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Suppression of HIV Replication by CD8(+) Regulatory T-Cells in Elite Controllers.

Lu W, Chen S, Lai C, Lai M, Fang H, Dao H, Kang J, Fan J, Guo W, Fu L, Andrieu JM - Front Immunol (2016)

Bottom Line: We previously demonstrated in the Chinese macaque model that an oral vaccine made of inactivated SIV and Lactobacillus plantarum induced CD8(+) regulatory T-cells, which suppressed the activation of SIV(+)CD4(+) T-cells, prevented SIV replication, and protected macaques from SIV challenges.For that purpose, we investigated the in vitro antiviral activity of fresh CD8(+) T-cells on HIV-infected CD4(+) T-cells taken from 10 ECs.Our findings provide the first evidence for an instrumental role of KIR-expressing CD8(+) regulatory T-cells in the natural control of HIV-1 infection.

View Article: PubMed Central - PubMed

Affiliation: Institut de Recherche sur les Vaccins et l'Immunothérapie des Cancers et du Sida, Université de Paris Descartes, Paris, France; Sino-French Collaborative Laboratory, Tropical Medicine Institute, Guangzhou University of Chinese Medicine, Guangzhou, China.

ABSTRACT
We previously demonstrated in the Chinese macaque model that an oral vaccine made of inactivated SIV and Lactobacillus plantarum induced CD8(+) regulatory T-cells, which suppressed the activation of SIV(+)CD4(+) T-cells, prevented SIV replication, and protected macaques from SIV challenges. Here, we sought whether a similar population of CD8(+) T-regs would induce the suppression of HIV replication in elite controllers (ECs), a small population (3‰) of HIV-infected patients with undetectable HIV replication. For that purpose, we investigated the in vitro antiviral activity of fresh CD8(+) T-cells on HIV-infected CD4(+) T-cells taken from 10 ECs. The 10 ECs had a classical genomic profile: all of them carried the KIR3DL1 gene and 9 carried at least 1 allele of HLA-B:Bw4-80Ile (i.e., with an isoleucine residue at position 80). In the nine HLA-B:Bw4-80Ile-positive patients, we demonstrated a strong viral suppression by KIR3DL1-expressing CD8(+) T-cells that required cell-to-cell contact to switch off the activation signals in infected CD4(+) T-cells. KIR3DL1-expressing CD8(+) T-cells withdrawal and KIR3DL1 neutralization by a specific anti-killer cell immunoglobulin-like receptor (KIR) antibody inhibited the suppression of viral replication. Our findings provide the first evidence for an instrumental role of KIR-expressing CD8(+) regulatory T-cells in the natural control of HIV-1 infection.

No MeSH data available.


Related in: MedlinePlus

KIR3DL1 expression on CD8+ T-cells is required for HLA-B:Bw4-80Ile-dependent viral suppression. (A) Cytometric analysis of KIR expression in CD8+ T-cells freshly taken from a representative EC (No. 3). (B) Pan-KIR (total inhibitory KIRs) and KIR3DL1-expressing CD8+ T-cells were significantly higher in ECs (No. 1–5) (green) than in HVLpts carrying KIR3DL1 gene (No. 2, 3, and 6–8). (C) CD8+ T-cell-mediated viral suppression was reduced by 4–5 logs when freshly pan-KIR or KIR3DL1-depleted CD8+ T-cells were added as compared with bulk CD8+ T-cells. (D) CD8+ T-cell-mediated viral suppression was reduced by 3–4 logs in Bw4-80I/KIR3DL1-matched patients (EC#1–5) when the anti-KIR3DL1 antibody (clone Dx9) was added as compared with parallel cultures in the presence of anti-KIR3DS1 antibody (clone z27) or medium alone. In contrast, the low levels of viral suppression observed in Bw4-80I/KIR3DL1-mismatched patients (EC#6, HVLpt#2, and HVLpt#4) remained unaffected by the anti-KIR3DL1 antibody (clone Dx9).
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Figure 5: KIR3DL1 expression on CD8+ T-cells is required for HLA-B:Bw4-80Ile-dependent viral suppression. (A) Cytometric analysis of KIR expression in CD8+ T-cells freshly taken from a representative EC (No. 3). (B) Pan-KIR (total inhibitory KIRs) and KIR3DL1-expressing CD8+ T-cells were significantly higher in ECs (No. 1–5) (green) than in HVLpts carrying KIR3DL1 gene (No. 2, 3, and 6–8). (C) CD8+ T-cell-mediated viral suppression was reduced by 4–5 logs when freshly pan-KIR or KIR3DL1-depleted CD8+ T-cells were added as compared with bulk CD8+ T-cells. (D) CD8+ T-cell-mediated viral suppression was reduced by 3–4 logs in Bw4-80I/KIR3DL1-matched patients (EC#1–5) when the anti-KIR3DL1 antibody (clone Dx9) was added as compared with parallel cultures in the presence of anti-KIR3DS1 antibody (clone z27) or medium alone. In contrast, the low levels of viral suppression observed in Bw4-80I/KIR3DL1-mismatched patients (EC#6, HVLpt#2, and HVLpt#4) remained unaffected by the anti-KIR3DL1 antibody (clone Dx9).

Mentions: Having observed the correlation between the combination of KIR3DL1 and HLA-B:Bw4-80Ile genes and HIV-1 suppression in vitro and in vivo, we further investigated the expression of KIRs on CD8+ T-cells in the 10 ECs (No. 1–10) and the 5 HVLpts carrying KIR3DL1 (No. 2, 3, and 6–8). On average, the mean expression of all inhibitory KIRs (including KIR2DL1, KIR2DL2, KIR2DL3, KIR2DL5, KIR3DL1, and KIR3DL2, hereafter collectively referred as pan-KIR) in the CD8+ T-cells from the 10 ECs was 27.1% (range 9.2–45.7%). The expression of pan-KIR in the CD8+ T-cells from the 5 HVLpts (mean 10.3%, range 3.8–20.4%) was significantly lower (P < 0.05). The same was true for the expression of KIR3DL1 in the CD8+ T-cells from the 10 ECs (mean 8%, range 0.9–15.5%), a percentage significantly higher than that observed in HVLpts (mean 2.2%, range 0.5–5.7%, P < 0.05) (Figures 5A,B; Table S4 in Supplementary Material).


Suppression of HIV Replication by CD8(+) Regulatory T-Cells in Elite Controllers.

Lu W, Chen S, Lai C, Lai M, Fang H, Dao H, Kang J, Fan J, Guo W, Fu L, Andrieu JM - Front Immunol (2016)

KIR3DL1 expression on CD8+ T-cells is required for HLA-B:Bw4-80Ile-dependent viral suppression. (A) Cytometric analysis of KIR expression in CD8+ T-cells freshly taken from a representative EC (No. 3). (B) Pan-KIR (total inhibitory KIRs) and KIR3DL1-expressing CD8+ T-cells were significantly higher in ECs (No. 1–5) (green) than in HVLpts carrying KIR3DL1 gene (No. 2, 3, and 6–8). (C) CD8+ T-cell-mediated viral suppression was reduced by 4–5 logs when freshly pan-KIR or KIR3DL1-depleted CD8+ T-cells were added as compared with bulk CD8+ T-cells. (D) CD8+ T-cell-mediated viral suppression was reduced by 3–4 logs in Bw4-80I/KIR3DL1-matched patients (EC#1–5) when the anti-KIR3DL1 antibody (clone Dx9) was added as compared with parallel cultures in the presence of anti-KIR3DS1 antibody (clone z27) or medium alone. In contrast, the low levels of viral suppression observed in Bw4-80I/KIR3DL1-mismatched patients (EC#6, HVLpt#2, and HVLpt#4) remained unaffected by the anti-KIR3DL1 antibody (clone Dx9).
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Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4834299&req=5

Figure 5: KIR3DL1 expression on CD8+ T-cells is required for HLA-B:Bw4-80Ile-dependent viral suppression. (A) Cytometric analysis of KIR expression in CD8+ T-cells freshly taken from a representative EC (No. 3). (B) Pan-KIR (total inhibitory KIRs) and KIR3DL1-expressing CD8+ T-cells were significantly higher in ECs (No. 1–5) (green) than in HVLpts carrying KIR3DL1 gene (No. 2, 3, and 6–8). (C) CD8+ T-cell-mediated viral suppression was reduced by 4–5 logs when freshly pan-KIR or KIR3DL1-depleted CD8+ T-cells were added as compared with bulk CD8+ T-cells. (D) CD8+ T-cell-mediated viral suppression was reduced by 3–4 logs in Bw4-80I/KIR3DL1-matched patients (EC#1–5) when the anti-KIR3DL1 antibody (clone Dx9) was added as compared with parallel cultures in the presence of anti-KIR3DS1 antibody (clone z27) or medium alone. In contrast, the low levels of viral suppression observed in Bw4-80I/KIR3DL1-mismatched patients (EC#6, HVLpt#2, and HVLpt#4) remained unaffected by the anti-KIR3DL1 antibody (clone Dx9).
Mentions: Having observed the correlation between the combination of KIR3DL1 and HLA-B:Bw4-80Ile genes and HIV-1 suppression in vitro and in vivo, we further investigated the expression of KIRs on CD8+ T-cells in the 10 ECs (No. 1–10) and the 5 HVLpts carrying KIR3DL1 (No. 2, 3, and 6–8). On average, the mean expression of all inhibitory KIRs (including KIR2DL1, KIR2DL2, KIR2DL3, KIR2DL5, KIR3DL1, and KIR3DL2, hereafter collectively referred as pan-KIR) in the CD8+ T-cells from the 10 ECs was 27.1% (range 9.2–45.7%). The expression of pan-KIR in the CD8+ T-cells from the 5 HVLpts (mean 10.3%, range 3.8–20.4%) was significantly lower (P < 0.05). The same was true for the expression of KIR3DL1 in the CD8+ T-cells from the 10 ECs (mean 8%, range 0.9–15.5%), a percentage significantly higher than that observed in HVLpts (mean 2.2%, range 0.5–5.7%, P < 0.05) (Figures 5A,B; Table S4 in Supplementary Material).

Bottom Line: We previously demonstrated in the Chinese macaque model that an oral vaccine made of inactivated SIV and Lactobacillus plantarum induced CD8(+) regulatory T-cells, which suppressed the activation of SIV(+)CD4(+) T-cells, prevented SIV replication, and protected macaques from SIV challenges.For that purpose, we investigated the in vitro antiviral activity of fresh CD8(+) T-cells on HIV-infected CD4(+) T-cells taken from 10 ECs.Our findings provide the first evidence for an instrumental role of KIR-expressing CD8(+) regulatory T-cells in the natural control of HIV-1 infection.

View Article: PubMed Central - PubMed

Affiliation: Institut de Recherche sur les Vaccins et l'Immunothérapie des Cancers et du Sida, Université de Paris Descartes, Paris, France; Sino-French Collaborative Laboratory, Tropical Medicine Institute, Guangzhou University of Chinese Medicine, Guangzhou, China.

ABSTRACT
We previously demonstrated in the Chinese macaque model that an oral vaccine made of inactivated SIV and Lactobacillus plantarum induced CD8(+) regulatory T-cells, which suppressed the activation of SIV(+)CD4(+) T-cells, prevented SIV replication, and protected macaques from SIV challenges. Here, we sought whether a similar population of CD8(+) T-regs would induce the suppression of HIV replication in elite controllers (ECs), a small population (3‰) of HIV-infected patients with undetectable HIV replication. For that purpose, we investigated the in vitro antiviral activity of fresh CD8(+) T-cells on HIV-infected CD4(+) T-cells taken from 10 ECs. The 10 ECs had a classical genomic profile: all of them carried the KIR3DL1 gene and 9 carried at least 1 allele of HLA-B:Bw4-80Ile (i.e., with an isoleucine residue at position 80). In the nine HLA-B:Bw4-80Ile-positive patients, we demonstrated a strong viral suppression by KIR3DL1-expressing CD8(+) T-cells that required cell-to-cell contact to switch off the activation signals in infected CD4(+) T-cells. KIR3DL1-expressing CD8(+) T-cells withdrawal and KIR3DL1 neutralization by a specific anti-killer cell immunoglobulin-like receptor (KIR) antibody inhibited the suppression of viral replication. Our findings provide the first evidence for an instrumental role of KIR-expressing CD8(+) regulatory T-cells in the natural control of HIV-1 infection.

No MeSH data available.


Related in: MedlinePlus