Centre for Virus Research, The Westmead Millennium Institute, University of Sydney, and The Australian National Centre for HIV Research, Sydney, Australia
Correspondence: Anthony L. Cunningham, The Westmead Millennium Institute, P.O. Box 412, Westmead NSW 2145, Sydney, Australia. E-mail: tony_cunningham{at}wmi.usyd.edu.au
The outcome of HIV infection in vivo and in
vitro depends on the interaction of viral and cellular genotypes.
Analysis of infection of blood monocyte-derived macrophages by primary
HIV strains shows that approximately one-third of 32 isolates was
consistently high-replicating, one-third was consistently
low-replicating, and one-third was dependent on the donor of the
macrophages (i.e., variable). HIV isolates from patients with AIDS
showed enhanced replication within macrophages and predominant use of
CCR5 for entry, although 13% did use CXCR4. Tissue isolates from brain
and CSF showed an enhanced ability to infect 1-day-old monocytes
compared with blood isolates from patients with AIDS. The ability of
primary isolates to infect neonatal or adult monocytes maturing into
macrophages or placental macrophages correlated directly with the
extent of CCR5 expression. Studies of macrophages from pairs of
identical twins and unrelated donors showed genetic control over CCR5
expression, which was independent of the CCR5
32 genotype.
Furthermore, these studies showed a marked host-cell genetic effect on
the variable primary HIV strains. Although CCR5 was essential for the
entry of most primary isolates, it was not the essential
"bottleneck" determining productivity of infection. The location of
this bottleneck in the HIV replication cycle differs according to viral
strain and host-cell donor, but it was exerted before the stage of
reverse transcription in 80–90% of cases. Such host-cell genetic
factors may affect viral load in vivo where macrophages are
the predominant target cells.
Key Words: genetics • twins • monocytes
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