HIV-1 induced activation of CD4+ T cells creates new targets for HIV-1 infection in human lymphoid tissue ex vivo

Abstract

We demonstrate mechanisms by which HIV-1 appears to facilitate its own infection in ex vivo-infected human lymphoid tissue. In this system, HIV-1 readily infects various CD4+ T cells, but productive viral infection was supported predominantly by activated T cells expressing either CD25 or HLA-DR or both (CD25/HLA-DR) but not other activation markers: There was a strong positive correlation (r=0.64, P=.001) between virus production and the number of CD25+/HLA-DR+ T cells. HIV-1 infection of lymphoid tissue was associated with activation of both HIV-1-infected and uninfected (bystanders) T cells. In these tissues, apoptosis was selectively increased in T cells expressing CD25/HLA-DR and p24gag but not in cells expressing either of these markers alone. In the course of HIV-1 infection, there was a significant increase in the number of activated (CD25+/HLA-DR+) T cells both infected and uninfected (bystander). By inducing T cells to express particular markers of activation that create new targets for infection, HIV-1 generates in ex vivo lymphoid tissues a vicious destructive circle of activation and infection. In vivo, such self-perpetuating cycle could contribute to HIV-1 disease.

Figure 1

Kinetics of expression of different activation markers in human lymphoid tissue ex vivo. Tissues from 8 to 22 different donors were immunostained for different activation markers (CD69, CD25, and HLA-DR). The graphs represent the means (± SEM) of T cells expressing these markers at days 1, 6, 9, and 12 after the beginning of culture. Shown are the fractions of cells positive for CD25, CD69, and HLA-DR expression.

Figure 2

Activation in infected and uninfected CD4⁺ T cells in HIV-1–infected tissues. Tissue blocks from 3 different donors (54 blocks for each data point) were infected with X4_LAI.04. CD4⁺ T cells from infected and matched uninfected tissues were stained for activation markers (HLA-DR and CD25) and for p24gag and analyzed by flow cytometry. The graphs represent the averages (± SEM) of CD25⁺/HLA-DR⁺ CD4⁺ T cells at days 5 and 12 after infection. CD25⁺/HLA-DR⁺ CD4⁺ T cells in uninfected control tissue. CD25⁺/HLA-DR⁺ CD4⁺ T cells were divided in X4_LAI.04 infected tissue in productively infected cells (p24gag⁺) and bystander cells (p24gag⁻). * Represents significant differences for a nonparametric paired T test.

Figure 3

Correlation between p24gag production and T-cell activation. Tissues from 8 to 32 different donors were infected with X4_LAI.04 or R5_SF162, and for each data point the amount of p24gag accumulated in culture medium bathing 54 infected tissue blocks was measured by p24gag ELISA. Matched uninfected tissue blocks were used as controls. T cells of either CD69⁺ or CD25⁺/HLA-DR⁺ phenotype were considered as activated. The graphs represent the linear regression between the fraction of activated T cells in noninfected tissues and the maximal p24gag production in the matched infected tissue. (A) X4_LAI.04 production correlated with CD25⁺/HLA-DR⁺ T cells. (B) R5_SF162 production correlated with CD25⁺/HLA-DR⁺ T cells. (C) X4_LAI.04 production correlated with CD69⁺ T cells. (D) R5_SF162 production correlated with CD69⁺ T cells.