Duration of an intermittent episode of viremia

Journal of acquired immune deficiency …, 2007

When antiretroviral therapy (ART) is administered for long periods to HIV-1-infected patients, most achieve viral loads that are ''undetectable'' by standard assay methods (ie, HIV-1 RNA ,50 copies/mL). Despite sustaining viral loads lower than the level of detection, a number of patients experience unexplained episodes of transient viremia or viral ''blips.'' We propose that transient activation of the immune system by infectious agents may explain these episodes of viremia. Using 2 different mathematic models, one in which blips arise because of target cell activation and subsequent infection and another in which latent cell activation generates blips, we establish nonlinear (power law) relations AU2 between blip amplitude and viral load (under ART) that suggest blips should be of lower amplitude, and thus harder to detect, as increasingly potent therapy is used. This effect can be more profound than is predicted by simply lowering the baseline viral load from which blips originate. Finally, we suggest that sporadic immune activation may elevate the level of chronically infected cells and replenish viral reservoirs, including the latent cell reservoir, providing a mechanism for recurrent viral blips and low levels of viremia under ART.

Mathematical Biosciences, 2004

Highly active antiretroviral therapy (HAART), administered to a HAART-na€ ıve patient, perturbs the steady state of chronic infection. This perturbation provides an opportunity to investigate the existence and dynamics of different sources of viral production. Models of HIV dynamics can be used to make a comparative analysis of the efficacies of different drug regimens. When HAART is administered for long periods of time, most patients achieve ÔundetectableÕ viral loads (VLs), i.e., below 50 copies/ml. Use of an ultrasensitive VL assay demonstrates that some of these patients obtain a low steady state VL in the range 5-50 copies/ml, while others continue to exhibit VL declines to below 5 copies/ml. Interestingly, when patients exhibit continued declines below 50 copies/ml the virus has a half-life of $6 months, consistent with some estimates of the rate of latent cell decline. Some patients, despite having sustained undetectable VLs, show periods of transient viremia (blips). We present a statistical characterization of the blips observed in a set of 123 patients, suggesting that patients have different tendencies to show blips during the period of VL suppression, that intermittent episodes of viremia have common amplitude profiles, and that VL decay from the peak of a blip may have two phases. Published by Elsevier Inc.

Journal of Theoretical Biology, 2009

We previously reported that in patients treated with highly active antiretroviral therapy (HAART) who achieve viral load (VL) suppression, low fluctuations of viral load over the threshold of detection (viral blips) more than 4 weeks apart occur at random, with a frequency that does not change with longer times of observation. The etiology of viral blips is currently unknown, but viral blip frequency inversely correlates with the decay of the latent reservoir, whose stability has been proposed as the major hurdle to HIV eradication. We show here that the distribution of viral blip amplitudes observed in a group of 272 patients successfully treated with highly active antiretroviral therapy appears to be power-law distributed. Such a distribution can be theoretically generated by randomly sampling the arrival of asynchronous and overlapping elementary pulses of viremia, with asymptotic exponential decay of kinetics, thus suggesting that the low fluctuations of viremia observed in patients during HAART treatment is, in part, a discrete phenomenon consistent with random activation of latently infected cells or release of virus and infected cells into the blood compartment from unknown sites of active viral replication.

Journal of Virology, 2003

Although intermittent episodes of low-level viremia are often observed in well-suppressed highly active antiretroviral therapy (HAART)-treated patients, the timing and amplitude of viral blips have never been examined in detail. We analyze here the dynamics of viral blips, i.e., plasma VL measurements of >50 copies/ml, in 123 HAART-treated patients monitored for a mean of 2.6 years (range, 5 months to 5.3 years). The mean (؎ the standard deviation) blip frequency was 0.09 ؎ 0.11/sample, with about one-third of patients showing no viral blips. The mean viral blip amplitude was 158 ؎ 132 human immunodeficiency virus type 1 (HIV-1) RNA copies/ml. Analysis of the blip frequency and amplitude distributions suggest that two blips less than 22 days apart have a significant chance of being part of the same episode of viremia. The data are consistent with a hypothetical model in which each episode of viremia consists of a phase of VL rise, followed by two-phase exponential decay. Thus, the term "viral blip" may be a misnomer, since viral replication appears to be occurring over an extended period. Neither the frequency nor the amplitude of viral blips increases with longer periods of observation, but the frequency is inversely correlated with the CD4 ؉ -T-cell count at the start of therapy, suggesting that host-specific factors but not treatment fatigue are determinants of blip frequency.

Highly active antiretroviral therapy (HAART) suppresses HIV RNA viral load below the limit of detection for many patients. However, clinical data demonstrates that the HIV virus is not eradicated by HAART, even in patients who have had no detectable virus for 7 years [1]. One possible reason is that a stable resting latent reservoir with a long half-life exists in resting memory CD4 + T cells . In this paper, we propose a mathematical model with a constant contribution of a stable latent reservoir and identified this constant by using one patient's data from AutoVac HAART interruption study . Many patients also have transient rebounds of plasma viral RNA (viral blips) under otherwise successful control of the virus by HAART. Activation of latently infected cells can explain these transient rebounds of viral load. Little quantitative analysis about the activation of reservoir has been done based on any clinical experiment data. Here, we model the activation dynamics of the reservoir by a time-independent activation rate and estimate this rate by using the clinical data from the AutoVac HAART interruption study .

JAIDS Journal of Acquired Immune Deficiency Syndromes, 2012

Journal of Virology, 2004

NIH grants AI 28433 and RR06555 (A.S.P.) and AI41534 and AI47033 (M.M.).

Journal of Infectious Diseases, 2012