CCR5-reactive antibodies in seronegative partners of HIV-seropositive individuals down-modulate surface CCR5 in vivo and neutralize the infectivity of R5 strains of HIV-1 In vitro.
Exposure to HIV does not necessarily result in infection. Because primary HIV infection is associated with CCR5-tropic HIV variants (R5), CCR5-specific Abs in the sera of HIV-seronegative, HIV-exposed individuals (ESN) might be associated with protection against infection. We analyzed sera from ESN, their HIV-infected sexual partners (HIV+), and healthy controls (USN) searching for CCR5-specific Abs, studying whether incubation of PBMC with sera could prevent macrophage inflammatory protein 1 beta (Mip1 beta) (natural ligand of CCR5) binding to CCR5. Results showed that Mip1 beta binding to CCR5 was not modified by sera of either 40 HIV+ or 45 USN but was greatly reduced by sera of 6/48 ESN. Binding inhibition was due to Abs reactive with CCR5. The CCR5-specific Abs neutralized the infectivity of primary HIV isolates obtained from the corresponding HIV+ partners and of R5-primary HIV strains, but not that of CXCR4-tropic or amphitropic HIV strains. Immunoadsorption on CCR5-transfected, but not on CXCR4-transfected, cells removed CCR5-specific and virus-neutralizing Abs. Epitope mapping on purified CCR5-specific Abs showed that these Abs recognize a conformational epitope in the first cysteine loop of CCR5 (aa 89-102). Affinity-purified anti-CCR5-peptide neutralized the infectivity of R5 strains of HIV-1. Anti-CCR5 Abs inhibited Mip1beta-induced chemotaxis of PBMC from healthy donors. PBMC from two ESN (with anti-CCR5 Abs) were CCR5-negative and could not be stimulated by Mip1beta in chemotaxis assays. These results contribute to clarifying the phenomenon of immunologic resistance to HIV and may have implications for the development of a protective vaccine.
Lopalco
L
L
Department of Biological and Technological Research and Infectious Diseases Clinic, San Raffaele Scientific Institute, Milano, Italy. lopalco.lucia@hsr.it
Barassi
C
C
Pastori
C
C
Longhi
R
R
Burastero
S E
SE
Tambussi
G
G
Mazzotta
F
F
Lazzarin
A
A
Clerici
M
M
Siccardi
A G
AG
D001666:Binding Sites, Antibody; D001667:Binding, Competitive / Q000276:immunology; D065100:CCR5 Receptor Antagonists; D002464:Cell Migration Inhibition; D054407:Chemokine CCL4; D002634:Chemotaxis, Leukocyte / Q000276:immunology; D015536:Down-Regulation / Q000276:immunology*; D018604:Epitope Mapping; D005260:Female; D015483:HIV Antibodies / Q000097:blood / Q000302:isolation & purification / Q000502:physiology*; D018023:HIV Seronegativity / Q000276:immunology*; D006679:HIV Seropositivity / Q000276:immunology* / Q000635:transmission; D015497:HIV-1 / Q000276:immunology* / Q000472:pathogenicity; D006801:Humans; D007106:Immune Sera / Q000378:metabolism; D007163:Immunosorbent Techniques; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D019402:Macrophage Inflammatory Proteins / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism; D008297:Male; D009500:Neutralization Tests; D011485:Protein Binding / Q000276:immunology; D019713:Receptors, CCR5 / Q000096:biosynthesis / Q000276:immunology* / Q000378:metabolism; D012307:Risk Factors; D014774:Virulence / Q000276:immunology
D065100:CCR5 Receptor Antagonists; D054407:Chemokine CCL4; D015483:HIV Antibodies; D007106:Immune Sera; D019402:Macrophage Inflammatory Proteins; D019713:Receptors, CCR5