Contribution of follicular dendritic cells to persistent HIV viremia

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.

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) = 10^3.2 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

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 k_r, releasing the virion back into solution. Once the virion is bound to the surface, the rate constant to form an additional bond is k_x, 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

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 σ_n = 7, association rate constant k_x = 0.38 k_−x/<R_T>, and those listed in Table 1.

Fig 4

Calculated V_FDC + V₄ can fit the long-term plasma viral load data. The calculated values of V_FDC + 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 V_FDC + 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

Plasma viral load data for two individual patients are fitted by V_FDC + V₄. The calculated values of V_FDC + V₄ are shown by the solid line. Fitting parameters are k_x = 0.38 k_−x/<R_T> and V₄ = 0.5 for patient 72127 and k_x = 0.35 k_−x/<R_T> 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

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 σ_n = 3.0 and association rate constant k_x = 0.55 k_−x/<R_T> 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

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

Lognormal distribution of R_T and normal distribution of n. The standard deviations are σ = 0.1 and σ_n = 7.0, respectively.

Fig A1

Correlation between baseline viral load and the viral load at weeks 4, 60, and 350.