Mechanisms of HIV-1 subtype C resistance to GRFT, CV-N and SVN.
We examined the ability of HIV-1 subtype C to develop resistance to the inhibitory lectins, griffithsin (GRFT), cyanovirin-N (CV-N) and scytovirin (SVN), which bind multiple mannose-rich glycans on gp120. Four primary HIV-1 strains cultured under escalating concentrations of these lectins became increasingly resistant tolerating 2 to 12 times their 50% inhibitory concentrations. Sequence analysis of gp120 showed that most had deletions of 1 to 5 mannose-rich glycans. Glycosylation sites at positions 230, 234, 241, 289 located in the C2 region and 339, 392 and 448 in the C3-C4 region were affected. Furthermore, deletions and insertions of up to 5 amino acids in the V4 region were observed in 3 of the 4 isolates. These data suggest that loss of glycosylation sites on gp120 as well as rearrangement of glycans in V4 are mechanisms involved in HIV-1 subtype C escape from GRFT, CV-N and SVN.
Centre for HIV and STIs, National Institute for Communicable Diseases, Johannesburg, South Africa; University of the Witwatersrand, Johannesburg, South Africa.
Kabamba B
KB
Alexandre
Penny L
PL
Moore
Molati
M
Nonyane
Elin S
ES
Gray
Nthabeleng
N
Ranchobe
Ereck
E
Chakauya
James B
JB
McMahon
Barry R
BR
O'Keefe
Rachel
R
Chikwamba
Lynn
L
Morris
D000998:Antiviral Agents / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000494:pharmacology*; D002352:Carrier Proteins / Q000494:pharmacology*; D002460:Cell Line; D024882:Drug Resistance, Viral; D004361:Drug Tolerance; D006031:Glycosylation; D015699:HIV Envelope Protein gp120 / Q000235:genetics; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development; D006801:Humans; D020128:Inhibitory Concentration 50; D037102:Lectins / Q000494:pharmacology*; D008565:Membrane Proteins; D008826:Microbial Sensitivity Tests; D050505:Mutant Proteins / Q000235:genetics; D020125:Mutation, Missense; D037121:Plant Lectins / Q000494:pharmacology*; D017422:Sequence Analysis, DNA; D012692:Serial Passage
D000998:Antiviral Agents; D001426:Bacterial Proteins; D002352:Carrier Proteins; D015699:HIV Envelope Protein gp120; D037102:Lectins; D008565:Membrane Proteins; D050505:Mutant Proteins; D037121:Plant Lectins; C514793:gp120 protein, Human immunodeficiency virus 1; C474342:scytovirin protein, S varium; C107733:cyanovirin N; C499654:griffithsin protein, Griffithsia
Cyanovirin-N; Entry inhibitor; Glycans; Griffithsin; HIV subtype C; Microbicide; Resistance; Scytovirin; Single genome amplification