Research

Evolution of SIV toward RANTES resistance in macaques rapidly progressing to AIDS upon coinfection with HHV-6A

Angélique Biancotto^1,2 , Jean-Charles Grivel¹ , Andrea Lisco¹ , Christophe Vanpouille¹ , Phillip D Markham³ , Robert C Gallo⁴ , Leonid B Margolis¹ and Paolo Lusso^5,6,7

¹  Laboratory of Molecular and Cellular Biophysics, National Institute of Child Health and Human Development, Bethesda, MD 20892, USA

²  Center for Human Immunology, National Heart, Lung and Blood Institute, Hematology Branch, Bethesda, MD 20892, USA

³  Advanced Bioscience Laboratories, Kensington, Maryland 20895, USA

⁴  Institute of Human Virology, University of Maryland Biotechnology Institute, Baltimore, MD 21202, USA

⁵  Unit of Human Virology, DIBIT San Raffaele Scientific institute, Milano, 20132, Italy

⁶  Department of Medical Sciences, University of Cagliari School of Medicine, Cagliari, 09149, Italy

⁷  Laboratory of Immunoregulation, NIAID, NIH, Bethesda, MD 20892, USA

author email corresponding author email

Retrovirology 2009, 6:61doi:10.1186/1742-4690-6-61

Published:	2 July 2009

Abstract

Background

Progression to AIDS is often associated with the evolution of HIV-1 toward increased virulence and/or pathogenicity. Evidence suggests that a virulence factor for HIV-1 is resistance to CCR5-binding chemokines, most notably RANTES, which are believed to play a role in HIV-1 control in vivo. HIV-1 can achieve RANTES resistance either by phenotypic switching from an exclusive CCR5 usage to an expanded coreceptor specificity, or by the acquisition of alternative modalities of CCR5 usage. An infectious agent that might promote the evolution of HIV-1 toward RANTES resistance is human herpesvirus 6A (HHV-6A), which is frequently reactivated in HIV-1-infected patients and is a potent RANTES inducer in lymphoid tissue.

Results

SIV isolates obtained from pig-tailed macaques (M. nemestrina) after approximately one year of single infection with SIV_smE660 or dual infection with SIV_smE660 and HHV-6A_GS were characterized for their growth capacity and sensitivity to HHV-6A- and RANTES-mediated inhibition in human or macaque lymphoid tissues ex vivo. Four out of 4 HHV-6A-coinfected macaques, all of which progressed to full-blown AIDS within 2 years of infection, were found to harbor SIV variants with a reduced sensitivity to both HHV-6A and RANTES, despite maintaining an exclusive CCR5 coreceptor specificity; viruses derived from two of these animals replicated even more vigorously in the presence of exogenous HHV-6A or RANTES. The SIV variants that emerged in HHV-6A-coinfected macaques showed an overall reduced ex vivo replication capacity that was partially reversed upon addition of exogenous RANTES, associated with suppressed IL-2 and enhanced IFN-γ production. In contrast, SIV isolates obtained from two singly-infected macaques, none of which progressed to AIDS, maintained HHV-6A/RANTES sensitivity, whereas the only AIDS progressor among singly-infected macaques developed an SIV variant with partial HHV-6A/RANTES resistance and increased replication capacity, associated with expanded coreceptor usage.

Conclusion

These results provide in vivo evidence of SIV evolution toward RANTES resistance in macaques rapidly progressing to AIDS. RANTES resistance may represent a common virulence factor allowing primate immunodeficiency retroviruses to evade a critical mechanism of host antiviral defense.