Mutation L33M in the HR1 region of HIV-1 gp41 may play a role in T20 resistance.
BACKGROUND
Although Enfuvirtide (T20) has not been used in China, investigating the natural occurrence of primary resistance mutations in the HR1 region of the gp41 sequence from T20 naïve patients would help in determining treatment strategies for AIDS patients.


OBJECTIVE
To investigate natural mutations in the HR1 region of the gp41 sequence in China and evaluate their biological function.


METHODS
The amino acid sequences in the HR1 region of 27 isolates including subtypes AE, BC and B' from Chinese T20 naïve patients were analyzed. All 27 isolates were constructed into pseudoviruses and their susceptibility to T20 was measured by using recombinant virus assays.


RESULTS
Mutations in a 10 amino acid motif, such as N42S and N42R, and those outside this motif, such as L33M, R46S, A50V, Q52H and L54M, were found in the 27 isolates. N in position 42 was mutated to S in all three AE subtype strains and 17 of 18 subtype BC strains, whilst it was mutated to R in all 6 subtypes B strains. Compared to the SF162 strain, the susceptibility of the mutants, except for L33M, to T20 was not significantly different. After L was mutated to M in position 33 of six strains by site directed mutagenesis, their IC50 values were increased by 3.7-7.9-fold.


CONCLUSIONS
Mutations outside a 10 amino acid motif in HR1, such as L33M, may cause T20 resistance.
Chong
Huihui
H
Institute of Pathogen Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Xu
Sihong
S
Zhang
Chuntao
C
Nie
Jianhui
J
Wang
Youchun
Y
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution / Q000235:genetics; D019380:Anti-HIV Agents / Q000494:pharmacology*; D002681:China; D024882:Drug Resistance, Viral; D000077560:Enfuvirtide; D015700:HIV Envelope Protein gp41 / Q000235:genetics* / Q000494:pharmacology*; D015658:HIV Infections / Q000821:virology*; D015497:HIV-1 / Q000187:drug effects* / Q000302:isolation & purification; D006801:Humans; D020128:Inhibitory Concentration 50; D008826:Microbial Sensitivity Tests / Q000379:methods; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010446:Peptide Fragments / Q000494:pharmacology*; D017422:Sequence Analysis, DNA
D019380:Anti-HIV Agents; D015700:HIV Envelope Protein gp41; D010446:Peptide Fragments; C514787:gp41 protein, Human immunodeficiency virus 1; D000077560:Enfuvirtide