Nonsense mutations in the vpr gene of HIV‐1 during in vitro virus passage and in HIV‐1 carrier‐derived peripheral blood mononuclear cells

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Abstract
Long‐term, persistent infection by HIV‐1 is a prerequisite for the development of AIDS. However, little is known of the determinants required for HIV‐1 to cause persistence. We have reported previously that persistent infection of a T cell line by a cytopathogenic strain of HIV‐1 became increasingly likely with in vitro serial passage of the virus. DNA sequencing of the persistent strains revealed a nonsense mutation in the vpr gene in all isolates tested. Here, we report the development and use of a semi‐quantitative PCR method to detect the vpr nonsense mutation within populations of virus. Our results show that vpr mutants also arise in cells during acute infection and increase progressively with serial passage of the virus. In addition, HIV‐1‐seropositive individuals were examined and found to carry the same vpr nonsense mutation at high frequency in virus‐infected PBMC. These data are consistent with a mechanism of HIV‐1 persistence in vivo and in vitro in which virus cytopathogenic potential is lost by the build up of nonsense mutations in vpr.