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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

Association between CD8+ T-cell-mediated viral suppression and HLA-B Bw4-80Ile/KIRsDL1 combined genotypes. For details, see Section “HLA and KIR Interaction in CD8+ T-Cell-Mediated Viral Suppression” in Section “Results.”
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Figure 4: Association between CD8+ T-cell-mediated viral suppression and HLA-B Bw4-80Ile/KIRsDL1 combined genotypes. For details, see Section “HLA and KIR Interaction in CD8+ T-Cell-Mediated Viral Suppression” in Section “Results.”

Mentions: In ECs No. 1–3 (who carried at least one Bw4-80Ile allele and were KIR3DL1), the CD8+ T-cell-mediated viral suppression was very strong (5–6 logs) whether target CD4+ T-cells were autologous or allogeneic (Figure 4, left green bars), In contrast, CD8+ T-cells from the same EC No. 1–3 had a much lower suppressive activity (barely reaching 3 logs) on target CD4+ T-cells of EC No. 6 or on those of HVLpts No. 1–3 who did not carry Bw4-80Ile (since they were Bw6/Bw6 or Bw6/Bw4-80Thr) (Figure 4, middle, green bars). Moreover, as already shown (Figure 2A), the same low level of viral suppression was achieved when EC No. 6 CD8+ T-cells were cocultured with their autologous target CD4+ T cells; EC No. 6 carried the KIR3DL1 gene but had no Bw4-80Ile allele (he was Bw6/Bw6). Interestingly, although EC No. 6 did carry the KIR3DL1 gene, his CD8+ T-cells also induced a low level of viral suppression when cocultured with HLA-B:Bw4-80Ile-carrying target CD4+ T cells from ECs No. 1–3 (Figure 4, blue bar); a baseline (1 log) viral suppression was finally observed in HLA-B:Bw4-80Ile-carrying target CD4+ T cells cocultured with KIR3DL1-carrying CD8+ T-cells from HDs (Figure 4, red bars). On the other hand, a strong CD8+ T-cell-mediated viral suppression was observed with allogeneic target CD4+ T-cells of HVLpt No. 4 and of HDs No. 1 and 2, because all three individuals carried at least one Bw4-80Ile allele, while the effector CD8+ T-cells carried the KIR3DL1 gene (Figure 4, right, green bars).


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)

Association between CD8+ T-cell-mediated viral suppression and HLA-B Bw4-80Ile/KIRsDL1 combined genotypes. For details, see Section “HLA and KIR Interaction in CD8+ T-Cell-Mediated Viral Suppression” in Section “Results.”
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Related In: Results  -  Collection

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

Figure 4: Association between CD8+ T-cell-mediated viral suppression and HLA-B Bw4-80Ile/KIRsDL1 combined genotypes. For details, see Section “HLA and KIR Interaction in CD8+ T-Cell-Mediated Viral Suppression” in Section “Results.”
Mentions: In ECs No. 1–3 (who carried at least one Bw4-80Ile allele and were KIR3DL1), the CD8+ T-cell-mediated viral suppression was very strong (5–6 logs) whether target CD4+ T-cells were autologous or allogeneic (Figure 4, left green bars), In contrast, CD8+ T-cells from the same EC No. 1–3 had a much lower suppressive activity (barely reaching 3 logs) on target CD4+ T-cells of EC No. 6 or on those of HVLpts No. 1–3 who did not carry Bw4-80Ile (since they were Bw6/Bw6 or Bw6/Bw4-80Thr) (Figure 4, middle, green bars). Moreover, as already shown (Figure 2A), the same low level of viral suppression was achieved when EC No. 6 CD8+ T-cells were cocultured with their autologous target CD4+ T cells; EC No. 6 carried the KIR3DL1 gene but had no Bw4-80Ile allele (he was Bw6/Bw6). Interestingly, although EC No. 6 did carry the KIR3DL1 gene, his CD8+ T-cells also induced a low level of viral suppression when cocultured with HLA-B:Bw4-80Ile-carrying target CD4+ T cells from ECs No. 1–3 (Figure 4, blue bar); a baseline (1 log) viral suppression was finally observed in HLA-B:Bw4-80Ile-carrying target CD4+ T cells cocultured with KIR3DL1-carrying CD8+ T-cells from HDs (Figure 4, red bars). On the other hand, a strong CD8+ T-cell-mediated viral suppression was observed with allogeneic target CD4+ T-cells of HVLpt No. 4 and of HDs No. 1 and 2, because all three individuals carried at least one Bw4-80Ile allele, while the effector CD8+ T-cells carried the KIR3DL1 gene (Figure 4, right, green bars).

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