Is the gut the major source of virus in early simian immunodeficiency virus infection?

Abstract

The acute phases of human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) infection are characterized by rapid and profound depletion of CD4+ T cells from the guts of infected individuals. The large number of CD4+ T cells in the gut (a large fraction of which are activated and express the HIV/SIV coreceptor CCR5), the high level of infection of these cells, and the temporal coincidence of this CD4+ T-cell depletion with the peak of virus in plasma in acute infection suggest that the intestinal mucosa may be the major source of virus driving the peak viral load. Here, we used data on CD4+ T-cell proportions in the lamina propria of the rectums of SIV-infected rhesus macaques (which progress to AIDS) and sooty mangabeys (which do not progress) to show that in both species, the depletion of CD4+ T cells from this mucosal site and its maximum loss rate are often observed several days before the peak in viral load, with few CD4+ T cells remaining in the rectum by the time of peak viral load. In contrast, the maximum loss rate of CD4+ T cells from bronchoalveolar lavage specimens and lymph nodes coincides with the peak in virus. Analysis of the kinetics of depletion suggests that, in both rhesus macaques and sooty mangabeys, CD4+ T cells in the intestinal mucosa are a highly susceptible population for infection but not a major source of plasma virus in acute SIV infection.

FIG. 1.

Plasma viral load and CD4⁺ T-cell kinetics in rhesus macaques. (a) The plasma viral load (black) and percent CD4⁺ T cells were measured in PB, LNs, rectum, and BAL specimens for an individual animal. The peak viral load (indicated by the dashed vertical line) varied between individual animals. The kinetics of CD4⁺ T-cell depletion in the rectum (b) BAL specimens (c) LNs (d), and PB (e) are shown relative to the time of the peak viral load in each animal. This reveals that depletion in the rectum often significantly precedes the peak in the viral load. Animals that deplete early in the rectum (indicated in red) do not necessarily deplete early in other sites. Note that BAL specimen CD4⁺ kinetics for animal RNr8 was not included, as baseline levels were not available.

FIG. 2.

CD4⁺ T-cell depletion in RB and BAL specimens. The rectum (RB) shows significantly higher levels of CD4⁺ T-cell depletion than the BAL specimens at the time of peak viral load (a) (P = 0.0001). However, by 28 days postinfection, the depletions are similar in both compartments (b) (P = 1.0).

FIG. 3.

The timing of peak CD4⁺ T-cell depletion rates in RB (a), BAL (b), PB (c), and LN (d) specimens relative to the time of peak viral load in rhesus macaques. The animals are aligned according to the time of the peak viral load, and the relative times of the peak CD4⁺ T-cell depletion rate are indicated for samples from different tissues. The time period in which the peak loss of CD4⁺ T cells (i.e., maximum percent per day) occurred is indicated as a horizontal bar.

FIG. 4.

CD4⁺ T-cell depletion occurs significantly earlier in the rectum. The time of peak CD4⁺ T-cell depletion relative to the peak viral load is indicated in different tissues for rhesus macaques (a) and sooty mangabeys (b). The time of peak depletion is taken as the midpoint of the interval in which the maximum depletion was observed. Each point represents an individual animal. The gray bars indicate the median differences. Peak depletion in RB samples from rhesus macaques occurred significantly before the peak viral load (P < 0.001; Wilcoxon). However, in other compartments, the time of peak depletion was not significantly different from the timing of the peak viral load.

FIG. 5.

Plasma viral load and CD4⁺ T-cell kinetics in sooty mangabeys. (a) The plasma viral load (black) and the percent CD4⁺ T cells were measured in PB, LNs, rectum, and BAL specimens for an individual animal. The peak viral loads (indicated by the dashed vertical line) varied between individual animals. The kinetics of CD4⁺ T-cell depletion in the rectum (b), BAL specimens (c), LN (d), and PB (e) are shown relative to the time of the peak viral load in each animal. The animals were aligned according to the timing of the peak viral load in order to observe the timing of depletion in different anatomical compartments.

FIG. 6.

Difference between the time of the peak CD4⁺ T-cell depletion rate and the peak viral load in RB (a), BAL (b), PB (c), and LN (d) specimens from sooty mangabeys. The times of peak CD4⁺ T-cell depletion (indicated as horizontal bars) and peak viral load (indicated as a vertical line) are shown in different compartments for SIV-infected sooty mangabeys. The peak rate of CD4⁺ T-cell depletion (taken as the midpoint of the time interval) in the rectum occurred before the peak viral load in all animals (although this is not significant due to the small number of animals studied). The depletion in other compartments occurred closer to the peak viral load.

FIG. 7.

Modeling the peak viral load and CD4⁺ T-cell depletion in compartments of different sizes or with different virus production rates. The dashed black lines represent viral loads; the colored lines are total observed (uninfected and infected; T + I) CD4⁺ T-cell numbers. The circles mark the fastest CD4⁺ T-cell depletion in each compartment. We first modeled infection in compartments differing in size and either susceptibility to infection or death rate (using equations 1 to 3). Before infection, the largest (red) compartment contained 900 cells, the medium-size compartment (blue) had 90 cells, and the smallest compartment (green) had 9 cells. (a) When all three compartments have same susceptibility to infection (k_L = k_M = k_S = 5 × 10⁻⁸ ml/copy/day), they are depleted synchronously. (b) If the largest compartment has the highest susceptibility (k_L = 10⁻⁷ ml/copy/day = 10k_M = 100k_S), then it is infected rapidly, driving the peak viral load. In the less susceptible compartments, maximum depletion occurs around the peak viral load, and thus depletion occurs almost synchronously in all compartments. (c) If the largest compartment has the lowest susceptibility (k_L = 10⁻⁸ ml/copy/day = 0.1k_M = 0.01k_S), then the smaller compartments are depleted first, but the peak viral load is not reached until the large compartment is infected. In panels a to c, the other parameters are as follows: δ = 1/day, p = 10⁶ copies/cell/day, and c = 20/day. (d) Early depletion cannot be driven by high death rates. If the compartments have the same susceptibility to infection but the death rates of infected cells vary, this has relatively little effect on driving early depletion. All compartments are infected synchronously (as in panel a), and differences in death rates do not affect the timing of depletion greatly. The largest compartment has the highest death rate of infected cells (δ_L = 2/day, δ_M = 1/day, and δ_S = 0.5/day). The other parameters are as follows: k = 10⁻⁷ ml/copy/day, p = 5 × 10⁵ copies/cell/day, and c = 20/day. Early depletion can also be seen if all compartments are the same size (333 cells) but differ in susceptibility to infection and the rate at which infected cells produce virus. (e) If compartments differ only in susceptibilities, with the first (red) compartment the least susceptible (k₁ = 10⁻⁸ ml/copy/day = 0.1k₂ = 0.01k₃), but with the same viral production in each compartment (p = 5 × 10⁵ copies/cell/day), then they differ in the timing of depletion, but with the most susceptible compartment still depleting around the peak of virus (not before it). (f) If compartments differ in virus production rates, as well as susceptibilities, then the highest-producing compartment (red) (producing a p₁ of 10 copies/cell/day, which is 10-fold more than the medium-producing [blue] and 100-fold more than the low-producing [green] compartment) drives the peak viral load. If the highest-producing, red, compartment is the least susceptible, then the other compartments are depleted earlier. Thus, low production and small compartment size in the gut are both compatible with the observed kinetics in vivo. The other parameters are as follows: δ = 1/day, and c = 20/day.

FIG. 8.

The peak depletion rate of CD4⁺ T cells coincides with the peak production of virus in the compartment. Shown is modeling of CD4⁺ T-cell depletion using the same parameters as in Fig. 7c but showing viral production from each compartment. The solid lines represent CD4⁺ T cells in each compartment, with circles at the maximum rates of loss of CD4⁺ T cells. The dotted lines represent the contributions of each compartment to the total viral load.