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Journal of Virology, September 1998, p. 7099-7107, Vol. 72, No. 9
Department of Preventive Medicine and Biometrics, Uniformed
Services University of the Health Sciences, Bethesda, Maryland
208141;
Center for Biologics Evaluation
and Research, Food and Drug Administration, Bethesda, Maryland
208502; and
Laboratory of Molecular
Microbiology, National Institutes of Allergy and Infectious
Diseases, Bethesda, Maryland 208923
Received 20 March 1998/Accepted 1 June 1998
The escape of human immunodeficiency virus type 1 from effects of
neutralizing antibodies was studied by using neutralization-resistant (NR) variants generated by growing the neutralization-sensitive (NS)
wild-type MN virus in the presence of human serum with neutralizing antibodies, more than 99% of which were directed at the V3 region of
gp120. The variants obtained had broad neutralization resistance to
human sera, without limitation with respect to the V3 specificity of
the sera. The molecular basis for the resistance was evaluated with
molecularly cloned viruses, as well as with pseudoviruses expressing
envelope glycoproteins of the NS and NR phenotypes. Nucleotide sequence
analyses comparing NS and NR clones revealed a number of polymorphisms,
including six in the V1/V2 region, two in C4/V5 of gp120, three in the
leucine zipper (LZ) domain of gp41, and two in the second external
putative
0022-538X/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
Mutations in both gp120 and gp41 Are Responsible for the Broad
Neutralization Resistance of Variant Human Immunodeficiency Virus
Type 1 MN to Antibodies Directed at V3 and Non-V3
Epitopes

-helix region of gp41. A series of chimeras from NS and NR
env genes was constructed, and each was presented on
pseudoviruses to locate the domain(s) which conferred the phenotypic
changes. The neutralization phenotypes of the chimeric clones were
found to be dependent on mutations in both the C4/V5 region of gp120
and the LZ region of gp41. Additionally, interaction between mutations
in gp120 and gp41 was demonstrated in that a chimeric env
gene consisting of a gp120 coding sequence from an NS clone and a gp41
sequence from an NR clone yielded a pseudovirus with minimal
infectivity. The possible significance of predicted amino acid changes
in these domains is discussed. The results indicate that polyvalent
antibodies predominantly directed against V3 can induce NR through
selection for mutations that alter interactions of other domains in the
envelope complex.
*
Corresponding author. Mailing address: Department of
Preventive Medicine and Biometrics, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Rd., Bethesda, MD 20814. Phone:
(301) 295-3734. Fax: (301) 295-1971. E-mail:
Quinnan{at}USUHSB.USUHS.mil.
Present address: Division of Research Grants, National Institutes
of Health, Bethesda, Md.
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