Lysis of HIV-1-infected cells and inhibition of viral replication by universal receptor T cells - PubMed (original) (raw)

Lysis of HIV-1-infected cells and inhibition of viral replication by universal receptor T cells

O O Yang et al. Proc Natl Acad Sci U S A. 1997.

Abstract

Increasing evidence suggests that HIV-1-specific cytotoxic T lymphocytes (CTLs) are a key host immune response to HIV-1 infection. Generation of CTL responses for prevention or therapy of HIV-1 infection has several intrinsic technical barriers such as antigen expression and presentation, the varying HLA restrictions between different individuals, and the potential for viral escape by sequence variation or surface molecule alteration on infected cells. A strategy to circumvent these limitations is the construction of a chimeric T cell receptor containing human CD4 or HIV-1-specific Ig sequences linked to the signaling domain of the T cell receptor zeta chain (universal T cell receptor). CD8+ CTLs transduced with this universal receptor can then bind and lyse infected cells that express surface HIV-1 gp120. We evaluated the ability of universal-receptor-bearing CD8+ cells from a seronegative donor to lyse acutely infected cells and inhibit HIV-1 replication in vitro. The kinetics of lysis and efficiency of inhibition were comparable to that of naturally occurring HIV-1-specific CTL clones isolated from infected individuals. Further study will be required to determine the utility of these cells as a therapeutic strategy in vivo.

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Figures

Figure 1

Figure 1

Lysis of acutely HIV-1-infected T1 cells by UR-T cells. T1 cells were acutely infected with HIV-1 IIIB and harvested daily for use as target cells in standard chromium release assays. Effector cells consisted of the UR-T cells T3F3 and T3F15, as well as a HLA A2-restricted CTL clone specific for RT (68/RT/A2). Controls included effector T3 cells (the parent nontransduced cell line of T3F3 and T3F15) and target infected or uninfected T1 cells with or without the addition of the cognate peptide for 68/RT/A2.

Figure 2

Figure 2

Lysis of acutely HIV-1-infected H9-B14 cells by UR-T cells. H9-B14 cells were acutely infected with HIV-1 IIIB harvested daily for use as target cells in standard chromium release assays. Effector cells consisted of the UR-T cells T3F3 and T3F15 and a HLA B14-restricted CTL clone specific for Gag (15160/Gag/B14). The effector/target cell ratio was 5:1. Controls included effector T3 cells (the parent nontransduced cell line of T3F3 and T3F15) and target infected or uninfected H9-B14 cells with or without the addition of the cognate peptide for 15160/Gag/B14.

Figure 3

Figure 3

Temporal relationship of UR-T cell recognition and virion production in acutely infected T1 cells. Supernatants from the HIV-1 IIIB-infected T1 and H9-B14 target cells used in Figs. 1 and 2 were harvested daily for viral quantitation by p24 ELISA and viral titration. Viral production in the absence of CTLs is plotted against the curves for specific lysis for each UR-T cell as depicted in Figs. 1 and 2.

Figure 4

Figure 4

Suppression of HIV-1 IIIB replication by UR-T cells in direct coculture with acutely infected T1 and H9-B14 cells. T1 (HLA A2+, B14−) and H9-B14 (B14+, A2−) cells were infected and cocultured 1:1 with UR-T cells, nontransduced T3 cells, and natural CTL clones 68/RT/A2 or 15160/Gag/B14. HIV-1 p24 antigen in the supernatant was quantitated on days 3–5 after infection.

Figure 5

Figure 5

Suppression of a monocytotropic HIV-1 strain in primary monocytes. Primary monocytes from a seronegative donor were acutely infected with the HIV-1 M-tropic strain JR-CSF and cocultured with UR-T cells or the control cell line T3. Supernatant was harvested at the indicated intervals for HIV-1 p24 quantitative ELISA.

Figure 6

Figure 6

Suppression of diverse HIV-1 strains in primary lymphocytes. Primary lymphocytes from a seronegative donor were acutely infected with the laboratory strains IIIB (T-tropic) or JR-CSF (M-tropic), as well as the primary patient isolate strains 115v or 18030v, and cocultured with the UR-T cell line T3F3 or the control cell line T3. Day 7 p24 ELISA data is shown. Although the control CD8+ cell line T3 was variably stimulatory for p24 production in this and other experiments (data not shown) presumably due to alloreactive stimulation of the target cells, the UR-T cell line T3F3 was reproducibly inhibitory compared with T3.

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