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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.

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Decay of the latent reservoir as a function of time for (A) different degrees of HAART suppression of viral infectivity, r = 0 (black), 0.769 (βcrit/βuntreated) (blue), 0.80 (green), 0.90 (red); and (B) different activation rates, αQ = 0.0005 day-1 (black), 0.001 day-1 (blue), 0.0025 day-1 (green) and 0.005 day-1 (red). Parameter values, unless otherwise specified, are: λ = 2 × 109 cells/day, β = 0, αQ = 0.0005 day-1, αR = αQ/100, δU = 0.02 day-1, δP = 0.50 day-1, δL = 0.0001 day-1 and  = 1 × 10-4.
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Figure 4: Decay of the latent reservoir as a function of time for (A) different degrees of HAART suppression of viral infectivity, r = 0 (black), 0.769 (βcrit/βuntreated) (blue), 0.80 (green), 0.90 (red); and (B) different activation rates, αQ = 0.0005 day-1 (black), 0.001 day-1 (blue), 0.0025 day-1 (green) and 0.005 day-1 (red). Parameter values, unless otherwise specified, are: λ = 2 × 109 cells/day, β = 0, αQ = 0.0005 day-1, αR = αQ/100, δU = 0.02 day-1, δP = 0.50 day-1, δL = 0.0001 day-1 and = 1 × 10-4.

Mentions: For values of β that are consistent with clinically observed viral load decay characteristics in the setting of HAART, the reservoir decay rate remains essentially constant at Λr = 0 Because Λr = 0 ≈ B = αQ + δL, the major determinants of the reservoir decay rate are the activation rate and the intrinsic death rate of latently infected cells. We used our model to compare the potential for increasing the decay rate of the latent reservoir by enhanced inhibition of viral infectivity, which would occur in the setting of intensified HAART, to enhanced reactivation of latently infected cells, a therapeutic option that is currently being developed [50-52]. Figure 4A describes the case of viral inhibition by HAART. For non-suppressive reductions in the infectivity (r > βcrit/β), the decay dynamics of the latent reservoir diverge from an exponential decay and asymptotically move toward a non-zero steady-state number of latently infected cells. However, for a suppressive reduction in infectivity (r <βcrit/β), the latent reservoir decays exponentially with a rate constant equal to B = αQ + δL towards zero latently infected cells (Figure 4A). Our model therefore predicts that any drug or drug combination reducing HIV infectivity by a factor r <βcrit/β will cause the latent reservoir to decay with the same dynamics. We do not know the value of r for current HAART regimens, although our analysis suggests that r <βcrit/β. Nonetheless, we must consider the possibility that r > 0, in which case intensified HAART may further reduce r without hastening the decay of the latent reservoir. It is also possible that standard HAART regimens reduce infectivity such that r = 0 (i.e. βHAART = 0), in which case intensification of standard HAART regimens would have no conceivable benefit.


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)

Decay of the latent reservoir as a function of time for (A) different degrees of HAART suppression of viral infectivity, r = 0 (black), 0.769 (βcrit/βuntreated) (blue), 0.80 (green), 0.90 (red); and (B) different activation rates, αQ = 0.0005 day-1 (black), 0.001 day-1 (blue), 0.0025 day-1 (green) and 0.005 day-1 (red). Parameter values, unless otherwise specified, are: λ = 2 × 109 cells/day, β = 0, αQ = 0.0005 day-1, αR = αQ/100, δU = 0.02 day-1, δP = 0.50 day-1, δL = 0.0001 day-1 and  = 1 × 10-4.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 4: Decay of the latent reservoir as a function of time for (A) different degrees of HAART suppression of viral infectivity, r = 0 (black), 0.769 (βcrit/βuntreated) (blue), 0.80 (green), 0.90 (red); and (B) different activation rates, αQ = 0.0005 day-1 (black), 0.001 day-1 (blue), 0.0025 day-1 (green) and 0.005 day-1 (red). Parameter values, unless otherwise specified, are: λ = 2 × 109 cells/day, β = 0, αQ = 0.0005 day-1, αR = αQ/100, δU = 0.02 day-1, δP = 0.50 day-1, δL = 0.0001 day-1 and = 1 × 10-4.
Mentions: For values of β that are consistent with clinically observed viral load decay characteristics in the setting of HAART, the reservoir decay rate remains essentially constant at Λr = 0 Because Λr = 0 ≈ B = αQ + δL, the major determinants of the reservoir decay rate are the activation rate and the intrinsic death rate of latently infected cells. We used our model to compare the potential for increasing the decay rate of the latent reservoir by enhanced inhibition of viral infectivity, which would occur in the setting of intensified HAART, to enhanced reactivation of latently infected cells, a therapeutic option that is currently being developed [50-52]. Figure 4A describes the case of viral inhibition by HAART. For non-suppressive reductions in the infectivity (r > βcrit/β), the decay dynamics of the latent reservoir diverge from an exponential decay and asymptotically move toward a non-zero steady-state number of latently infected cells. However, for a suppressive reduction in infectivity (r <βcrit/β), the latent reservoir decays exponentially with a rate constant equal to B = αQ + δL towards zero latently infected cells (Figure 4A). Our model therefore predicts that any drug or drug combination reducing HIV infectivity by a factor r <βcrit/β will cause the latent reservoir to decay with the same dynamics. We do not know the value of r for current HAART regimens, although our analysis suggests that r <βcrit/β. Nonetheless, we must consider the possibility that r > 0, in which case intensified HAART may further reduce r without hastening the decay of the latent reservoir. It is also possible that standard HAART regimens reduce infectivity such that r = 0 (i.e. βHAART = 0), in which case intensification of standard HAART regimens would have no conceivable benefit.

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