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HIV-1 variants with reduced sensitivity to sulfated oligosaccharide muparfostat contain mutations in the envelope glycoproteins gp120 and gp41

Journal article
Authors Joanna Said
Elin Andersson
Edward Trybala
Tomas Bergström
Published in Journal of Antivirals and Antiretrovirals
Volume 5
Issue 3
Pages 50-56
ISSN 1948-5964
Publication year 2013
Published at Institute of Biomedicine, Department of Infectious Medicine
Pages 50-56
Language en
Keywords Escape variants, gp120, gp41, HIV-1, Muparfostat, Resistance, glycoprotein gp 120, glycoprotein gp 41, heparin derivative, protein p21, protein variant, unclassified drug, amino acid substitution, antiviral activity, article, cell culture, controlled study, enzyme linked immunosorbent assay, gene mutation, gene sequence, glycosylation, human, human cell, Human immunodeficiency virus 1, IC 50, nucleotide sequence, point mutation, polymerase chain reaction, reverse transcription polymerase chain reaction, virus isolation, virus replication
Subject categories Infectious Medicine


Attachment of human immunodefciency virus type 1 (HIV-1) to host cells is primarily mediated by cell surface molecules CD4 and either of the chemokine co-receptors CCR5 or CXCR4, and is facilitated by cellular heparansulfate chains of syndecans. Although mimetics of heparansulfate exhibit potent anti-HIV-1 activity in cultured cells, these compounds failed to prevent infection in humans when used in clinical trials as microbicides. We have previously shown that the low molecular weight and extensively sulfated oligosaccharide muparfostat coupled to cholestanol exhibited virucidal activity while the non-conjugated muparfostat (formerly known as PI-88) inhibited HIV-1 infection of cultured cells in a reversible manner only. To initiate clarifcation of distinct anti-HIV-1 potencies of muparfostat and muparfostat-cholestanol conjugate, in this work we sought to select for viral resistance using the less potent muparfostat. The laboratory strain HIV-1IIIB was successively propagated in H9 cells in the presence of the compound. The virus selected for after 21-24 passages appeared to be approximately 3-4 times less sensitive to muparfostat than the original HIV-1IIIB strain or control virus passaged in parallel in the absence of muparfostat. Comparative analysis of nucleotide sequences of these viruses revealed presence of the I152V substitution in V2, the K276R change in V3, the deletion of fve amino acid repeat 366FNSTW370 in V4 of gp120, and the L33S and A101T alterations in transmembrane gp41 component of the muparfostat passaged virus. Selection for viral variants with mutations in gp41 was an unexpected observation as this protein of HIV-1 is seldom targeted by sulfated polysaccharides. © 2013 Said J, et al.

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