[MoOrA1001] Mechanisms of pathogenesis of CCR5- and CXCR4-using HIV-1 in human lymphoid tissue

14th International AIDS Conference

Barcelona, Spain — July 7-12, 2002

[TITLE:] Mechanisms of pathogenesis of CCR5- and CXCR4-using HIV-1 in human lymphoid tissue

[AUTHOR(S):] L. Margolis, J.C. Grivel, Y. Ito, C. Womack¹, P. Lusso²

Int Conf AIDS. 2002 Jul 7-12;14:Abstract No. MoOrA1001

BACKGROUND: HIV-1 infection is transmitted predominantly by CCR5-using (R5) HIV-1 variants. The switch to CXCR4-using variants (X4) (R5-X4 switch) that often occurs in the course of HIV disease is associated with a rapid decline in CD4+T cells. The cause of neither of the R5-X4 switch, nor of differential cytopathicity of X4 and R5 HIV-1 has been established. We address these problems in ex vivo human lymphoid tissue, where in vivo critical events of HIV disease occur. We asked: (i) what the mechanism of differential cytopacity of R5 and X4 HIV-1 is, and (ii) what causes the R5-X4 switch.

METHODS: Blocks of human lymphoid tissues were inoculated ex vivo with HIV-1 isolates and infection was monitored for up to 3 weeks.

RESULTS: (i) Infection with R5 HIV-1 of both B and non-B subtypes results in a mild depletion of CD4+T cells, whereas X4 infection causes severe depletion of these cells. X4 viruses induce apoptosis in the majority of CD4+ T cells that express CXCR4, whereas in R5-infected tissues apoptosis is restricted to the minority of CD4+T cells that express CCR5. HIV-induced apoptosis seems to be restricted to infected cells. (ii) We hypothesize that concurrent infections may contribute to the R5-X4 switch. Human herpesvirus 6 (HHV-6) affects HIV-1 infection in tissues ex vivo, dramatically suppressing R5 but not X4 HIV-1 replication. HHV-6 markedly increases the production of RANTES, providing a mechanism for the selective blockade of R5 HIV-1.

CONCLUSIONS: The accelerated CD4+T cell death after the coreceptor switch from R5 to X4 (or to R5X4) is the result of the expansion of the viral cell target repertoire and this switch alone may be sufficient for acceleration of disease progression. HHV-6 and other copathogens may be critical factors in containing CCR5-tropic HIV-1 infection, may contribute to the R5-X4 switch, and thus may play a profound role in modulating the progression of HIV disease.

Presenting author: Leonid Margolis

1National Institutes of Health, Bethesda, United States.

2DIBIT-San Raffaele Institute, Milano, Italy.

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