Regulation of HIV production by blood mononuclear cells from HIV-infected donors: II. HIV-1 production depends on T cell-monocyte interaction.
Cell-cell interactions induced between T cells and monocytes by certain soluble anti-CD3 monoclonal antibodies (MAbs) were previously shown to be required for high-level production of HIV-1 by peripheral blood mononuclear cells (PBMCs) from infected donors. Staphylococcal enterotoxin or superantigen (SAg) is another mitogen inducing monocytes-T cell interactions that exhibit potent induction of HIV-1 production. Antibodies to several adhesion molecules were used to test the requirements for T cell- and monocyte-associated adhesion molecules in HIV-1 production following activation with anti-CD3 or SAg. Blocking of either CD2-LFA-3, or CD18-ICAM-1, inhibited anti-CD3- or SAg-induced HIV-1 production by more than 90% without inhibiting CD4+ T cell proliferation. Inhibition of HIV production was observed when either the T cell or monocyte coreceptor was bound by MAbs to these adhesion molecules. Blocking of CD28-B7 interactions by soluble CTLA-4 fusion protein, a CD28 homolog, inhibited both HIV-1 production and CD4+ T cell proliferation. Fc binding was not required for HIV-1 inhibition by MAbs to CD2 and CD18, because Fab or F(ab')2 fragments of these MAbs inhibited HIV-1 production by more than 80%. A chimeric single-chain MAb to CD2 was produced, containing heavy and light chain variable regions from MAb 35.1 to CD2 linked to the constant regions of human IgG1 (CD2 SFv-Ig). This humanized CD2 SFv-Ig inhibited HIV-1 production by 30% to > 98%. These results thus indicate that simultaneous engagement of multiple adhesion pathways between T cells and monocytes are required for HIV production by patients PBMCs and may have implications for therapy of HIV infections.
Diegel
M L
ML
Bristol-Myers Squibb Pharmaceutical Research Institute, Seattle, WA 98121.
Moran
P A
PA
Gilliland
L K
LK
Damle
N K
NK
Hayden
M S
MS
Zarling
J M
JM
Ledbetter
J A
JA
D000069594:Abatacept; D000818:Animals; D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000943:Antigens, Differentiation; D000945:Antigens, Differentiation, T-Lymphocyte; D001782:Blood Donors; D018801:CD2 Antigens; D060908:CTLA-4 Antigen; D015815:Cell Adhesion Molecules / Q000276:immunology; D002450:Cell Communication / Q000276:immunology; D015658:HIV Infections / Q000276:immunology / Q000382:microbiology*; D015497:HIV-1 / Q000276:immunology / Q000502:physiology*; D006801:Humans; D018796:Immunoconjugates; D066298:In Vitro Techniques; D051379:Mice; D009000:Monocytes / Q000276:immunology; D011971:Receptors, Immunologic; D013601:T-Lymphocytes / Q000276:immunology; D014779:Virus Replication / Q000276:immunology
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000943:Antigens, Differentiation; D000945:Antigens, Differentiation, T-Lymphocyte; D018801:CD2 Antigens; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D015815:Cell Adhesion Molecules; C556707:Ctla4 protein, mouse; D018796:Immunoconjugates; D011971:Receptors, Immunologic; D000069594:Abatacept