Biomedical Engineering Reference
In-Depth Information
30.0
Vehicle
Vehicle
2.3 ± 0.3
HAART
42.2
HAART
1.3 ± 0.4
NNVC 5
42.2
NNVC 5
1.2 ± 0.1
NNVC 4
44.3
NNVC 4
1.1 ± 0.2 g/mouse
20
30
Survival (days)
40
0
10
20
Total Body Weight Loss (g)
FIGURE 7.7
Effect.of.nanoviricides.treatment.on.survival.and.body.weight.loss.in.HIV-1.infected.SCID-hu.Thy/Liv.mice..
The.mortality.and.body.weight.of.the.mice.were.monitored..In.the.right-hand.graph,.the.results.are.expressed.
as.total.body.weight.loss.per.group,.and.the.mean.weight.loss.+.SEM/mouse.is.shown.to.the.right.of.the.bar,.
N.=.10.
greater.eficacy..Additionally,.we.are.not.aware.of.any.anti-HIV.drug.candidates.that.are.
superior.by.themselves.to.the.HAART.cocktail.
While. published. studies. of. this. model. report. no. lethality. in. HIV-infected,. SCID-Hu,.
Thy/Liv.mice,.others.have.found.lethality.similar.to.that.observed.by.us.(K..Menon,.per-
sonal.communication)..Of.note.in.our.study,.a.reduction.in.lethality.was.associated.with.
a.reduction.in.thymus.depletion..Also,.no.lethality.was.observed.in.Thy/Liv-implanted,.
but.uninfected.and.untreated,.SCID.mice.(group.of.six.mice.observed.for.60.days),.indi-
cating.that.lethality.was.associated.with.HIV.infection..One.possibility.is.a.preacquired.
infection.that.leads.to.death.upon.HIV.superinfection.in.this.model.(K..Menon,.personal.
communication)..Finally,.both.the.biochemical.and.clinical.parameters.in.the.NNVC.4.and.
5.treatment.groups.were.comparable.to.those.of.the.positive.control,.the.HAART.treatment.
group,.providing.credence.to.the.study.results.
The.ligands.we.have.designed.in.the.case.of.HIV-1.are.thought.to.be.broadly.neutral-
izing..In.silico.modeling.indicates.that.our.ligands.dock.to.the.CD4.binding.site.of.gp120.
from.the.HIV-1.JRFL.(HAART-resistant).strain..Further.study.is.needed.to.determine.the.
binding.interactions.in.silico.as.well.as.in.vitro.
If.the.results.of.this.study.can.be.extrapolated.to.humans,.then.it.is.likely.that.a.clinically.
relevant.dosing.frequency.such.as.once.weekly.i.v..injection.of.a.relatively.small.quantity.of.
an.appropriate.nanoviricide.may.be.equivalent.to.the.current.HAART.treatment.protocol..
Additionally,.the.putative.mechanism.of.nanoviricides.is.orthogonal.and.complementary.
to.the.mechanisms.of.existing.agents.(other.than.antibodies.and.fusion.inhibitors)..Thus,.
the.existing.intracellular.HIV.replication.inhibitors.could.be.combined.with.nanoviricide.
therapy.with.potentially.signiicant.advantages..It.is.not.unlikely.that.such.a.combination.
would.result.in.a.“functional.cure”.of.HIV,.wherein.the.clinical.pathology.of.HIV.is.elimi-
nated,.other.than.the.reservoirs.in.memory.cells,.allowing.the.patient.to.lead.a.normal.life,.
and.possibly.also.minimizing.the.spread.of.the.disease..It.is.interesting.to.note.here.that.
the.intracellular.viral.count.was.signiicantly.diminished.by.nanoviricide.treatments..This.
is.understandable.in.light.of.the.increased.CD4
+
/CD8
+
.double-positive.counts..The.newly.
formed.cells.may.have.been.protected.from.infection.by.HIV.particles.in.the.presence.of.
nanoviricide.treatment..HIV-1.is.capable.of.infecting.cells.by.cell-to-cell.direct-spread.mech-
anisms.in.cell.cultures..The.signiicance.of.this.pathway.in.vivo.is.not.known..However,.in.
this.model,.such.cell-to-cell.spread.could.account.for.the.small.amount.of.virus.particles.
still.found.inside.the.human.lymphoid.cells.in.nanoviricide-treated.animals.
