Limits...
Low-level HIV-1 replication and the dynamics of the resting CD4+ T cell reservoir for HIV-1 in the setting of HAART.

Sedaghat AR, Siliciano RF, Wilke CO - BMC Infect. Dis. (2008)

Bottom Line: Unfortunately, the latent reservoir decays slowly, with a half-life of up to 44 months, making it the major known obstacle to the eradication of HIV-1 infection.However, the mechanism underlying the long half-life of the latent reservoir is unknown.The most likely potential mechanisms are low-level viral replication and the intrinsic stability of latently infected cells.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Medicine, Johns Hopkins University School of Medicine, Baltimore Maryland 21205, USA. sedaghat@jhmi.edu

ABSTRACT

Background: In the setting of highly active antiretroviral therapy (HAART), plasma levels of human immunodeficiency type-1 (HIV-1) rapidly decay to below the limit of detection of standard clinical assays. However, reactivation of remaining latently infected memory CD4+ T cells is a source of continued virus production, forcing patients to remain on HAART despite clinically undetectable viral loads. Unfortunately, the latent reservoir decays slowly, with a half-life of up to 44 months, making it the major known obstacle to the eradication of HIV-1 infection. However, the mechanism underlying the long half-life of the latent reservoir is unknown. The most likely potential mechanisms are low-level viral replication and the intrinsic stability of latently infected cells.

Methods: Here we use a mathematical model of T cell dynamics in the setting of HIV-1 infection to probe the decay characteristics of the latent reservoir upon initiation of HAART. We compare the behavior of this model to patient derived data in order to gain insight into the role of low-level viral replication in the setting of HAART.

Results: By comparing the behavior of our model to patient derived data, we find that the viral dynamics observed in patients on HAART could be consistent with low-level viral replication but that this replication would not significantly affect the decay rate of the latent reservoir. Rather than low-level replication, the intrinsic stability of latently infected cells and the rate at which they are reactivated primarily determine the observed reservoir decay rate according to the predictions of our model.

Conclusion: The intrinsic stability of the latent reservoir has important implications for efforts to eradicate HIV-1 infection and suggests that intensified HAART would not accelerate the decay of the latent reservoir.

Show MeSH

Related in: MedlinePlus

Dependence of the latent reservoir decay rate, Λ, on the degree of residual viral replication, r, plotted as Λ vs. 1 - r, for parameter values: λ = 2 × 109 cells/day, αR = αQ/100, δU = 0.02 day-1, δL = 0.0001 day-1, and  = 1 × 10-4. We consider 3 different pairs of δP and αQ values. The predicted value of r*, color coded for each case, is marked at the top of the plot. The marker * indicates the similar r = βcrit/βuntreated value for every pair of δP and αQ.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC2254415&req=5

Figure 2: Dependence of the latent reservoir decay rate, Λ, on the degree of residual viral replication, r, plotted as Λ vs. 1 - r, for parameter values: λ = 2 × 109 cells/day, αR = αQ/100, δU = 0.02 day-1, δL = 0.0001 day-1, and = 1 × 10-4. We consider 3 different pairs of δP and αQ values. The predicted value of r*, color coded for each case, is marked at the top of the plot. The marker * indicates the similar r = βcrit/βuntreated value for every pair of δP and αQ.

Mentions: Further, we observe that Λ increases as A(1 - r)/(αR + B) until it approximately reaches its maximum (Λr = 0) when r = r* ≈ (δP - δL - αR - αQ)/δP, at which point the reservoir decay rate is virtually independent of β (Figure 2). This relationship between Λ and 1 - r, a consequence of the nonlinear structure of the model, reflects the threshold of viral replication. Once viral replication has been reduced to a level so low that the virus population cannot sustain itself anymore, the replenishment of the latent CD4+ T cell reservoir through ongoing replication becomes negligible and has virtually no effect on the reservoir decay rate. This relationship between Λ and 1 - r also holds for other parameter combinations and the predicted reservoir decay rates closely match simulation results. (Note that for β > βcrit, Λ describes the decay of the reservoir towards the new steady state, not towards zero.) In deriving an expression for the decay rate, we assume that the model parameters remain constant from when HAART is started. However, we also consider the consequences of linearizing around the post-HAART value of . At long time scales, the system might approach the post-HAART steady-state; therefore we must consider this possibility. For the case of β ≤ βcrit, we find that linearization around the post-HAART value of does not significantly change our previous calculations – the reservoir continues to decay at a constant rate determined by equation 11 except that r = βHAART/βcrit, which does not significantly change the numerical value of Λ. For the case of β > βcrit, linearization around the post-HAART value of leads to Λ ≈ 0 (because r → 1 in equation 11), suggesting a very slow (almost infinitely slow) decay of the latent reservoir near the post-HAART steady-state. These calculations predict that for the case of β > βcrit, the reservoir decay rate (as defined by the asymptotic eigenvalue of the equations defining our model) slows down as the post-HAART steady-state is achieved. Consistent with results that we have described in a previous study (regimes 1–3 of reference [27]), the decay of the resting CD4+ T cell reservoir cannot be accurately described as an exponential decay near the post-HAART steady-state in the setting of viral replication sufficient for continual replenishment of the reservoir (β > βcrit).


Low-level HIV-1 replication and the dynamics of the resting CD4+ T cell reservoir for HIV-1 in the setting of HAART.

Sedaghat AR, Siliciano RF, Wilke CO - BMC Infect. Dis. (2008)

Dependence of the latent reservoir decay rate, Λ, on the degree of residual viral replication, r, plotted as Λ vs. 1 - r, for parameter values: λ = 2 × 109 cells/day, αR = αQ/100, δU = 0.02 day-1, δL = 0.0001 day-1, and  = 1 × 10-4. We consider 3 different pairs of δP and αQ values. The predicted value of r*, color coded for each case, is marked at the top of the plot. The marker * indicates the similar r = βcrit/βuntreated value for every pair of δP and αQ.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2254415&req=5

Figure 2: Dependence of the latent reservoir decay rate, Λ, on the degree of residual viral replication, r, plotted as Λ vs. 1 - r, for parameter values: λ = 2 × 109 cells/day, αR = αQ/100, δU = 0.02 day-1, δL = 0.0001 day-1, and = 1 × 10-4. We consider 3 different pairs of δP and αQ values. The predicted value of r*, color coded for each case, is marked at the top of the plot. The marker * indicates the similar r = βcrit/βuntreated value for every pair of δP and αQ.
Mentions: Further, we observe that Λ increases as A(1 - r)/(αR + B) until it approximately reaches its maximum (Λr = 0) when r = r* ≈ (δP - δL - αR - αQ)/δP, at which point the reservoir decay rate is virtually independent of β (Figure 2). This relationship between Λ and 1 - r, a consequence of the nonlinear structure of the model, reflects the threshold of viral replication. Once viral replication has been reduced to a level so low that the virus population cannot sustain itself anymore, the replenishment of the latent CD4+ T cell reservoir through ongoing replication becomes negligible and has virtually no effect on the reservoir decay rate. This relationship between Λ and 1 - r also holds for other parameter combinations and the predicted reservoir decay rates closely match simulation results. (Note that for β > βcrit, Λ describes the decay of the reservoir towards the new steady state, not towards zero.) In deriving an expression for the decay rate, we assume that the model parameters remain constant from when HAART is started. However, we also consider the consequences of linearizing around the post-HAART value of . At long time scales, the system might approach the post-HAART steady-state; therefore we must consider this possibility. For the case of β ≤ βcrit, we find that linearization around the post-HAART value of does not significantly change our previous calculations – the reservoir continues to decay at a constant rate determined by equation 11 except that r = βHAART/βcrit, which does not significantly change the numerical value of Λ. For the case of β > βcrit, linearization around the post-HAART value of leads to Λ ≈ 0 (because r → 1 in equation 11), suggesting a very slow (almost infinitely slow) decay of the latent reservoir near the post-HAART steady-state. These calculations predict that for the case of β > βcrit, the reservoir decay rate (as defined by the asymptotic eigenvalue of the equations defining our model) slows down as the post-HAART steady-state is achieved. Consistent with results that we have described in a previous study (regimes 1–3 of reference [27]), the decay of the resting CD4+ T cell reservoir cannot be accurately described as an exponential decay near the post-HAART steady-state in the setting of viral replication sufficient for continual replenishment of the reservoir (β > βcrit).

Bottom Line: Unfortunately, the latent reservoir decays slowly, with a half-life of up to 44 months, making it the major known obstacle to the eradication of HIV-1 infection.However, the mechanism underlying the long half-life of the latent reservoir is unknown.The most likely potential mechanisms are low-level viral replication and the intrinsic stability of latently infected cells.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Medicine, Johns Hopkins University School of Medicine, Baltimore Maryland 21205, USA. sedaghat@jhmi.edu

ABSTRACT

Background: In the setting of highly active antiretroviral therapy (HAART), plasma levels of human immunodeficiency type-1 (HIV-1) rapidly decay to below the limit of detection of standard clinical assays. However, reactivation of remaining latently infected memory CD4+ T cells is a source of continued virus production, forcing patients to remain on HAART despite clinically undetectable viral loads. Unfortunately, the latent reservoir decays slowly, with a half-life of up to 44 months, making it the major known obstacle to the eradication of HIV-1 infection. However, the mechanism underlying the long half-life of the latent reservoir is unknown. The most likely potential mechanisms are low-level viral replication and the intrinsic stability of latently infected cells.

Methods: Here we use a mathematical model of T cell dynamics in the setting of HIV-1 infection to probe the decay characteristics of the latent reservoir upon initiation of HAART. We compare the behavior of this model to patient derived data in order to gain insight into the role of low-level viral replication in the setting of HAART.

Results: By comparing the behavior of our model to patient derived data, we find that the viral dynamics observed in patients on HAART could be consistent with low-level viral replication but that this replication would not significantly affect the decay rate of the latent reservoir. Rather than low-level replication, the intrinsic stability of latently infected cells and the rate at which they are reactivated primarily determine the observed reservoir decay rate according to the predictions of our model.

Conclusion: The intrinsic stability of the latent reservoir has important implications for efforts to eradicate HIV-1 infection and suggests that intensified HAART would not accelerate the decay of the latent reservoir.

Show MeSH
Related in: MedlinePlus