Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2013 Jul;87(14):7893-901.
doi: 10.1128/JVI.00556-13. Epub 2013 May 8.

Contribution of follicular dendritic cells to persistent HIV viremia

Jingshan Zhang  1 , Alan S Perelson
Affiliations

Contribution of follicular dendritic cells to persistent HIV viremia

Jingshan Zhang et al. J Virol. 2013 Jul.

Erratum in

  • J Virol. Jul;87(14):7893

Abstract

HIV-1 infections cannot be completely eradicated by drug therapy, as the virus persists in reservoirs. Low-level plasma viremia has been detected in patients treated for over 7 years, but the cellular compartments that support this low-level viremia have not been identified. The decay of HIV-1 during treatment appears to occur in four phases, with the 3rd and 4th phases occurring when the virus is below the limit of detection of conventional assays. Here, we focus on the 3rd phase of decay, which has been estimated to have a half-life of 39 months. We show that follicular dendritic cells (FDC), which have been identified as an HIV reservoir, can be the main source of the low-level viremia detected during the 3rd phase of decay and contribute to viremia at even longer times. Our calculations show that the kinetics of leakage of virus from FDC is consistent with three types of available clinical data.

PubMed Disclaimer

Figures

Fig 1
Fig 1
Four-phase decay of plasma viral load. The median viral load decay observed by Palmer et al. (8) is shown by the thick black line. The four phases are indicated by the arrows, and the four corresponding terms in equation 1 are shown by solid (green), dashed (red), dash-dotted (blue), and dotted (black) lines, respectively, where we use V1(0) = 105 copies/ml, V2(0) = 103.2 copies/ml, V3(0) = 11.6 copies/ml, and V4(0) = 1.5 copies/ml, as well as half-lives τ1 = 1.5 days, τ2 = 4 weeks, and τ3 = 39 weeks, as reported in the work of Palmer et al. (8).
Fig 2
Fig 2
Multivalent binding and unbinding steps between an HIV-1 virion (circle) and surface receptors on FDC. Free virions attach to the FDC surface and first form a single bond with rate constant α. This bond can break with rate constant kr, releasing the virion back into solution. Once the virion is bound to the surface, the rate constant to form an additional bond is kx, and the reverse rate constant is k−x. Equation 2 in Materials and Methods describes the kinetics of these reactions and includes statistical factors that incorporate the number of ways that bonds can form and break.
Fig 3
Fig 3
Acute infection dynamics. The plasma viral RNA load in an acutely infected patient (dots) and best fit curve (solid line) are taken from the work of Stafford et al. (43). The density of virions bound to FDC (dashed line), calculated using the generalized form of equations 2 and 3, changes with the plasma viral load. The parameter values used in the calculation, chosen to fit the clinical data (8, 38), are σn = 7, association rate constant kx = 0.38 k−x/<RT>, and those listed in Table 1.
Fig 4
Fig 4
Calculated VFDC + V4 can fit the long-term plasma viral load data. The calculated values of VFDC + V4 are shown by the black solid line. The plasma viral load data for the patients were reported by Palmer et al. (8). Each dot and bar represent the average and standard deviation, respectively, of the logarithmic HIV RNA loads of all patient measured at a given treatment time. The ability of VFDC + V4 to fit the data from the work of Palmer et al. (8) is comparable to that of V3 + V4 (red dashed line). This indicates that the FDC reservoir can be the dominating source of viremia during the 3rd phase of decay. The parameters in the calculation are the same as in Fig. 3.
Fig 5
Fig 5
Plasma viral load data for two individual patients are fitted by VFDC + V4. The calculated values of VFDC + V4 are shown by the solid line. Fitting parameters are kx = 0.38 k−x/<RT> and V4 = 0.5 for patient 72127 and kx = 0.35 k−x/<RT> and V4 = 1.0 for patient 72191. The other parameters used in calculations are the same as in Fig. 4. Note that the parameter values in the fits are close to those used in Fig. 4.
Fig 6
Fig 6
The decay of the FDC viral pool in the first months and years of treatment. The solid lines show the model calculation. The averages and standard deviations of the logarithm of the measured HIV RNA on FDC (12) are shown by dots and bars, respectively. We use parameter values σn = 3.0 and association rate constant kx = 0.55 k−x/<RT> in the calculation. The other parameters used in calculations are the same as those in Fig. 4. The decay of the FDC viral pool slows down steadily over 5 years (right).
Fig 7
Fig 7
Relationship between the plasma viral load at baseline and week 60 of treatment. The calculated plasma viral load at week 60 (solid line) assuming that V3 is contributed by FDC is consistent with the data (dots) and linear regression (dashed line) in the work of Maldarelli et al. (38). The parameters in the calculation are the same as those in Fig. 4.
Fig 8
Fig 8
Lognormal distribution of RT and normal distribution of n. The standard deviations are σ = 0.1 and σn = 7.0, respectively.
Fig A1
Fig A1
Correlation between baseline viral load and the viral load at weeks 4, 60, and 350.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Ho DD, Neumann AU, Perelson AS, Chen W, Leonard JM, Markowitz M. 1995. Rapid turnover of plasma virions and CD4 lymphocytes in HIV-1 infection. Nature 373:123–126 - PubMed
    1. Perelson AS, Neumann AU, Markowitz M, Leonard JM, Ho DD. 1996. HIV-1 dynamics in vivo: virion clearance rate, infected cell life-span, and viral generation time. Science 271:1582–1586 - PubMed
    1. Bonhoeffer S, Coffin JM, Nowak MA. 1997. Human immunodeficiency virus drug therapy and virus load. J. Virol. 71:3275–3278 - PMC - PubMed
    1. Perelson AS, Essunger P, Cao Y, Vesanen M, Hurley A, Saksela K, Markowitz M, Ho DD. 1997. Decay characteristics of HIV-1-infected compartments during combination therapy. Nature 387:188–191 - PubMed
    1. Finzi D, Siliciano RF. 1998. Viral dynamics in HIV-1 infection. Cell 93:665–671 - PubMed

Publication types

LinkOut - more resources