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HIV-1[15,16], HIV-2[17], FIV[18] and equine infectious anemia virus (EIAV)
have been tested[19].
Methods for transferring genes into hematopoietic cells must be tested in rel-
evant animal models before their application to humans [20,21]. Studies in non-
human primates (NH)P provide an ideal compromise, because these species are
phylogenetically closely related to humans and a high level of nucleotide sequence
identity is observed between the genes encoding many hematopoietic growth
factors and cytokines in these mammals and their counterparts in humans[22].
Moreover, hematopoiesis in macaques is very similar to that in humans, and the
HSC biology of macaques is much more similar to that of humans than is that of
rodents, making macaques good candidates for hematopoietic stem cell engraft-
ment studies [23-26]. In addition, testing lentiviral based gene transfer strategies
need to be assessed in species that are susceptible to lentivirus induced disease. Or
particular interest are the Feline immunodeficiency virus (FIV) infection which
causes a clinical disease in cats that is remarkably similar to HIV disease in human
[27-30] and experimental infection of macaques with the simian immunodefi-
ciency virus (SIV) reproducing both chronic infection and an AIDS-like disease
very similar to those observed in human patients infected with HIV. Despite the
theoretical advantages of lentiviral vectors over oncoretroviral vectors, non human
primate lentiviruses clearly have pathogenic properties [31]. The use of lentivi-
ral vectors derived from potentially pathogenic primate lentiviruses, such as SIV,
therefore continues to raise serious clinical acceptance concerns. SIV-based vec-
tors, such as SIVmac239[31,32] and SIVmac251[33,34], may provide a unique
opportunity to test the safety and efficacy of primate lentiviral vectors in vivo.
Recent improvements in the efficiency of gene transfer to NHP repopulat-
ing cells[11,35,36] have provided new opportunities to follow the progeny of
each primitive progenitor and stem cells directly in vivo, using retroviral marking
to track individual progenitor or stem cell clones[37]. Clinically relevant levels
(around 10%) of genetically modified cells in the peripheral blood have been
achieved by ex vivo gene transfer into HSC and the autologous transplantation
of these cells into macaques[37]. Successful and persistent engraftment (up to six
months) has also been reported in non human primates with primitive CD34+
progenitors genetically modified with a murine retrovirus vector encoding the
murine CD24 gene as a reporter gene[38]. In both trials, marked cells of multiple
hematopoietic lineages were identified in the blood: granulocytes, monocytes and
B and T cells, including naive T lymphocytes[37,38]. The efficacy of HSC gene
transfer could theoretically be improved by the use of newly developed retroviral
or lentiviral vectors. Particles bearing an alternative envelope protein, such as that
of the feline endogenous virus (RD114), have been shown to be superior to am-
photropic vectors for the transduction of NHP stem cells followed by autologous
transplantation [39,40].
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