title: Evolution of SIV toward RANTES resistance in macaques rapidly progressing to AIDS upon coinfection with HHV-6A.
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-gamma 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.
  
  
  CONCLUSIONS
  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.
authors: Laboratory of Molecular and Cellular Biophysics, National Institute of Child Health and Human Development, Bethesda, MD 20892, USA. biancoa@nhlbi.nih.gov
authors: Angélique
authors: A
authors: Biancotto
authors: Jean-Charles
authors: JC
authors: Grivel
authors: Andrea
authors: A
authors: Lisco
authors: Christophe
authors: C
authors: Vanpouille
authors: Phillip D
authors: PD
authors: Markham
authors: Robert C
authors: RC
authors: Gallo
authors: Leonid B
authors: LB
authors: Margolis
authors: Paolo
authors: P
authors: Lusso
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D018946:Chemokine CCL5 / Q000276:immunology*; D015654:Herpesvirus 6, Human / Q000276:immunology*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000821:virology; D008198:Lymph Nodes / Q000276:immunology / Q000821:virology; D008251:Macaca; D009924:Organ Culture Techniques; D014066:Palatine Tonsil / Q000276:immunology / Q000821:virology; D019349:Roseolovirus Infections / Q000150:complications* / Q000276:immunology / Q000821:virology; D016097:Simian Acquired Immunodeficiency Syndrome / Q000150:complications* / Q000276:immunology / Q000821:virology*; D015302:Simian Immunodeficiency Virus / Q000254:growth & development / Q000276:immunology* / Q000302:isolation & purification
chemical_list: D018946:Chemokine CCL5