Anti-CCR5 gene targeting Ref Evidence Benefits Limits
Natural Delta32
homozygosis
[2-6] Spontaneous mutation occurring
in 4-18% of European and
Askenazi Jews people.
Not found in Asian and Pacific
indigens.
Lack of CCR5 surface
expression.
No signs of immune alterations.
Resistance to R5 HIV infection.
No resistance to X4 or dual R5/X4
strains.
High sensitivity to West Nile virus
and tick-borne encephalitis.
Transplantation of CCR5-/-
cells (HST or T
lymphocytes)
[19, 20,
29]
Clinical infusion of modified
cells in patients undergoing
cytoreductive treatment.
Resistance to HIV infection.
Long-term cell survival
GI mucosal colonization.
Brain colonization
Reduction of HIV reservoirs ?
Heritable DNA modification.
Definitive cell cure .
Off-target genotoxicity (e.g. CCR2).
Oncogenesis.
CXCR4 is required for HSC
maturation in bone marrow.
Multiple treatment cycles ?
Selection of resistant strains.
Mucosal efficacy?
CCR5 and/or CXCR4 KO
by Zn-finger Nucleases in
T cells
[29] Ex vivo transient expression of
viral vectors carrying ZFNs
Resistance to HIV infection.
Mucosal protection?
Reduction of HIV reservoirs ?
Definitive cell cure ?
Off-target toxicity
Insertional mutagenesis?
Lentivirus-induced activation or
mobilization of endogenous LTR?
Unknown long-term safety issues.
CCR5 KO
by TALENs or CRISPRs in
T cells
  Preclinical study in mice
receiving ex vivo modified T
cells
Lower off-target activity than
ZFNs.
Double CCR5+CXCR4
KO
by ZFNs in T cells
  Ex vivo trial Total resistance to HIV
infection.
Ribozymes   In vitro
Ex vivo trial
Preventing CCR5 expression. Lentivirus-induced activation or
mobilization of endogenous LTR?
Intrabodies-mediated
CCR5 intracellular
retention
  Ex vivo assay Preventing CCR5 expression.
Resistance to R5-HIV infection.
Excess of intracellular protein
entrapment
Table 1: Anti-CCR5 gene/expression targeting.
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