PMID- 10074102
OWN - NLM
STAT- MEDLINE
DCOM- 19990506
LR  - 20210107
IS  - 0022-538X (Print)
IS  - 0022-538X (Linking)
VI  - 73
IP  - 4
DP  - 1999 Apr
TI  - Effect of mutations in the second extracellular loop of CXCR4 on its utilization 
      by human and feline immunodeficiency viruses.
PG  - 2576-86
AB  - CCR5 and CXCR4 are the principal CD4-associated coreceptors used by human
      immunodeficiency virus type 1 (HIV-1). CXCR4 is also a receptor for the feline
      immunodeficiency virus (FIV). The rat CXCR4 cannot mediate infection by HIV-1NDK 
      or by FIVPET (both cell line-adapted strains) because of sequence differences
      with human CXCR4 in the second extracellular loop (ECL2). Here we made similar
      observations for HIV-189.6 (a strain also using CCR5) and for a primary HIV-1
      isolate. It showed the role of ECL2 in the coreceptor activity of CXCR4 for
      different types of HIV-1 strains. By exchanging ECL2 residues between human and
      rat CXCR4, we found that several amino acid differences contributed to the
      inactivity of the rat CXCR4 toward HIV-189.6. In contrast, its inactivity toward 
      HIV-1NDK seemed principally due to a serine at position 193 instead of to an
      aspartic acid (Asp193) in human CXCR4. Likewise, a mutation of Asp187 prevented
      usage of CXCR4 by FIVPET. Different mutations of Asp193, including its
      replacement by a glutamic acid, markedly reduced or suppressed the activity of
      CXCR4 for HIV-1NDK infection, indicating that the negative charge was not the
      only requirement. Mutations of Asp193 and of arginine residues (Arg183 and
      Arg188) of CXCR4 reduced the efficiency of HIV-1 infection for all HIV-1 strains 
      tested. Other ECL2 mutations tested had strain-specific effects or no apparent
      effect on HIV-1 infection. The ECL2 mutants allowed us to identify residues
      contributing to the epitope of the 12G5 monoclonal antibody. Overall, residues
      with different charges and interspersed in ECL2 seem to participate in the
      coreceptor activity of CXCR4. This suggests that a conformational rather than
      linear epitope of ECL2 contributes to the HIV-1 binding site. However, certain
      HIV-1 and FIV strains seem to require the presence of a particular ECL2 residue.
FAU - Brelot, A
AU  - Brelot A
AD  - INSERM U.332, Institut Cochin de Genetique Moleculaire, 75014 Paris, France.
FAU - Heveker, N
AU  - Heveker N
FAU - Adema, K
AU  - Adema K
FAU - Hosie, M J
AU  - Hosie MJ
FAU - Willett, B
AU  - Willett B
FAU - Alizon, M
AU  - Alizon M
LA  - eng
GR  - WT_/Wellcome Trust/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - J Virol
JT  - Journal of virology
JID - 0113724
RN  - 0 (Receptors, CXCR4)
SB  - IM
MH  - Amino Acid Sequence
MH  - Animals
MH  - Cats
MH  - HIV-1/*physiology
MH  - Humans
MH  - Immunodeficiency Virus, Feline/*physiology
MH  - Molecular Sequence Data
MH  - Mutation
MH  - Protein Conformation
MH  - Rats
MH  - Receptors, CXCR4/chemistry/*genetics
MH  - Virus Replication/*genetics
PMC - PMC104012
EDAT- 1999/03/12 00:00
MHDA- 1999/03/12 00:01
CRDT- 1999/03/12 00:00
PHST- 1999/03/12 00:00 [pubmed]
PHST- 1999/03/12 00:01 [medline]
PHST- 1999/03/12 00:00 [entrez]
AID - 10.1128/JVI.73.4.2576-2586.1999 [doi]
PST - ppublish
SO  - J Virol. 1999 Apr;73(4):2576-86. doi: 10.1128/JVI.73.4.2576-2586.1999.