Activity of alpha- and theta-defensins against primary isolates of HIV-1.
Theta-defensins are lectin-like, cyclic octadecapeptides found in the leukocytes of nonhuman primates. They are also homologues of the more familiar alpha-defensins expressed by humans and certain other mammals. This study compares the ability of six theta-defensins (hominid retrocyclins 1-3 and rhesus theta-defensins 1-3) and four human alpha-defensins (human neutrophil peptides (HNPs) 1-4) to bind gp120 and CD4. In addition, we compared the ability of these theta-defensins and HNP-1 to protect J53-BL cells (an indicator cell line) from primary HIV-1 isolates that varied in subtype and coreceptor usage. The most potent theta-defensin, retrocyclin-2, bound with exceptionally high affinity to gp120 (K(D), 9.4 nM) and CD4 (K(D), 6.87 nM), and its effectiveness against subtype B isolates (IC(50), 1.05 +/- 0.28 microg/ml; 520 +/- 139 nM) was approximately twice as great as that of HNP-1 on a molar basis. We also show, for the first time, that human alpha-defensins, HNPs 1-3, are lectins that bind with relatively high affinity to gp120 (K(D) range, 15.8-52.8 nM) and CD4 (K(D) range, 8.0-34.9 nM). Proteins found in human and FBS bound exogenous HNP-2 and retrocyclin-1, and competed with their ability to bind gp120. However, even the low concentrations of alpha-defensins found in normal human serum suffice to bind over half of the gp120 spikes on HIV-1 and a higher percentage of cell surface CD4 molecules. Although this report principally concerns the relationship between carbohydrate-binding and the antiviral properties of alpha- and theta-defensins, the lectin-like behavior of defensins may contribute to many other activities of these multifunctional peptides.
Wang
Wei
W
Department of Medicine, David Geffen School of Medicine at University of California-Los Angeles, 10833 LeConte Avenue, Los Angeles, CA 90095, USA.
Owen
Sherry M
SM
Rudolph
Donna L
DL
Cole
Alexander M
AM
Hong
Teresa
T
Waring
Alan J
AJ
Lal
Renu B
RB
Lehrer
Robert I
RI
D000595:Amino Acid Sequence; D015704:CD4 Antigens / Q000378:metabolism; D023082:Defensins / Q000494:pharmacology*; D015699:HIV Envelope Protein gp120 / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D008969:Molecular Sequence Data; D023084:alpha-Defensins / Q000494:pharmacology*
D015704:CD4 Antigens; D023082:Defensins; D015699:HIV Envelope Protein gp120; D023084:alpha-Defensins; C450142:theta-defensin