Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2020 Dec;17(12):1257-1265.
doi: 10.1038/s41423-020-0408-9. Epub 2020 Mar 24.

Virtual memory CD8+ T cells restrain the viral reservoir in HIV-1-infected patients with antiretroviral therapy through derepressing KIR-mediated inhibition

Jie-Hua Jin #  1   2   3 , Hui-Huang Huang #  2   3 , Ming-Ju Zhou  2   3   4 , Jing Li  2   3   4 , Wei Hu  2   3 , Lei Huang  2   3 , Zhe Xu  2   3 , Bo Tu  2   3 , Guang Yang  2   3 , Ming Shi  1   2   3 , Yan-Mei Jiao  2   3 , Xing Fan  2   3 , Jin-Wen Song  2   3 , Ji-Yuan Zhang  2   3 , Chao Zhang  5   6 , Fu-Sheng Wang  7   8   9
Affiliations

Virtual memory CD8+ T cells restrain the viral reservoir in HIV-1-infected patients with antiretroviral therapy through derepressing KIR-mediated inhibition

Jie-Hua Jin et al. Cell Mol Immunol. 2020 Dec.

Abstract

The viral reservoir is the major hurdle in developing and establishing an HIV cure. Understanding factors affecting the size and decay of this reservoir is crucial for the development of therapeutic strategies. Recent work highlighted that CD8+ T cells are involved in the control of viral replication in ART-treated HIV-1-infected individuals, but how CD8+ T cells sense and restrict the HIV reservoir are not fully understood. Here, we demonstrate that a population of unconventional CD45RA+, PanKIR+, and/or NKG2A+ virtual memory CD8+ T cells (TVM cells), which confer rapid and robust protective immunity against pathogens, plays an important role in restraining the HIV DNA reservoir in HIV-1-infected patients with effective ART. In patients undergoing ART, TVM cells negatively correlate with HIV DNA and positively correlate with circulating IFN-α2 and IL-15. Moreover, TVM cells constitutively express high levels of cytotoxic granule components, including granzyme B, perforin and granulysin, and demonstrate the capability to control HIV replication through both cytolytic and noncytolytic mechanisms. Furthermore, by using an ex vivo system, we showed that HIV reactivation is effectively suppressed by TVM cells through KIR-mediated recognition. This study suggests that TVM cells are a promising target to predict posttreatment virological control and to design immune-based interventions to reduce the reservoir size in ART-treated HIV-1-infected individuals.

Keywords: HIV reservoir; KIR; virtual memory CD8+ T cells.

PubMed Disclaimer

Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
TVM cells are expanded in HIV-infected patients and negatively correlate with the HIV reservoir in ART-treated patients. a, b Comparison of the frequencies (a) and absolute count (b) of TVM cells in CD8+ T cells of HCs, TN patients and ART patients. Statistical tests were performed using the Kruskal–Wallis test (nonparametric one-way ANOVA) with Dunn’s multiple comparisons test. *p < 0.05, ***p < 0.001, ns, not significant. c Comparison of phenotypical features between TVM and CD8+ T cells in HC, TN and ART patients. The expression levels of PD-1, CD57, EOMES, T-BET, CD122, NKG2C, CD16/56, Ki67, and Bcl-2 were detected by flow cytometry, and the data are shown as a heatmap. Each column represents a group of samples. The color in each cell reflects the level of expression of the indicated marker relative to the expression percentage of all the samples (z-score). d Correlation of the TVM cell frequency among CD8+ T cells with the HIV CA DNA level. e Correlation of the TVM cell frequency among CD8+ T cells with the HIV CA RNA level. f Correlation of the TVM cell count with the HIV CA DNA level. g Correlation of the TVM cell count with the HIV CA RNA level. For statistical analyses, data were log transformed, and Pearson correlations were performed
Fig. 2
Fig. 2
TVM cells from ART patients are enriched with cytotoxic T lymphocytes and highly responsive to cytokine stimulation. a Comparison between TVM and CD8+ T cells regarding the frequencies of cells expressing granzyme B (GZMB), granulysin (GNLY) and perforin (PRF) in ART patients. b, c PBMCs from ART patients were stimulated with IL-12 (20 ng/mL), IL-15 (10 ng/mL), and IL-18 (20 ng/mL) for 48 h. Comparison between TVM and CD8+ T cells regarding the frequencies of cells expressing CD107a, GZMB, and PRF (b) and secreting IFN-γ, IL-2, and TNF-α (c). d PBMCs from ART patients were primed with IL-15 (50 ng/mL) for 42 h and then stimulated with anti-CD3 (1 μg/mL), anti-CD28 (1 μg/mL), and anti-CD49d (1 μg/mL) antibodies for 6 h. Comparison between TVM and CD8+ T cells regarding the frequencies of cells making CC chemokines, including CCL-3, CCL-4, and CCL-5. For statistical analyses, the Wilcoxon matched-pairs signed rank test was performed. *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001, ns, not significant
Fig. 3
Fig. 3
TVM cells positively correlate with IL-15 and IFN-α2 in ART patients. a, b Correlations of the TVM cell frequency among CD8+ T cells with IL-15 (a) and IFN-α2 (b) levels in ART patients. Plasma levels of IL-15 and IFN-α2 in ART patients were detected by an AimPlex Kit. Correlations were calculated by using Pearson’s correlations
Fig. 4
Fig. 4
Sensing of the activation of the HIV reservoir by TVM cells is dependent on HLA-I/KIR signaling. a Diagram of the ex vivo killing assay. b CD8- and CD56-depleted cells from ART patients were stimulated with PHA (5 μg/mL) for 48 h. The frequencies of p24+ CD4+ T cells were analyzed by flow cytometry. c PHA-stimulated CD8- and CD56-depleted cells were cocultured with or without CD8+ T cells for 24 h. The frequencies of p24+ CD4+ T cells were analyzed by flow cytometry. d PHA-stimulated CD8- and CD56-depleted cells were cocultured with purified TVM–, NK- or TVM-depleted CD8+ T cells, and the frequencies of p24+ CD4+ T cells were analyzed by flow cytometry. e Cells were treated as in panel C, but in the presence of GolgiPlug, cytokines, cytotoxic molecules and CC chemokines in total CD8+ T cells and TVM cells were analyzed by flow cytometry. f PHA-stimulated CD8- and CD56-depleted cells were cocultured with CD8+ T cells in the presence of CD122-blocking antibody (clone TU27, dilution 1:50), KIR-blocking antibody (clone NKVFS1, dilution 1:11), HLA-I-blocking antibody (clone W6/32, dilution 1:50), or KIR- and HLA-I-blocking antibodies. The frequencies of p24+ CD4+ T cells were analyzed by flow cytometry. g A proposed schematic of TVM cells in surveillance of HIV-1 reservoir activation. For statistical analyses, the Wilcoxon matched-pairs signed rank test was performed. *p < 0.05, **p < 0.01, ***p < 0.001
See this image and copyright information in PMC

Comment in

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Volberding PA, Deeks SG. Antiretroviral therapy and management of HIV infection. Lancet. 2010;376:49–62. - PubMed
    1. Furtado MR, et al. Persistence of HIV-1 transcription in peripheral-blood mononuclear cells in patients receiving potent antiretroviral therapy. N. Engl. J. Med. 1999;340:1614–1622. - PubMed
    1. Williams JP, et al. HIV-1 DNA predicts disease progression and post-treatment virological control. Elife. 2014;3:e03821. - PMC - PubMed
    1. Graf EH, et al. Elite suppressors harbor low levels of integrated HIV DNA and high levels of 2-LTR circular HIV DNA compared to HIV+ patients on and off HAART. PLoS Pathog. 2011;7:e1001300. - PMC - PubMed
    1. Hocqueloux L, et al. Long-term immunovirologic control following antiretroviral therapy interruption in patients treated at the time of primary HIV-1 infection. Aids. 2010;24:1598–1601. - PubMed

Publication types

MeSH terms