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  • Title: Effect of R77Q, R77A and R80A changes in Vpr on HIV-1 replication and CD4 T cell depletion in human lymphoid tissue ex vivo.
    Author: Rajan D, Wildum S, Rücker E, Schindler M, Kirchhoff F.
    Journal: AIDS; 2006 Apr 04; 20(6):831-6. PubMed ID: 16549966.
    Abstract:
    BACKGROUND: It has been suggested that mutations of R77A and R80A in the HIV-1 viral protein R (Vpr) impair its proapoptotic activity and that a naturally occurring R77Q variation is associated with non-progressive HIV-1 infection. RATIONALE: To assess the effect of Vpr R77Q, R77A and R80A mutations on the efficiency of CCR5(R5)- and CXCR4(X4)-tropic HIV-1 replication and cytopathicity in human lymphoid tissue (HLT). METHODS: Vpr mutants of the X4-tropic HIV-1 NL4-3 clone and an R5-tropic derivative were generated by PCR mutagenesis. Virus stocks established by transfection of 293T cells were used to infect macrophages and ex vivo HLT. HIV-1 replication was assessed by measuring p24 core antigen in the culture supernatants and CD4 T-cell depletion and apoptosis were measured by flow cytometric analysis. RESULTS: The R5-tropic HIV-1 Vpr mutants replicated with slightly (R77A, R77Q) to moderately (R80A) reduced efficiency in ex vivo-infected HLT and macrophages. In comparison, the changes in Vpr had negligible effects on replication of the X4-tropic forms in lymphatic tissues. Mutation of R77Q and R80A reduced apoptosis of HIV-1-infected cells in ex vivo-infected HLT independently of the viral coreceptor tropism. However, only the R5-tropic HIV-1 Vpr mutants caused markedly less CD4 T-cell depletion than wild-type HIV-1 at the end of ex vivo HLT culture. CONCLUSIONS: The observation that Vpr R77Q reduces the cytopathicity of R5-tropic HIV-1 in lymphoid tissues supports a role in non-progressive HIV-1 infection but the attenuating effects might be dependent on the viral subtype and coreceptor tropism.
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