1fc6d008e630cf444aa664438c4faf04 pmc_31805700.pdf 6a88b91d5eebaee6214cb211907a8d688e7ba1bd pmc_31805700.pdf 88b72b47d68d9a26511e3f75802c6ba36cc69d462bdb716fd62d5cc098dddce0 pmc_31805700.pdf Title: Enhancement of Antiviral CD8+ T-Cell Responses and Complete Remission of Metastatic Melanoma in an HIV-1-Infected Subject Treated with Pembrolizumab Subject: 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.12pt Keywords: Immune checkpoint inhibitors; pembrolizumab; HIV-1 reservoir; HIV-specific CD8+ T cells; HIV-1 curative strategies Author: Oscar Blanch-Lombarte, Cristina Gálvez, Boris Revollo, Esther Jiménez-Moyano, Josep M. Llibre, José Luís Manzano, Aram Boada, Judith Dalmau, Daniel E. Speiser, Bonaventura Clotet, Julia G. Prado and Javier Martinez-Picado Creator: LaTeX with hyperref package Producer: pdfTeX-1.40.18 CreationDate: Sun Dec 1 10:24:30 2019 CET ModDate: Sun Dec 1 10:24:30 2019 CET Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 11 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 2048660 bytes Optimized: no PDF version: 1.5 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- PBWJNP+URWPalladioL-Ital Type 1 Custom yes yes no 66 0 ZVBVJM+URWPalladioL-Bold Type 1 Custom yes yes no 67 0 YBEWNB+Rpxb Type 1 Builtin yes yes no 68 0 QTLELQ+Pxbsy Type 1 Builtin yes yes no 69 0 IOJCNK+VnURWPalladioL-Bold Type 1 Custom yes yes no 70 0 PBEMUL+URWPalladioL-Roma Type 1 Custom yes yes no 71 0 KORLVE+VnURWPalladioL Type 1 Custom yes yes no 72 0 ANZACO+Pxsy Type 1 Builtin yes yes no 73 0 HAKARX+Rpxr Type 1 Builtin yes yes no 74 0 BSDWLC+TimesNewRomanPSMT Type 1C WinAnsi yes 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PageMode: UseNone Outlines: Item: Title: ぉのぴひはつふっぴどはのぜ〴〩਼㰠⽓ 䝯呯 䐠⡳散瑩潮⸲ Item: Title: ぅへばづひどねづのぴちぬぜ〴ぜ〰こづっぴどはのぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮ㄩ‾㸊⡜㌷㙜㌷㝜〰ぉねねふのづぜ〴ぜ〰ぐとづのはぴべばづぜ〴ぜ〰はてぜ〴ぜ〰ごはぴちぬぜ〴ぜ〰ぃい〸〫ぜ〴ぜ〰ちのつぜ〴ぜ〰えぉざ〭〱ぜ〴ぜ〰こばづっどてどっ〭ぃい〸〫ぜ〴ぜ〰ごぜ〴ぜ〰ぃづぬぬびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㈩‾㸊⡜㌷㙜㌷㝜〰ごはぴちぬぜ〴ぜ〰えぉざ〭〱ぜ〴ぜ〰いぎぁ〬ぜ〴ぜ〰ぃづぬぬ〭ぁびびはっどちぴづつぜ〴ぜ〰えぉざ〭〱ぜ〴ぜ〰げぎぁ〬ぜ〴ぜ〰ちのつぜ〴ぜ〰さぬぴひちびづのびどぴどぶづぜ〴ぜ〰ざどひちぬぜ〴ぜ〰がはちつぜ〴〩਼㰠⽓ 䝯呯 䐠⡳散瑩潮⸳ Children: Item: Title: ぉねねふのづぜ〴ぜ〰ぐとづのはぴべばづぜ〴ぜ〰はてぜ〴ぜ〰ごはぴちぬぜ〴ぜ〰ぃい〸〫ぜ〴ぜ〰ちのつぜ〴ぜ〰えぉざ〭〱ぜ〴ぜ〰こばづっどてどっ〭ぃい〸〫ぜ〴ぜ〰ごぜ〴ぜ〰ぃづぬぬびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㈩‾㸊⡜㌷㙜㌷㝜〰ごはぴちぬぜ〴ぜ〰えぉざ〭〱ぜ〴ぜ〰いぎぁ〬ぜ〴ぜ〰ぃづぬぬ〭ぁびびはっどちぴづつぜ〴ぜ〰えぉざ〭〱ぜ〴ぜ〰げぎぁ〬ぜ〴ぜ〰ちのつぜ〴ぜ〰さぬぴひちびづのびどぴどぶづぜ〴ぜ〰ざどひちぬぜ〴ぜ〰がはちつぜ〴〩਼㰠⽓ 䝯呯 䐠⡳散瑩潮⸳ Item: Title: ごはぴちぬぜ〴ぜ〰えぉざ〭〱ぜ〴ぜ〰いぎぁ〬ぜ〴ぜ〰ぃづぬぬ〭ぁびびはっどちぴづつぜ〴ぜ〰えぉざ〭〱ぜ〴ぜ〰げぎぁ〬ぜ〴ぜ〰ちのつぜ〴ぜ〰さぬぴひちびづのびどぴどぶづぜ〴ぜ〰ざどひちぬぜ〴ぜ〰がはちつぜ〴〩਼㰠⽓ 䝯呯 䐠⡳散瑩潮⸳ Item: Title: げづびふぬぴびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㌮ㄩ‾㸊⡜㌷㙜㌷㝜〰ぐづねぢひはぬどぺふねちぢぜ〴ぜ〰ぁつねどのどびぴひちぴどはのぜ〴ぜ〰ぉのつふっづびぜ〴ぜ〰ちぜ〴ぜ〰きちひにづつぜ〴ぜ〰ちのつぜ〴ぜ〰ごひちのびどづのぴぜ〴ぜ〰ぉのっひづちびづぜ〴ぜ〰はてぜ〴ぜ〰えがぁ〭いげ〯〫ぃい〳〸〫ぜ〴ぜ〰ぅへばひづびびどはのぜ〴ぜ〰どのぜ〴ぜ〰ごぅきぜ〴ぜ〰ちのつぜ〴ぜ〰ごぅぜ〴ぜ〰ぃい〸〫ぜ〴ぜ〰ごぜ〴ぜ〰ぃづぬぬびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㌮㈩‾㸊⡜㌷㙜㌷㝜〰ぅのとちのっづねづのぴぜ〴ぜ〰はてぜ〴ぜ〰ごぎうぜ〴ぜ〰ぐひはつふっぴどはのぜ〴ぜ〰どのぜ〴ぜ〰えぉざ〭〱ぜ〴ぜ〰こばづっどてどっ〭ぃい〸〫ぜ〴ぜ〰ご〭ぃづぬぬぜ〴ぜ〰げづびばはのびづびぜ〴ぜ〰ちてぴづひぜ〴ぜ〰ぐづねぢひはぬどぺふねちぢぜ〴ぜ〰ぉのどぴどちぴどはのぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㌮㌩‾㸊⡜㌷㙜㌷㝜〰うふのっぴどはのちぬぜ〴ぜ〰こぷどぴっとぜ〴ぜ〰てひはねぜ〴ぜ〰ごぎうぜ〴ぜ〰ぴはぜ〴ぜ〰ぉが〭〲ぜ〴ぜ〰ぐひはてどぬづぜ〴ぜ〰どのぜ〴ぜ〰えぉざ〭〱ぜ〴ぜ〰こばづっどてどっ〭ぃい〸〫ぜ〴ぜ〰ご〭ぃづぬぬぜ〴ぜ〰げづびばはのびづびぜ〴ぜ〰ちてぴづひぜ〴ぜ〰ぐづねぢひはぬどぺふねちぢぜ〴ぜ〰うはぬぬはぷぜ〴ぜ〰さばぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㌮㐩‾㸊⡜㌷㙜㌷㝜〰ごひちのびどづのぴぜ〴ぜ〰いづっちべびぜ〴ぜ〰はてぜ〴ぜ〰ごはぴちぬぜ〴ぜ〰えぉざ〭〱ぜ〴ぜ〰いぎぁぜ〴〩਼㰠⽓ 䝯呯 䐠⡳散瑩潮⸴ Children: Item: Title: ぐづねぢひはぬどぺふねちぢぜ〴ぜ〰ぁつねどのどびぴひちぴどはのぜ〴ぜ〰ぉのつふっづびぜ〴ぜ〰ちぜ〴ぜ〰きちひにづつぜ〴ぜ〰ちのつぜ〴ぜ〰ごひちのびどづのぴぜ〴ぜ〰ぉのっひづちびづぜ〴ぜ〰はてぜ〴ぜ〰えがぁ〭いげ〯〫ぃい〳〸〫ぜ〴ぜ〰ぅへばひづびびどはのぜ〴ぜ〰どのぜ〴ぜ〰ごぅきぜ〴ぜ〰ちのつぜ〴ぜ〰ごぅぜ〴ぜ〰ぃい〸〫ぜ〴ぜ〰ごぜ〴ぜ〰ぃづぬぬびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㌮㈩‾㸊⡜㌷㙜㌷㝜〰ぅのとちのっづねづのぴぜ〴ぜ〰はてぜ〴ぜ〰ごぎうぜ〴ぜ〰ぐひはつふっぴどはのぜ〴ぜ〰どのぜ〴ぜ〰えぉざ〭〱ぜ〴ぜ〰こばづっどてどっ〭ぃい〸〫ぜ〴ぜ〰ご〭ぃづぬぬぜ〴ぜ〰げづびばはのびづびぜ〴ぜ〰ちてぴづひぜ〴ぜ〰ぐづねぢひはぬどぺふねちぢぜ〴ぜ〰ぉのどぴどちぴどはのぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㌮㌩‾㸊⡜㌷㙜㌷㝜〰うふのっぴどはのちぬぜ〴ぜ〰こぷどぴっとぜ〴ぜ〰てひはねぜ〴ぜ〰ごぎうぜ〴ぜ〰ぴはぜ〴ぜ〰ぉが〭〲ぜ〴ぜ〰ぐひはてどぬづぜ〴ぜ〰どのぜ〴ぜ〰えぉざ〭〱ぜ〴ぜ〰こばづっどてどっ〭ぃい〸〫ぜ〴ぜ〰ご〭ぃづぬぬぜ〴ぜ〰げづびばはのびづびぜ〴ぜ〰ちてぴづひぜ〴ぜ〰ぐづねぢひはぬどぺふねちぢぜ〴ぜ〰うはぬぬはぷぜ〴ぜ〰さばぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㌮㐩‾㸊⡜㌷㙜㌷㝜〰ごひちのびどづのぴぜ〴ぜ〰いづっちべびぜ〴ぜ〰はてぜ〴ぜ〰ごはぴちぬぜ〴ぜ〰えぉざ〭〱ぜ〴ぜ〰いぎぁぜ〴〩਼㰠⽓ 䝯呯 䐠⡳散瑩潮⸴ Item: Title: ぅのとちのっづねづのぴぜ〴ぜ〰はてぜ〴ぜ〰ごぎうぜ〴ぜ〰ぐひはつふっぴどはのぜ〴ぜ〰どのぜ〴ぜ〰えぉざ〭〱ぜ〴ぜ〰こばづっどてどっ〭ぃい〸〫ぜ〴ぜ〰ご〭ぃづぬぬぜ〴ぜ〰げづびばはのびづびぜ〴ぜ〰ちてぴづひぜ〴ぜ〰ぐづねぢひはぬどぺふねちぢぜ〴ぜ〰ぉのどぴどちぴどはのぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㌮㌩‾㸊⡜㌷㙜㌷㝜〰うふのっぴどはのちぬぜ〴ぜ〰こぷどぴっとぜ〴ぜ〰てひはねぜ〴ぜ〰ごぎうぜ〴ぜ〰ぴはぜ〴ぜ〰ぉが〭〲ぜ〴ぜ〰ぐひはてどぬづぜ〴ぜ〰どのぜ〴ぜ〰えぉざ〭〱ぜ〴ぜ〰こばづっどてどっ〭ぃい〸〫ぜ〴ぜ〰ご〭ぃづぬぬぜ〴ぜ〰げづびばはのびづびぜ〴ぜ〰ちてぴづひぜ〴ぜ〰ぐづねぢひはぬどぺふねちぢぜ〴ぜ〰うはぬぬはぷぜ〴ぜ〰さばぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㌮㐩‾㸊⡜㌷㙜㌷㝜〰ごひちのびどづのぴぜ〴ぜ〰いづっちべびぜ〴ぜ〰はてぜ〴ぜ〰ごはぴちぬぜ〴ぜ〰えぉざ〭〱ぜ〴ぜ〰いぎぁぜ〴〩਼㰠⽓ 䝯呯 䐠⡳散瑩潮⸴ Item: Title: うふのっぴどはのちぬぜ〴ぜ〰こぷどぴっとぜ〴ぜ〰てひはねぜ〴ぜ〰ごぎうぜ〴ぜ〰ぴはぜ〴ぜ〰ぉが〭〲ぜ〴ぜ〰ぐひはてどぬづぜ〴ぜ〰どのぜ〴ぜ〰えぉざ〭〱ぜ〴ぜ〰こばづっどてどっ〭ぃい〸〫ぜ〴ぜ〰ご〭ぃづぬぬぜ〴ぜ〰げづびばはのびづびぜ〴ぜ〰ちてぴづひぜ〴ぜ〰ぐづねぢひはぬどぺふねちぢぜ〴ぜ〰うはぬぬはぷぜ〴ぜ〰さばぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㌮㐩‾㸊⡜㌷㙜㌷㝜〰ごひちのびどづのぴぜ〴ぜ〰いづっちべびぜ〴ぜ〰はてぜ〴ぜ〰ごはぴちぬぜ〴ぜ〰えぉざ〭〱ぜ〴ぜ〰いぎぁぜ〴〩਼㰠⽓ 䝯呯 䐠⡳散瑩潮⸴ Item: Title: ごひちのびどづのぴぜ〴ぜ〰いづっちべびぜ〴ぜ〰はてぜ〴ぜ〰ごはぴちぬぜ〴ぜ〰えぉざ〭〱ぜ〴ぜ〰いぎぁぜ〴〩਼㰠⽓ 䝯呯 䐠⡳散瑩潮⸴ Item: Title: いどびっふびびどはのぜ〴〩਼㰠⽓ 䝯呯 䐠⡳散瑩潮⸴ Item: Title: げづてづひづのっづび Filters: FilterPipeline: FlateDecode Fonts: Type1: Font: BaseFont: LEVXPH+EURM10 FontSubset: true FirstChar: 11 LastChar: 22 FontDescriptor: FontName: LEVXPH+EURM10 Flags: Symbolic 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