Human immunodeficiency virus (HIV) gp41 escape mutants: cross-resistance to peptide inhibitors of HIV fusion and altered receptor activation of gp120.
Human immunodeficiency virus (HIV) infects cells by fusing with cellular membranes. Fusion occurs when the envelope glycoprotein (Env) undergoes conformational changes while binding to cellular receptors. Fusogenic changes involve assembly of two heptad repeats in the ectodomain of the gp41 transmembrane subunit to form a six-helix bundle (6HB), consisting of a trimeric N heptad repeat (N-HR) coiled-coil core with three antiparallel C heptad repeats (C-HRs) that pack in the coiled-coil grooves. Peptides corresponding to the N-and C-HRs (N and C peptides, respectively) interfere with formation of the 6HB in a dominant-negative manner and are emerging as a new class of antiretroviral therapeutics for treating HIV infection. We generated an escape mutant virus with resistance to an N peptide and show that early resistance involved two mutations, one each in the N- and C-HRs. The mutations conferred resistance not only to the selecting N peptide but also to C peptides, as well as other types of N-peptide inhibitors. Moreover, the N-HR mutation altered sensitivity to soluble CD4. Biophysical studies suggest that the 6HB with the resistance mutations is more stable than the wild-type 6HB and the 6HB formed by inhibitor binding to either wild-type or mutant C-HR. These findings provide new insights into potential mechanisms of resistance to HIV peptide fusion inhibitors and dominant-negative inhibitors in general. The results are discussed in the context of current models of Env-mediated membrane fusion.
Desmezieres
Emmanuel
E
U.S. Food and Drug Administration, Center for Biologics Evaluation and Research, HFM-466, Bldg. 29, Room 532, 8800 Rockville Pike, Bethesda, MD 20892-4555, USA.
Gupta
Nidhi
N
Vassell
Russell
R
He
Yong
Y
Peden
Keith
K
Sirota
Lev
L
Yang
Zhongning
Z
Wingfield
Paul
P
Weiss
Carol D
CD
D000595:Amino Acid Sequence; D015704:CD4 Antigens / Q000276:immunology; D002460:Cell Line; D002942:Circular Dichroism; D015699:HIV Envelope Protein gp120 / Q000502:physiology*; D015700:HIV Envelope Protein gp41 / Q000235:genetics*; D015658:HIV Infections / Q000517:prevention & control; D006801:Humans; D007668:Kidney; D008969:Molecular Sequence Data; D009154:Mutation; D011489:Protein Denaturation; D019718:Receptors, CXCR4 / Q000276:immunology; D015728:Receptors, HIV / Q000502:physiology*
D015704:CD4 Antigens; D015699:HIV Envelope Protein gp120; D015700:HIV Envelope Protein gp41; D019718:Receptors, CXCR4; D015728:Receptors, HIV