Suppression of CCR5- but not CXCR4-tropic HIV-1 in lymphoid tissue by human herpesvirus 6.
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 disease. 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 progression. Here we show that in human lymphoid tissue ex vivo, 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 chemokine, 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.
Grivel
J C
JC
Laboratory of Cellular and Molecular Biophysics, National Institute of Child Health and Human Development, Bethesda, Maryland, USA.
Ito
Y
Y
Fagà
G
G
Santoro
F
F
Shaheen
F
F
Malnati
M S
MS
Fitzgerald
W
W
Lusso
P
P
Margolis
L
L
D018946:Chemokine CCL5 / Q000096:biosynthesis / Q000494:pharmacology; D046508:Culture Techniques; D015658:HIV Infections / Q000150:complications / Q000209:etiology / Q000821:virology; D015497:HIV-1 / Q000187:drug effects / Q000235:genetics / Q000472:pathogenicity* / Q000502:physiology*; D015654:Herpesvirus 6, Human / Q000502:physiology*; D006801:Humans; D008221:Lymphoid Tissue / Q000276:immunology / Q000821:virology; D019713:Receptors, CCR5 / Q000502:physiology; D019718:Receptors, CXCR4 / Q000502:physiology; D019349:Roseolovirus Infections / Q000150:complications / Q000209:etiology / Q000821:virology; D014779:Virus Replication / Q000187:drug effects
D018946:Chemokine CCL5; D019713:Receptors, CCR5; D019718:Receptors, CXCR4