Drastic decrease of the HIV reservoir in a patient treated with nivolumab for lung cancer

Guihot, Amélie; Marcelin, Anne‐Geneviève; Massiani, Marie-Ange; Samri, Assia; Soulié, Cathia; Autran, Brigitte; Spano, Jean‐Philippe

doi:10.1093/annonc/mdx696

Cited by 146 publications

(123 citation statements)

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“…Previous clinical studies have shown that PD-1/PD-L1 blockade can intervene in both the development of HIV infection and in complications associated with chronic HBV infection [21,35,36]. In this study, PD-L1 blockade induced higher production of MCP-1 by activated monocytes and was associated with decreased levels of EV-A71 replication, indicating that PD-L1 blockade can recover monocyte function to some extent, thereby inhibiting virus replication in vitro.…”

Section: Discussionsupporting

confidence: 52%

Low frequency, weak MCP-1 secretion and exhausted immune status of peripheral monocytes were associated with progression of severe enterovirus A71-infected hand, foot and mouth disease

Pei

Fan

Zhang

et al. 2019

Clinical and Experimental Immunology

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A minority of hand, foot and mouth disease (HFMD) caused by enterovirus A71 (EV-A71) results in severe neural complications. However, whether monocyte-mediated immunity is involved in the disease progression of HFMD remains unknown. One hundred and twenty mild and 103 severe HFMD patients were recruited and enzyme-linked immunosorbent assay (ELISA), flow cytometry and Transwell culture were performed in the study. Peripheral monocyte counts were lower in both absolute counts and frequencies in severe cases compared to mild cases. After screening 10 monocyte-related cytokines by ELISA, only monocyte chemoattractant protein-1 (MCP-1) was found at higher levels in sera of mild cases compared to those with severe symptoms. Monocytes purified from mild cases produced more MCP-1 than the cells from severe patients when stimulated in vitro. We observed that immune exhaustion markers programmed death 1 (PD-1) and programmed death ligand 1 (PD-L1) were highly regulated on the surface of monocytes from severe cases compared to mild cases. PD-L1 blockade induced a higher production of MCP-1 in the supernatant of a Transwell system. The production of MCP-1 also increased following PD-L1 blockade of purified monocytes activated by granulocyte-macrophage colony-stimulating factor (GM-CSF) combined with R848 or EV-A71 virus. Our results indicate that absolute count, frequency and levels of MCP-1 secretion of peripheral monocytes, together with their immune status, probably contribute to differential disease prognosis in EV-A71associated HFMD.Keywords: enterovirus A71 (EV-A71), hand, foot and mouth disease (HFMD), monocyte, monocyte chemoattractant protein-1 (MCP-1), programmed cell death-1 (PD-1)

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Section: Discussionsupporting

confidence: 52%

Low frequency, weak MCP-1 secretion and exhausted immune status of peripheral monocytes were associated with progression of severe enterovirus A71-infected hand, foot and mouth disease

Pei

Fan

Zhang

et al. 2019

Clinical and Experimental Immunology

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“…Blocking interactions between PD-1 and PD-L1, as well as CTLA-4 and its ligands (CD80 and CD86), has been shown to increase HIV-specific CD4 + and CD8 + T-cell function both ex vivo [23] , and in vivo in SIV-infected macaques [24] . In a recent case report, the administration of multiple repeat doses of anti-PD-1 (nivolumab) to an HIV-infected individual on ART was well tolerated and resulted in a dramatic increase in HIV-specific CD8 + T-cells, a modest and delayed increase in plasma HIV RNA and a 3 log decrease in HIV DNA [25] . The mechanism of how HIV DNA decreased in this case was unclear, but could potentially be a consequence of T-cell proliferation, which would dilute unintegrated HIV DNA that is also included in a total DNA assay.…”

Section: Discussionmentioning

confidence: 99%

Programmed cell death-1 contributes to the establishment and maintenance of HIV-1 latency

Evans

Sluis

Solomon

et al. 2018

Aids

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128

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Objective In HIV-infected individuals on antiretroviral therapy (ART), latent HIV is enriched in CD4+ T-cells expressing immune checkpoint molecules (ICs), in particular programmed cell death-1 (PD-1). We therefore assessed the effect of blocking PD-1 on latency, both in vitro and in vivo. Methods HIV latency was established in vitro following co-culture of resting CD4+ T-cells with myeloid dendritic cells. Expression of PD-1 was quantified by flow cytometry, and latency assessed in sorted PD-1high and PD-1low/− non-proliferating CD4+ memory T-cells. The role of PD-1 in the establishment of latency was determined by adding anti-PD-1 (pembrolizumab) to co-cultures before and after infection. Additionally, a single infusion of anti-PD-1 (nivolumab) was administered to an HIV-infected individual on ART with metastatic melanoma, and cell-associated (CA) HIV DNA and RNA, and plasma HIV RNA were quantified. Results HIV latency was significantly enriched in PD-1high compared to PD-1low/− nonproliferating, CD4+ memory T-cells. Sorting for an additional IC, T-cell immunoglobulin domain and mucin domain-3 (Tim-3), in combination with PD-1 further enriched for latency. Blocking PD-1 prior to HIV infection, in vitro, resulted in a modest but significant decrease in latently infected cells in all donors (n=6). The administration of anti-PD-1 to an HIV-infected individual on ART, resulted in a significant increase in CA HIV RNA in CD4+ T-cells, without significant changes in HIV DNA or plasma HIV RNA, consistent with reversal of HIV latency. Conclusions PD-1 contributes to the establishment and maintenance of HIV latency and should be explored as a target, in combination with other ICs, to reverse latency.

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“…Peripheral blood mononuclear cells (PBMCs) and plasma samples were collected before each pembrolizumab administration at weeks (w) 0, 3,9,18,27, and 36 ( Figure 1A). Additionally, we evaluated the short-term effect of pembrolizumab in a sample one day after pembrolizumab administration at w18 (w18+1).…”

mentioning

confidence: 99%

Enhancement of Antiviral CD8+ T-Cell Responses and Complete Remission of Metastatic Melanoma in an HIV-1-Infected Subject Treated with Pembrolizumab

Blanch-Lombarte

Gálvez

Revollo

et al. 2019

JCM

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Background: Pembrolizumab is an immune checkpoint inhibitor against programmed cell death protein-1 (PD-1) approved for therapy in metastatic melanoma. PD-1 expression is associated with a diminished functionality in HIV-1 specific-CD8 + T cells. It is thought that PD-1 blockade could contribute to reinvigorate antiviral immunity and reduce the HIV-1 reservoir. Methods: Upon metastatic melanoma diagnosis, an HIV-1-infected individual on stable suppressive antiretroviral regimen was treated with pembrolizumab. A PET-CT was performed before and one year after pembrolizumab initiation. We monitored changes in the immunophenotype and HIV-1 specific-CD8 + T-cell responses during 36 weeks of treatment. Furthermore, we assessed changes in the viral reservoir by total HIV-1 DNA, cell-associated HIV-1 RNA, and ultrasensitive plasma viral load. Results: Complete metabolic response was achieved after pembrolizumab treatment of metastatic melanoma. Activated CD8 + T-cells expressing HLA-DR + /CD38 + transiently increased over the first nine weeks of treatment. Concomitantly, there was an augmented response of HIV-1 specific-CD8 + T cells with TNF production and poly-functionality, transitioning from TNF to an IL-2 profile. Furthermore, a transient reduction of 24% and 32% in total HIV-1 DNA was observed at weeks 3 and 27, respectively, without changes in other markers of viral persistence. Conclusions: These data demonstrate that pembrolizumab may enhance the HIV-1 specific-CD8 + T-cell response, marginally affecting the HIV-1 reservoir. A transient increase of CD8 + T-cell activation, TNF production, and poly-functionality resulted from PD-1 blockade. However, the lack of sustained changes in the viral reservoir suggests that viral reactivation is needed concomitantly with HIV-1-specific immune enhancement.

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Drastic decrease of the HIV reservoir in a patient treated with nivolumab for lung cancer

Abstract: current, and future developments of therapeutic agents for treatment of chronic hepatitis B virus infection.

Cited by 146 publications

References 4 publications

Low frequency, weak MCP-1 secretion and exhausted immune status of peripheral monocytes were associated with progression of severe enterovirus A71-infected hand, foot and mouth disease

Low frequency, weak MCP-1 secretion and exhausted immune status of peripheral monocytes were associated with progression of severe enterovirus A71-infected hand, foot and mouth disease

Programmed cell death-1 contributes to the establishment and maintenance of HIV-1 latency

Enhancement of Antiviral CD8+ T-Cell Responses and Complete Remission of Metastatic Melanoma in an HIV-1-Infected Subject Treated with Pembrolizumab

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