Impacts of epitope expression kinetics and class I downregulation on the antiviral activity of human immunodeficiency virus type 1-specific cytotoxic T lymphocytes.
The determinants of CD8(+) cytotoxic T-lymphocyte (CTL) antiviral activity against human immunodeficiency virus type 1 (HIV-1) remain poorly defined. Although recent technological advances have markedly enhanced the ability to detect HIV-1-specific T cells, commonly used assays do not reveal their direct interaction with virus. We investigated two determinants of CTL antiviral efficiency by manipulating HIV-1 and measuring the effects on CTL suppression of viral replication in acutely infected cells. Translocation of a Gag epitope into the early protein Nef markedly increased the activity of CTL recognizing that epitope, in comparison to HIV-1 expressing the epitope normally in the late protein Gag. Because this epitope translocation resulted not only in earlier expression but also in loss of major histocompatibility complex class I downregulation by Nef, the activities of CTL against a panel of viral constructs differing in kinetics of epitope expression and class I downmodulation were compared. The results indicated that both the timing of epitope expression and the reduction of class I have profound effects on the ability of CTL to suppress HIV-1 replication in acutely infected cells. The epitope targeting of CTL and viral control of class I therefore likely play important roles in the ability of CTL to exert pressure on HIV-1.
Ali
Ayub
A
Department of Medicine, AIDS Institute, Geffen School of Medicine, UCLA Medical Center, University of California, Los Angeles, Los Angeles, California 90095, USA.
Lubong
Rachel
R
Ng
Hwee
H
Brooks
David G
DG
Zack
Jerome A
JA
Yang
Otto O
OO
D000595:Amino Acid Sequence; D015536:Down-Regulation; D018984:Epitopes, T-Lymphocyte / Q000737:chemistry / Q000378:metabolism*; D017353:Gene Deletion; D015683:Gene Products, gag / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D015693:Gene Products, nef / Q000737:chemistry / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D015497:HIV-1 / Q000276:immunology*; D015395:Histocompatibility Antigens Class I / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D008969:Molecular Sequence Data; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014779:Virus Replication; D054311:nef Gene Products, Human Immunodeficiency Virus
D018984:Epitopes, T-Lymphocyte; D015683:Gene Products, gag; D015693:Gene Products, nef; D015395:Histocompatibility Antigens Class I; D054311:nef Gene Products, Human Immunodeficiency Virus