Adhesion co-receptor expression and intracellular signalling in HIV disease: implications for immunotherapy.
OBJECTIVE
To investigate, in lymphocytes from HIV-1-infected individuals, the phenotypic expression of various adhesion co- or counter-receptors [lymphocyte function-associated antigen (LFA)-3, LFA-1 and intercellular adhesion molecule (ICAM)-1] involved in providing the co-stimulatory signal through the phospholipase C-gamma pathway in relation to inositol polyphosphate metabolism.


METHODS
Cell adhesion molecule profiles of peripheral blood lymphocytes (PBL) from 39 HIV-1-infected individuals at various stages of infection and 20 healthy laboratory controls were studied using flow cytometry. These were studied in 14 patients with late-stage disease in conjunction with their inositol polyphosphate metabolic profiles measured by high performance liquid chromatography. Levels of HIV-1 present in cell lysates were concurrently measured by a p24 antigen capture assay. In addition, the effects of a specific anti-ICAM-1 antisense oligonucleotide on the intracellular phosphatase activities of lymphocytes from a separate group of eight HIV-1-infected individuals were examined.


RESULTS
The expression of LFA-1, a beta 2 integrin, was upregulated among patient PBL in parallel with disease progression, whereas that of LFA-3 (CD58) was found to be significantly reduced among the CD4+ lymphocyte subset in all stages of infection. The 5-phosphatase activity, which we previously observed to be defective in HIV disease, was found to correlate linearly with the expression of both LFA-1 and its ligand, ICAM-1. Treatment of patient lymphocytes with an antisense oligonucleotide, which reduced the cell surface expression of ICAM-1 by blocking the translation of its mRNA, resulted in further reduction of intracellular phosphatase activities.


CONCLUSIONS
Our results suggest a pivotal role for adhesion co- and counter-receptors in influencing lymphocyte signalling and hence cellular response to recall antigens in HIV-1-infected individuals.
Ng
T T
TT
Department of Immunology, St Bartholomew's Hospital, London, UK.
Guntermann
C
C
Nye
K E
KE
Parkin
J M
JM
Anderson
J
J
Norman
J E
JE
Morrow
W J
WJ
D015703:Antigens, CD / Q000378:metabolism; D001483:Base Sequence; D018968:CD58 Antigens; D015815:Cell Adhesion Molecules / Q000378:metabolism*; D015658:HIV Infections / Q000276:immunology* / Q000378:metabolism / Q000628:therapy*; D015497:HIV-1; D006801:Humans; D007167:Immunotherapy; D066298:In Vitro Techniques; D007295:Inositol Phosphates / Q000378:metabolism; D000072181:Inositol Polyphosphate 5-Phosphatases; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D016169:Lymphocyte Function-Associated Antigen-1 / Q000378:metabolism; D008214:Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D008969:Molecular Sequence Data; D016376:Oligonucleotides, Antisense / Q000235:genetics / Q000494:pharmacology; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism; D015398:Signal Transduction
D015703:Antigens, CD; D018968:CD58 Antigens; D015815:Cell Adhesion Molecules; D007295:Inositol Phosphates; D016169:Lymphocyte Function-Associated Antigen-1; D008562:Membrane Glycoproteins; D016376:Oligonucleotides, Antisense; D018799:Intercellular Adhesion Molecule-1; D010744:Phosphoric Monoester Hydrolases; D000072181:Inositol Polyphosphate 5-Phosphatases