Virus Research 121 (2006) 161–168 Human herpesvirus 6A decreases the susceptibility of macrophages to R5 variants of human immunodeficiency virus 1: Possible role of RANTES and IL-8 Eszter Csoma a,∗ , Tam´ as Deli b ,J´ ozsef K ´ onya a , L´ aszl´ o Csernoch b , Zolt´ an Beck a , Lajos Gergely a,c a Department of Medical Microbiology, Medical and Health Science Centre, University of Debrecen, P.O. Box 17, H-4012 Debrecen, Hungary b Department of Physiology, Medical and Health Science Centre, University of Debrecen, P.O. Box 22, H-4012 Debrecen, Hungary c Tumourvirus Research Group of the Hungarian Academy of Sciences, P.O. Box 17, H-4012 Debrecen, Hungary Received 13 February 2006; received in revised form 17 May 2006; accepted 24 May 2006 Available online 3 July 2006 Abstract Human herpesvirus 6 (HHV-6) frequently reactivates in human immunodeficiency virus 1 (HIV-1) infected patients, and is thought to be a cofactor in AIDS progression. Macrophages are targets and reservoirs of HIV-1 and HHV-6; hence, they have an important role in dissemination and pathogenesis of these viruses. The present study examined the effects of HHV-6 A variant on replication of R5 variants of HIV-1 in macrophages. For this purpose, HIV-1 replication was investigated in macrophages infected with HIV-1 alone or along with HHV-6A. Our results demonstrated that HHV-6A significantly suppressed HIV-1 replication in coinfected cultures. HHV-6A infection resulted in increased secretion of RANTES and IL-8. Experiments with exogenous RANTES and IL-8 revealed that these chemokines also significantly suppressed HIV-1 replication in infected macrophages. RANTES is able to induce desensitization and internalization of CCR5, the chemokine coreceptor of R5 variants. In addition, IL-8 receptor activation results in cross-desensitization and cross-internalization of CCR5. We found that CCR5 sensitivity and expression level is diminished in HHV-6A-infected macrophage cultures compared with uninfected cells. Taken together, our results indicate that HHV-6A infection decreases the susceptibility of macrophages to R5 variants of HIV-1 in which the HHV-6A induced RANTES and IL-8 may have importance. © 2006 Elsevier B.V. All rights reserved. Keywords: HHV-6A; HIV-1; CCR5 1. Introduction Human immunodeficiency virus 1 (HIV-1) infection is asso- ciated with the appearance of other infections which may affect the pathogenesis of HIV-1. Human herpesvirus 6 (HHV-6) is ubiquitous in the population, the seropositivity exceeds 90% (Irving and Cunningham, 1990). Primary infection with HHV- 6 occurs in early childhood (Hall et al., 1994) after which latent infection is established. HHV-6 frequently reactivates in HIV-infected patients, and is thought to be a cofactor in AIDS progression (Lusso and Gallo, 1995). Variant A (Ablashi et al., ∗ Correspondence to: Department of Medical Microbiology, Medical and Health Science Centre, University of Debrecen, P.O. Box 17, H-4012 Debrecen, Hungary. Tel.: +36 52 417 565; fax: +36 52 417 565. E-mail address: csomae@freemail.hu (E. Csoma). 1991) of HHV-6 (HHV-6A) has been isolated most frequently from immunocompromised patients (Knox and Carrigan, 1994; Secchiero et al., 1995). During acute phase of HHV-6 infection, monocyte/ macrophage cells are major targets for the virus (Kondo et al., 2002), in addition HHV-6 establishes latency in monocyte–macrophage lineage (Kondo et al., 1991). Macrophages in vivo serve as primary targets and reservoirs for HIV-1, and as a result of their ability to migrate, they play an important role in virus dissemination and pathogenesis of the infection (Kedzierska and Crowe, 2002; Verani et al., 2005). Generally, HIV-1 infection occurs via transmission of R5 vari- ants, also known as macrophage-tropic, which dominate in the early and asymptomatic phase of infection (Moore et al., 2004), and persist throughout the course of the disease. R5 variants infect cells interacting with CD4 and chemokine coreceptors. 0168-1702/$ – see front matter © 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.virusres.2006.05.007