HIV entry is mediated by an interaction between CD4 and members of the chem
okine receptor family of proteins. It is likely that CD4 induces conformati
onal changes in the viral envelope glycoproteins that facilitate a subseque
nt interaction with the chemokine receptor. To understand these events, var
iants of HIV-2 and HIV-I have been derived that are able to interact direct
ly with CXCR4 in the absence of CD4. One HIV-2 variant, termed HIV-2/vcp, h
as an expanded host range that includes CXCR4(+)/CD4(-) lymphoid and nonlym
phoid cell lines. In contrast to T-tropic isolates of HIV-I, HIV-2/vcp was
shown to induce >95% downregulation of CXCR4 on chronically infected cells
and was able to superinfect HIV-l-infected cells. A variant of HIV-1/IIIB t
ermed HIV-1/IIIBx was also derived that is both replication competent and f
usogenic for a CD4-negative subclone of SupT1 cells, termed BC7. Infection
of BC7 cells by HIV-1/IIIBx was resistant to anti-CD4 monoclonal antibodies
but inhibited by the anti-CXCR4 mAb, 12G5. HIV-1/IIIBx was highly fusogeni
c on 3T3 cells expressing CXCR4 in the absence of CD4. In contrast to HIV-2
/vcp, the host range of HIV-1/IIIBx was highly restricted and replication i
n several CD4(+)/CXCR4(+) lymphoid cell lines was reduced compared to HIV-1
/IIIB. In addition, HIV-1/IIIBx failed to downregulate CXCR4 on chronically
infected cells. These studies indicate that HIV-1 and HIV-2 variants can b
e derived in vitro that utilize CXCR4 in the absence of CD4. Although the m
echanism(s) for these changes remain unclear, possibilities include an incr
eased avidity of the viral envelope glycoprotein for CXCR4 and/or the incre
ased exposure of the chemokine receptor binding site. Further biochemical a
nd molecular analysis of the envelope glycoproteins from these viruses shou
ld be helpful in addressing these and other possibilities. (C) 1998 Elsevie
r Science Ireland Ltd. All rights reserved.