AIDSWEEKLY Plus; Monday, September 7 & 14, 1998
Daniel J. DeNoon, Senior Editor
New data suggest that epitopes carried in the V3 loop of the HIV-1 envelope elicit antibodies. These antibodies don't seem to hurt HIV: but they attack and immobilize beta chemokines, the body's first-line defense against HIV infection.
"Our data indicate that anti-chemokine activities in the sera of HIV(+) patients are due to a cross-reaction of anti-V3-loop antibodies with chemokines," noted Caner Susal and colleagues of the University of Heidelberg, Germany.
Susal reported the findings at the 12th World AIDS Conference, held June 28-July 3, 1998, in Geneva, Switzerland.
Macrophage tropic (M-tropic) strains of HIV-1 require the CCR5 receptor to enter cells. The normal ligands for CCR5 are the beta chemokines RANTES, MIP-1(alpha), and MIP-1(beta). M-tropic HIV-1 causes the vast majority of infections and is the predominant form of the virus until just prior to the onset of AIDS, when T-cell-tropic (T-tropic) strains suddenly predominate and M-tropic strains virtually disappear. T-tropic HIV-1 preferentially uses the CXCR4 receptor for cell entry; the natural ligand for CXCR4 is the alpha chemokine SDF-1.
The beta chemokines are potent inhibitors of M-tropic HIV-1 infection, acting to down-regulate the CCR5 receptor. SDF-1 inhibits T-tropic HIV-1.
Susal et al. hypothesized that the humoral immune response to HIV is tricked into making antibodies against anti-HIV chemokines. They tested sera from HIV infected hemophilia patients for IgG anti- chemokine antibodies.
Their test was fairly rigorous: they defined positivity as enzyme-linked immunosorbent assay (ELISA) optical density scores greater than two standard deviations above the mean value obtained in healthy control subjects.
By this yardstick, 80 percent of the HIV(+) sera were positive for anti-MIP-1, 58 percent were positive for RANTES, and 50 percent were positive for SDF-1.
Interestingly, patients with CD4 counts of 50 cells/(micro)L or less had significantly lower levels of antibody to MIP-1 and RANTES than sera from patients with higher CD4 counts. But in the late-stage disease patients, anti-SDF-1 levels remained high.
"The disappearance of M-tropic virus in advanced disease causes a decrease in anti-beta-chemokine activity," Susal et al. suggested.
In patients with relatively normal CD4 counts (>500 cells/(micro)L), antibodies to beta chemokines were strongly associated with anti-V3 antibody activity and had a significant inverse correlation with CD4 counts.
Anti-RANTES isolated from five different patients showed that the sera cross-reacted with gp120 V3 peptides, and anti-V3 antibody cross reacted with MIP-1 and RANTES in vitro.
"Anti-chemokine activity may play a deleterious role in AIDS pathogenesis by reducing the chemokine's potential to inhibit HIV-1 entry into CD4(+) cells, especially in early disease," Susal concluded.
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