Coinfection studies in structurally intact human lymphoid tissue ex vivo does HHV6 favor the phenotypic switch of HIV1

Coinfection studies in human lymphoid tissue ex vivo have recently provided a new paradigm to understand the interactions between HHV-6 and HIV-1, clearly documenting a divergent effect of HHV-6 according to the coreceptor specificity of

HIV-1: while the replication of CXCR4-tropic HIV-1 (either X4 or R5X4) was generally enhanced by HHV-6 coinfection, the growth of CCR5-tropic strains was consistently suppressed (Grivel et al., 2001). In turn, HHV-6 replication was generally enhanced by coinfection with HIV-1. In addition, HHV-6 was shown to potently induce the production of RANTES, the most effective HIV-inhibitory chemokine, providing a potential mechanism for the divergent effects seen on the different HIV-1 variants. Strikingly, RANTES induction by HHV-6 specifically occurs in structurally intact lymphoid tissue, because in mononuclear cell cultures grown in suspension, including cells extracted from minced tonsil or lymph node tissue, the effect is only marginal (Lusso et al., unpublished), suggesting that it requires a triggering action of specific cells, such as stromal cells, that are not present in suspension cultures.

Altogether, the observations made in lymphoid tissue ex vivo suggest a novel mechanism whereby HHV-6 can influence the course of HIV-1 infection. Thus, when HHV-6 is reactivated in vivo during the progression of HIV-1 disease, it may selectively suppress the dominant CCR5-dependent HIV-1 variants, while favoring the replication of CXCR4-tropic variants, which are kept under tight control, most likely by immunological mechanisms, during the asymptomatic phase of the infection. Thus, HHV-6 replication may be one of the factors driving the coreceptor switch of HIV-1 from CCR5 to CXCR4 usage.

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