Effect of ipilimumab on the HIV reservoir in an HIV-infected individual with metastatic melanoma

Wightman, Fiona; Solomon, Ajantha; Kumar, Sanjeev; Urriola, Nicolás; Gallagher, Kerri; Hiener, Bonnie; Palmer, Sarah; McNeil, Catriona M.; Garsia, Roger; Lewin, Sharon R.

doi:10.1097/qad.0000000000000562

Cited by 131 publications

(106 citation statements)

References 16 publications

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“…In a previous case report of an HIV-infected individual on ART, we demonstrated a 20-fold increase in CA-US HIV RNA in CD4 + T-cells following multiple infusions of anti-CTLA-4 (ipilimumab), consistent with reversal of HIV latency [16] . This same individual received a single intravenous infusion of anti-PD-1 (nivolumab, 3mg/kg; Figure 2A) for the treatment of metastatic melanoma.…”

Section: Resultsmentioning

confidence: 77%

“…Fourth, the activity of anti-PD-1 (or anti-PD-L1) on latency reversal could potentially vary significantly in different recipients, as well described in responses to both antibodies for the management of malignancy [29] . Finally, it is unclear whether the degree of latency reversal observed here was in any way related to the prior administration of ipilimumab [16] . In clinical trials of individuals with metastatic melanoma, a clinical response to ipilimumab may predict a subsequent response to nivolumab [30] .…”

Section: Discussionmentioning

confidence: 99%

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

Evans

Sluis

Solomon

et al. 2018

Aids

Self Cite

134

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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Section: Resultsmentioning

confidence: 77%

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

Self Cite

134

128

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“…Moreover, CTLA-4 blockade has also been explored as a monotherapy in viremic, SIV-infected RMs, where its use was associated with increased viral reactivation (Cecchinato et al, 2008; Hryniewicz et al, 2006). Importantly, a recent case report demonstrates the ability of ipilimumab (anti-CTLA-4 antibody) to increase cell-associated HIV-1 RNA in an ART-suppressed, HIV-infected melanoma patient (Wightman et al, 2015). This case study, by revealing the impact of targeting extracellular CTLA-4, supports the capacity of immunotherapeutic blockades to bind this transiently expressed molecule.…”

Section: Discussionmentioning

confidence: 99%

CTLA-4+PD-1− Memory CD4+ T Cells Critically Contribute to Viral Persistence in Antiretroviral Therapy-Suppressed, SIV-Infected Rhesus Macaques

et al. 2017

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Summary Antiretroviral therapy (ART) suppresses viral replication in HIV-infected individuals, but does not eliminate the reservoir of latently infected cells. Recent work identified PD-1+ follicular helper T cells (Tfh) as an important cellular compartment for viral persistence. Here, using ART-treated, SIV-infected rhesus macaques, we show that CTLA-4+PD-1− memory CD4+ T cells, which share phenotypic markers with regulatory T cells, were enriched in SIV-DNA in blood, lymph nodes (LN), spleen, and gut, and contained replication-competent and infectious virus. In contrast to PD-1+ Tfh, SIV-enriched CTLA-4+PD-1− CD4+ T cells were found outside the B-cell follicle of the LN, predicted the size of the persistent viral reservoir during ART, and significantly increased their contribution to the SIV reservoir with prolonged ART-mediated viral suppression. We have shown that CTLA-4+PD-1− memory CD4+ T cells are a previously unrecognized component of the SIV and HIV reservoir that should be therapeutically targeted for a functional HIV-1 cure.

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“…This has led to the idea of using these antibodies to restore HIV-specific function in HIV infection, which will likely be a key component of a successful eradication strategy [101]. A single case report study has evaluated the in vivo effects of CTLA-4 blockade (ipilimumab) on the HIV reservoir in an HIV-infected individual with metastatic melanoma [102]. Treatment with ipilimumab induced a marked increase in cell-associated unspliced HIV RNA and was associated with a subsequent decline in plasma HIV RNA.…”

Section: Clinical Interventions: Breaking the Vicious Circlementioning

confidence: 99%

Residual inflammation and viral reservoirs

Massanella

Fromentin

Chomont

2016

Current Opinion in HIV and AIDS

125

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Purpose of review HIV persists in cellular and anatomical reservoirs during antiretroviral therapy (ART). Viral persistence is ensured by a variety of mechanisms including ongoing viral replication and proliferation of latently infected cells. In this review, we summarize recent findings establishing a link between the unresolved levels of inflammation observed in virally suppressed individuals on ART and the mechanisms responsible for HIV persistence. Recent findings Residual levels of viral replication during ART are associated with persistent low levels of immune activation, suggesting that unresolved inflammation can promote the replenishment of the HIV reservoir in tissues. In addition, the recent findings that the latent HIV reservoir is maintained by continuous proliferation of latently infected cells provide another mechanism by which residual inflammation could contribute to HIV persistence. Summary Residual inflammation during ART is likely to be a critical parameter contributing to HIV persistence. Therefore, reducing inflammation may be an efficient way to interfere with the maintenance of the HIV reservoir in virally suppressed individuals on ART.

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Effect of ipilimumab on the HIV reservoir in an HIV-infected individual with metastatic melanoma

Cited by 131 publications

References 16 publications

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

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

CTLA-4+PD-1− Memory CD4+ T Cells Critically Contribute to Viral Persistence in Antiretroviral Therapy-Suppressed, SIV-Infected Rhesus Macaques

Residual inflammation and viral reservoirs

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