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

• 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.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Infektionsmedicin (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Infectious Medicine (hsv//eng)

Nyckelord

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

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