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Abstract
Increasing evidence suggests that HIV-1 Vpr is required in vivo for viral pathogenesis.
Since Vpr displays multiple activities, little is known about which Vpr-specific activities
are conserved in naturally occurring viruses or how natural mutations in Vpr might
modulate viral pathogenesis in HIV-infected individuals. The goals of this study were
to evaluate the functional variability of Vpr in naturally occurring viruses. The
Vpr-specific activities of nuclear localization, induction of cell cycle G2 arrest
and cell death were compared between viruses isolated from the fast progressing AIDS
patients and a mother-child pair of long-term non-progressors (LTNPs). Wild-type Vpr
activities were found in all of the viruses that were isolated from the fast progressing
AIDS patients except for the truncated Vpr(IIIB) which lacked these activities. In
contrast, defective Vpr were readily detected in viral populations isolated, over
an 11-year period, from the mother-child pair. Sequence analyses indicated that these
Vpr carried unique amino acid substitutions that frequently interrupted a highly conserved
domain containing an N-terminal alpha-helix-turn-alpha-helix. Thus, Vpr activities
are generally conserved in naturally occurring viruses. The functionally defective
Vpr identified in the mother-child pair of LTNPs are likely to be unique and may possibly
contribute to the slow disease progression.