 may profoundly influence the course of HIV-1 infection.

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Figure 1: Differential effect of HHV-6 on replication of HIV-1 of different coreceptor tropism.
Figure 2: Production of RANTES in human lymphoid tissues infected ex vivo with HHV-6 alone or in combination with either CCR5- or CXCR4-tropic HIV-1.
Figure 3: Suppression of CCR5-tropic HIV-1 replication by RANTES in human lymphoid tissue.

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Acknowledgements

We thank R. Collman for providing us with 89.6 and 89-v345.SF HIV-1 variants; J. Zimmerberg for his support and encouragement. The work of J.-C.G., Y.I., W.F. and L.M. was supported, in part, by the NASA/NIH Center for Three-Dimensional Tissue Culture. The work of P.L. and M.S.M. was partly supported by Grants from Istituto Superiore di Sanita, Rome, Italy.

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Authors and Affiliations

  1. Laboratory of Cellular and Molecular Biophysics, National Institute of Child Health and Human Development, Bethesda, Maryland, USA

    Jean-Charles Grivel, Yoshinori Ito, Wendy Fitzgerald & Leonid Margolis

  2. Unit of Human Virology, DIBIT-San Raffaele Scientific Institute, Milano, Italy

    Giovanni Fagà, Fabio Santoro, Mauro S. Malnati & Paolo Lusso

  3. Department of Clinical and Experimental Medicine, University of Bologna, Bologna, Italy

    Paolo Lusso

  4. University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA

    Farida Shaheen

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  1. Jean-Charles Grivel
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Correspondence to Paolo Lusso or Leonid Margolis.

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Grivel, JC., Ito, Y., Fagà, G. et al. Suppression of CCR5- but not CXCR4-tropic HIV-1 in lymphoid tissue by human herpesvirus 6. Nat Med 7, 1232–1235 (2001). https://doi.org/10.1038/nm1101-1232

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