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. 1998 Feb 3;95(3):1154-9.
doi: 10.1073/pnas.95.3.1154.

Kinetics of CD4+ T cell repopulation of lymphoid tissues after treatment of HIV-1 infection

Z Q Zhang  1 , D W Notermans, G Sedgewick, W Cavert, S Wietgrefe, M Zupancic, K Gebhard, K Henry, L Boies, Z Chen, M Jenkins, R Mills, H McDade, C Goodwin, C M Schuwirth, S A Danner, A T Haase
Affiliations

Kinetics of CD4+ T cell repopulation of lymphoid tissues after treatment of HIV-1 infection

Z Q Zhang et al. Proc Natl Acad Sci U S A. .

Abstract

Potent combinations of antiretroviral drugs diminish the turnover of CD4+ T lymphocytes productively infected with HIV-1 and reduce the large pool of virions deposited in lymphoid tissue (LT). To determine to what extent suppression of viral replication and reduction in viral antigens in LT might lead correspondingly to repopulation of the immune system, we characterized CD4+ T lymphocyte populations in LT in which we previously had quantitated viral load and turnover of infected cells before and after treatment. We directly measured by quantitative image analysis changes in total CD4+ T cell counts, the CD45RA+ subset, and fractions of proliferating or apoptotic CD4+ T cells. Compared with normal controls, we documented decreased numbers of CD4+ T cells and increased proliferation and apoptosis. After treatment, proliferation returned to normal levels, and total CD4+ T and CD45RA+ cells increased. We discuss the effects of HIV-1 on this subset based on the concept that renewal mechanisms in the adult are operating at full capacity before infection and cannot meet the additional demand imposed by the loss of productively infected cells. The slow increases in the CD45RA+ CD4+ T cells are consistent with the optimistic conclusions that (i) renewal mechanisms have not been damaged irreparably even at relatively advanced stages of infection and (ii) CD4+ T cell populations can be partially restored by control of active replication without eradication of HIV-1.

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Figures

Figure 1
Figure 1
Quantitative image analysis of CD4+ T cells in lymphoid tissue. (A and B) Color and black and white video images of CD4+ T cells in a tissue section stained immunohistochemically with antibody to CD4 and vector red substrate. (C) The darker stained cells in B are identified with a red overlay. The number of CD4+ T cells in the field is computed automatically from the measured area of the objects highlighted in red and the standard area of a cell.
Figure 2
Figure 2
Quantitative image analysis of doubly labeled CD4+ T cells in LT. The upper panels display the color images of immunohistochemically stained CD4+ T cells and the binary derivative (A) of the digitized information. All cells with a binary value of 1 are white. The arrow points to two CD4+ T cells that are Ki67+. In the lower panels, proliferating cells, mainly the B lymphocytes concentrated in the germinal center, have been identified by staining with antibodies to Ki67 and fluoresceinated secondary antibody. Positive cells are green in the color image and white in the binary derivative image (B). The arrow again points to two double-positive cells, identified in the panel at the right by multiplying the binary derivatives A × B to locate and count the CD4+ Ki67+ cells.
Figure 3
Figure 3
Treatment-induced changes in LT in total body CD4+ T cells and naive CD45RA+ cells, were determined as described in this report. Total CD4+ T cell body counts were calculated by extrapolation as described; this number times the percentage of RA+ cells equals the total CD45RA+ CD4+ T cell count. The fractions of Ki67+ and TUNEL+ CD4+ T cells in tonsillar biopsies were determined as described in this report, before and at designated times after treatment.
Figure 4
Figure 4
CD4+ T cell subsets in LT were counted as described, and the mean body totals ± 1 SD (indicated by I) from Tables 1 and 2 are shown for uninfected and infected individuals before and after 3 weeks, 6 months, and 12–14 months of triple antiretroviral therapy.
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