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*
Partners AIDS Research Center and Infectious Disease Division, and
Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129;
AIDS Research Center, First Affiliated Hospital China Medical University, Shenyang, China;
Nuffield Department of Medicine, John Radcliffe Hospital, Oxford, United Kingdom;
¶ Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115; and
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Fenway Community Health Center, Boston, MA 02116
The HIV-1 accessory proteins Vpr, Vpu, and Vif are essential for
viral replication, and their cytoplasmic production suggests that they
should be processed for recognition by CTLs. However, the extent to
which these proteins are targeted in natural infection, as well as
precise CTL epitopes within them, remains to be defined. In this study,
CTL responses against HIV-1 Vpr, Vpu, and Vif were analyzed in 60
HIV-1-infected individuals and 10 HIV-1-negative controls using
overlapping peptides spanning the entire proteins. Peptide-specific
IFN-
production was measured by ELISPOT assay and flow-based
intracellular cytokine quantification. HLA class I restriction and
cytotoxic activity were confirmed after isolation of peptide-specific
CD8+ T cell lines. CD8+ T cell responses
against Vpr, Vpu, and Vif were found in 45%, 2%, and 33% of
HIV-1-infected individuals, respectively. Multiple CTL epitopes were
identified in functionally important regions of HIV-1 Vpr and Vif.
Moreover, in infected individuals in whom the breadth of HIV-1-specific
responses was assessed comprehensively, Vpr and p17 were the most
preferentially targeted proteins per unit length by CD8+ T
cells. These data indicate that despite the small size of these
proteins Vif and Vpr are frequently targeted by CTL in natural HIV-1
infection and contribute importantly to the total HIV-1-specific
CD8+ T cell responses. These findings will be important in
evaluating the specificity and breadth of immune responses during acute
and chronic infection, and in the design and testing of candidate HIV
vaccines.
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