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Immuno-modulatory strategies for reduction of HIV reservoir cells.

  • HT Banks
  • Kevin B Flores
  • Shuhua Hu
  • Eric Rosenberg
  • Maria Buzon
  • Xu Yu
  • Matthias Lichterfeld
J. Theor. Biol. 2015; 372 : 146-158
Abstract
Antiretroviral therapy is able to suppress the viral load to below the detection limit, but it is not able to eradicate HIV reservoirs. Thus, there is a critical need for a novel treatment to eradicate (or reduce) the reservoir in order to eliminate the need for a lifelong adherence to antiretroviral therapy, which is expensive and potentially toxic. In this paper, we investigate the possible pharmacological strategies or combinations of strategies that may be beneficial to reduce or possibly eradicate the latent reservoir. We do this via studies with a validated mathematical model, where the parameter values are obtained with newly acquired clinical data for HIV patients. Our findings indicate that the strategy of reactivating the reservoir combined with enhancement of the killing rate of HIV-specific CD8+ T cells is able to eradicate the reservoir. In addition, our analysis shows that a targeted suppression of the immune system is also a possible strategy to eradicate the reservoir.

Unit definitions have no effect on the numerical analysis of the model. It remains the responsibility of the modeler to ensure the internal numerical consistency of the model. If units are provided, however, the consistency of the model units will be checked.

Name Definition
Id Name Spatial dimensions Size
default 1.0
Id Name Initial quantity Compartment Fixed
E1 0.0682 default
E2 0.691 default
T1 79.5 default
T2 289.0 default
Tstar1 58.2 default
Tstar2 0.0654 default
Ttot 426.7654 default
VI 150000.0 default
VNI 3570.0 default

Initial assignments are expressions that are evaluated at time=0. It is not recommended to create initial assignments for all model entities. Restrict the use of initial assignments to cases where a value is expressed in terms of values or sizes of other model entities. Note that it is not permitted to have both an initial assignment and an assignment rule for a single model entity.

Definition
Id Name Objective coefficient Reaction Equation and Kinetic Law Flux bounds
v1 T1 + Ttot = ∅

d1*T1
v10 ∅ = Tstar1 + Ttot

(aTS*pT*Tstar2*VI)/(KV + VI)
v11 ∅ = Tstar1 + Ttot

aAS*pT*Tstar2
v12 ∅ = T2 + Ttot

(KS*lambdaT)/(KS + VI)
v13 ∅ = T2 + Ttot

gammaT*T1
v14 T2 + Ttot = ∅

d2*T2
v15 T2 = Tstar2

k2*T2*VI
v16 Tstar2 = T2

f*k2*zeta1*T2*VI
v17 T2 + Ttot = ∅

(aT*T2*VI)/(KV + VI)
v18 T2 + Ttot = ∅

aA*T2
v19 Tstar2 + Ttot = ∅

d2*Tstar2
v2 T1 = Tstar1

k1*T1*VI
v20 Tstar2 + Ttot = ∅

(aTS*Tstar2*VI)/(KV + VI)
v21 Tstar2 + Ttot = ∅

aAS*Tstar2
v22 ∅ = VI

1000*delta*NT*Tstar1
v23 VI = VNI

1000*delta*NT*zeta2*Tstar1
v24 VI = ∅

c*VI
v25 VI = ∅

1000*k1*rho1*T1*VI
v26 ∅ = VI

1000*k1*rho1*zeta1*T1*VI
v27 VI = ∅

1000*k2*rho2*T2*VI
v28 ∅ = VI

1000*f*k2*rho2*zeta1*T2*VI
v29 VNI = ∅

c*VNI
v3 Tstar1 = T1

k1*zeta1*T1*VI
v30 ∅ = E1

lambdaE
v31 ∅ = E1

(bE1*E1*Tstar1)/(Kb1 + Tstar1)
v32 E1 = ∅

(dE*E1*Tstar1)/(Kd + Tstar1)
v33 E1 = ∅

deltaE1*E1
v34 E1 = E2

(gammaE*E1*(T1 + Tstar1))/(Kgamma + T1 + Tstar1)
v35 ∅ = E1

(aE*pE*E2*VI)/(KV + VI)
v36 ∅ = E2

(bE2*Kb2*E2)/(Kb2 + E2)
v37 E2 = ∅

deltaE2*E2
v38 E2 = ∅

(aE*E2*VI)/(KV + VI)
v4 T1 + Ttot = ∅

gammaT*T1
v5 ∅ = T1 + Ttot

(aT*pT*T2*VI)/(KV + VI)
v6 ∅ = T1 + Ttot

aA*pT*T2
v7 Tstar1 + Ttot = ∅

delta*Tstar1
v8 Tstar1 + Ttot = ∅

m*E1*Tstar1
v9 Tstar1 = Tstar2

gammaTS*Tstar1

Global parameters

Id Value
KS 27900.0
KV 1060.0
Kb1 0.0249
Kb2 87.0
Kd 0.12
Kgamma 1.36
NT 11.7
aA 0.00407
aAS 0.0000958
aE 0.0168
aT 0.00985
aTS 0.000449
bE1 0.0693
bE2 0.0061
c 12.7
d1 0.0912
d2 0.0031
dE 0.0472
delta 0.171
deltaE1 0.0597
deltaE2 0.00145
f 0.507
gammaE 0.000689
gammaT 0.000646
gammaTS 0.00000798
k1 0.00000797
k2 0.0000000105
lambdaE 0.000488
lambdaT 8.66
m 1.1
pE 0.395
pT 9.85
rho1 1.0
rho2 1.0
viruscopiesperml
zeta1 0.524
zeta2 0.16

Local parameters

Id Value Reaction

Assignment rules

Definition
viruscopiesperml = VNI + VI

Rate rules

Definition

Algebraic rules

Definition
Trigger Assignments