Abstract
Human defensins are at the forefront of the host responses to HIV and other pathogens in mucosal tissues. However, their ability to inactivate HIV in the bloodstream has been questioned due to the antagonistic effect of serum. In this study, we have examined the effect of sub-inhibitory concentrations of human α-defensin HNP-1 on the kinetics of early steps of fusion between HIV-1 and target cells in the presence of serum. Direct measurements of HIV-cell fusion using an enzymatic assay revealed that, in spite of the modest effect on the extent of fusion, HNP-1 prolonged the exposure of functionally important transitional epitopes of HIV-1 gp41 on the cell surface. The increased lifetime of gp41 intermediates in the presence of defensin was caused by a delay in the post-coreceptor binding steps of HIV-1 entry that correlated with the marked enhancement of the virus' sensitivity to neutralizing anti-gp41 antibodies. By contrast, the activity of antibodies to gp120 was not affected. HNP-1 appeared to specifically potentiate antibodies and peptides targeting the first heptad repeat domain of gp41, while its effect on inhibitors and antibodies to other gp41 domains was less prominent. Sub-inhibitory concentrations of HNP-1 also promoted inhibition of HIV-1 entry into peripheral blood mononuclear cells by antibodies and, more importantly, by HIV-1 immune serum. Our findings demonstrate that: (i) sub-inhibitory doses of HNP-1 potently enhance the activity of a number of anti-gp41 antibodies and peptide inhibitors, apparently by prolonging the lifetime of gp41 intermediates; and (ii) the efficiency of HIV-1 fusion inhibitors and neutralizing antibodies is kinetically restricted. This study thus reveals an important role of α-defensin in enhancing adaptive immune responses to HIV-1 infection and suggests future strategies to augment these responses.
Highlights
HIV envelope glycoprotein (Env) is a trimer each monomer of which consists of non-covalently associated transmembrane and surface subunits [1]
We demonstrate that sub-inhibitory doses of Human neutrophil peptide 1 (HNP-1) in the presence of serum can strongly enhance the activity of neutralizing antibodies and inhibitors targeting transiently exposed intermediate conformations of HIV-1 gp41
HNP-1 appears to exert this effect by delaying post-coreceptor binding steps of fusion and thereby prolonging the exposure of gp41 intermediates
Summary
HIV envelope glycoprotein (Env) is a trimer each monomer of which consists of non-covalently associated transmembrane (gp41) and surface (gp120) subunits [1]. The lifetime of PHIs on the cell surface is a function of the relative rates of their formation upon CD4 binding and disappearance, which could be due to: (i) conversion to 6HBs upon virus fusion with the plasma membrane and/or (ii) virus clearance from the cell surface followed by fusion with endosomes [15]. The former pathway is operational in a cellcell fusion model (e.g., [8,16]), whereas the second mechanism appears to be responsible for the HIV-1 escape from peptide inhibitors [10,15] (see below)
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