Vpr is preferentially targeted by CTL during HIV-1 infection.
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-gamma 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.
Altfeld
M
M
Partners AIDS Research Center and Infectious Disease Division, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA.
Addo
M M
MM
Eldridge
R L
RL
Yu
X G
XG
Thomas
S
S
Khatri
A
A
Strick
D
D
Phillips
M N
MN
Cohen
G B
GB
Islam
S A
SA
Kalams
S A
SA
Brander
C
C
Goulder
P J
PJ
Rosenberg
E S
ES
Walker
B D
BD
D000595:Amino Acid Sequence; D016022:Case-Control Studies; D000939:Epitopes / Q000235:genetics; D016346:Gene Products, vif / Q000235:genetics / Q000276:immunology; D016336:Gene Products, vpr / Q000235:genetics / Q000276:immunology*; D015658:HIV Infections / Q000276:immunology*; D015497:HIV-1 / Q000235:genetics / Q000276:immunology*; D054298:Human Immunodeficiency Virus Proteins; D006801:Humans; D066298:In Vitro Techniques; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000235:genetics / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D054334:Viral Regulatory and Accessory Proteins / Q000235:genetics / Q000276:immunology; D054320:vif Gene Products, Human Immunodeficiency Virus; D054325:vpr Gene Products, Human Immunodeficiency Virus; D000086082:Viroporin Proteins
D000939:Epitopes; D016346:Gene Products, vif; D016336:Gene Products, vpr; D054298:Human Immunodeficiency Virus Proteins; D010446:Peptide Fragments; D054334:Viral Regulatory and Accessory Proteins; D054320:vif Gene Products, Human Immunodeficiency Virus; D054325:vpr Gene Products, Human Immunodeficiency Virus; C514859:vpu protein, Human immunodeficiency virus 1; D000086082:Viroporin Proteins