Vpr is preferentially targeted by CTL during HIV-1 infection

TY - JOUR

T1 - Vpr is preferentially targeted by CTL during HIV-1 infection

AU - Altfeld, Marcus

AU - Addo, M M

AU - Eldridge, R L

AU - Yu, X G

AU - Thomas, S

AU - Khatri, A

AU - Strick, D

AU - Phillips, M N

AU - Cohen, G B

AU - Islam, S A

AU - Kalams, S A

AU - Brander, C

AU - Goulder, P J

AU - Rosenberg, E S

AU - Walker, B D

AU - HIV Study Collaboration

PY - 2001/9/1

Y1 - 2001/9/1

N2 - 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.

AB - 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.

KW - Amino Acid Sequence

KW - Case-Control Studies

KW - Epitopes/genetics

KW - Gene Products, vif/genetics

KW - Gene Products, vpr/genetics

KW - HIV Infections/immunology

KW - HIV-1/genetics

KW - Human Immunodeficiency Virus Proteins

KW - Humans

KW - In Vitro Techniques

KW - Molecular Sequence Data

KW - Peptide Fragments/genetics

KW - T-Lymphocytes, Cytotoxic/immunology

KW - Viral Regulatory and Accessory Proteins/genetics

KW - vif Gene Products, Human Immunodeficiency Virus

KW - vpr Gene Products, Human Immunodeficiency Virus

U2 - 10.4049/jimmunol.167.5.2743

DO - 10.4049/jimmunol.167.5.2743

M3 - SCORING: Journal article

C2 - 11509618

VL - 167

SP - 2743

EP - 2752

JO - J IMMUNOL

JF - J IMMUNOL

SN - 0022-1767

IS - 5

ER -