Abstract
The auxiliary protein Vif is essential for productive HIV-1 infection of primary lymphocytes and macrophages. Vif is required for the synthesis of infectious progeny virus and infection of peripheral blood lymphocytes (PBLs) by Vif-negative HIV-1 was thought to be confined to a single cycle. Here we define conditions for the maintenance of Vif-negative HIV-1 in PBLs during multiple rounds of viral infection. PBLs were infected with Vif-negative HIV-1 and then were serially cocultivated with uninfected PBLs. As determined by measurement of viral DNA, viral burdens declined but then rebounded and reached 1 copy per 30 cells after 7 weeks of culture. Viral core antigen p24 levels dropped and remained below detection limits after three cocultivations with no observed cytotoxicity. Viral RNA was also undetectable in cocultivated cells. The incapacitating deletion in vif was maintained during cocultivation as shown by the size of the vif amplicon. The presence of viral DNA in the absence of viral p24 RNA or protein suggested that the cells were capable of control of HIV-1 expression. This regulatory capacity was confirmed by the demonstration of resistance of PBLs or isolated CD4-positive cells to expression of exogenous wild-type R5 or X4 HIV-1. Resistant PBLs were susceptible to fusion with HIV-1 envelope-expressing cells and to reverse transcription of incoming viral DNA, indicating that the block to replication of exogenous virus was imposed after viral entry and DNA synthesis. Using a dual-chamber apparatus, we demonstrated that resistant Vif-negative HIV-1-infected PBLs secrete soluble factors that confer resistance on naive cells. These findings indicate that Vif-negative HIV-1 infection of primary CD4-positive lymphocytes results in maintenance of unexpressed virus and induces the production of soluble factors conferring resistance to wild-type HIV-1 replication on uninfected cells.
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