Kaposi's sarcoma-associated herpesvirus-specific immune reconstitution and antiviral effect of combined HAART/chemotherapy in HIV clade C-infected individuals with Kaposi's sarcoma

Bihl, Florian; Mosam, Anisa; Henry, Leah N; Chisholm, John V.; Dollard, Sheila; Gumbi, Pamela P.; Cassol, Edana; Page, Taryn; Mueller, Nicolas J.; Kiepiela, Photini; Martin, Jeff; Coovadia, Hoosen M.; Scadden, David T.; Berthou, Christian

doi:10.1097/qad.0b013e328182df03

Cited by 75 publications

(60 citation statements)

References 35 publications

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“…Patients with KS have decreased KSHV-specific T-cell responses when compared with KSHVinfected individuals without KS. 6 Increases in KSHV-specific T-cell responses have been observed in patients with HIV-associated KS treated with ART 7 and in transplant recipients whose KS regressed with reduced immunosuppression. 8 In patients with HIV-associated KS, ART is the foundation of therapy 2,9 ; HIV control allows restoration of KSHV-directed cellular immunity, and institution of ART alone can lead to regression of KS in a minority of patients.…”

Section: Introductionmentioning

confidence: 99%

“…8 In patients with HIV-associated KS, ART is the foundation of therapy 2,9 ; HIV control allows restoration of KSHV-directed cellular immunity, and institution of ART alone can lead to regression of KS in a minority of patients. 7,10 For patients with HIV-associated KS whose response to ART is incomplete, the most commonly added KS-specific therapies are liposomal anthracyclines and paclitaxel; each is approved by the United States Food and Drug Administration for HIV-associated KS, with response rates ranging from 46% to 76%.…”

Section: Introductionmentioning

confidence: 99%

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Pomalidomide for Symptomatic Kaposi's Sarcoma in People With and Without HIV Infection: A Phase I/II Study

Polizzotto¹,

Uldrick

Wyvill

et al. 2016

JCO

101

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Kaposi's sarcoma (KS) is a multicentric tumor caused by Kaposi's sarcoma-associated herpesvirus. Unmet needs include therapies that are oral, anthracycline sparing, and deliverable in resourcelimited settings. We evaluated pomalidomide, an oral immune modulatory agent, in patients with symptomatic KS. MethodsThe primary objectives were to assess tolerability, pharmacokinetics, and activity. Initial dosage level was 5 mg once per day for 21 days per 28-day cycle, with a de-escalated level of 3 mg if not tolerable, and aspirin 81 mg once per day thromboprophylaxis. HIV-infected patients required controlled viremia with either persistent KS despite 3 months of antiretroviral therapy (ART) or progressive KS despite 2 months of ART. Evaluations included tumor response and health-related quality of life (HRQL). ResultsTwenty-two patients were treated; 15 (68%) were HIV infected, 17 (77%) had advanced (T1) disease, and 19 (86%) previous KS therapy excluding ART. All were treated with 5 mg because no dose-limiting toxicities occurred. Over 156 cycles, the grade 3/4 adverse events possibly attributable to therapy were neutropenia (23 cycles, 10 patients), infection (1 cycle), and edema (1 cycle). Sixteen patients responded (73%; 95% CI, 50% to 89%): nine of 15 HIV-infected patients (60%; 95% CI, 32% to 84%) and all seven HIV-uninfected patients (100%; 95% CI, 59% to 100%). Median time to response was 4 weeks (range, 4 to 36 weeks). HRQL showed no impairment during therapy and improved satisfaction with appearance at end therapy (P = .03). Significant increases in CD4 + and CD8 + cells were seen in patients with and without HIV, together with a transient increase in Kaposi's sarcoma-associated herpesvirus viral load at week 4 (P = .05). ConclusionPomalidomide is well tolerated and active in KS regardless of HIV status. Responses were rapid, with improved self-reported outcomes, and occurred in advanced and heavily pretreated disease. Correlative studies support, at least in part, an immunologic mechanism of activity.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Pomalidomide for Symptomatic Kaposi's Sarcoma in People With and Without HIV Infection: A Phase I/II Study

Polizzotto¹,

Uldrick

Wyvill

et al. 2016

JCO

101

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“…The regimen with HAART and chemotherapy demonstrate an effective suppression of HHV8 viral replication. HHV8 viral loads have been found to correlate with the extent of KS lesions, suggesting that the chemotherapeutic compounds could exert a direct antiproliferative effect on HHV8-infected cells, thereby limiting viral replication [15]. However, the number of chemotherapy cycles needed for IRIS-SK is still unclear [10].…”

Section: Discussionmentioning

confidence: 99%

AIDS-Related Kaposi’s sarcoma and Associated Immune Reconstitution Inflammatory Syndrome

Melé‐Ninot¹,

Sola-Ortigosa²

2016

Clin Microbiol

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“…An important finding from studying KS patients either with HIV, or those immunosuppressed after solid organ transplantation, is that this malignancy can resolve on restoration of immune function through the administration of highly active antiretroviral therapy (HAART) 2 or relaxation of immunosuppression, 3 respectively. These findings and the increased incidence of PEL and MCD in HIV patients 4 suggest that T-cell immunity is critical for control of KSHV infection and disease.…”

Section: Introductionmentioning

confidence: 99%

“…[7][8][9][10][11] The administration of HAART to HIVassociated KS patients has been associated with the detection and increase in KSHV-specific responses over time. 2,12 Little is known, however, about the size of responses made to the potential tumor antigens vFLIP or vCyclin in healthy donors or patients with disease.How T-cell control is exercised over KSHV-associated malignancies is unclear, particularly in view of the immune evasion mechanisms used by the virus. Thus, LANA encodes an extensive acidic repeat sequence that inhibits efficient synthesis and proteasomal degradation of itself.…”

mentioning

confidence: 99%

T-cell immunity to Kaposi sarcoma–associated herpesvirus: recognition of primary effusion lymphoma by LANA-specific CD4+ T cells

Sabbah

Jagne

Zuo

et al. 2012

Blood

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T-cell immunity is important for controlling Kaposi sarcoma-associated herpesvirus (KSHV) diseases IntroductionKaposi sarcoma-associated herpesvirus (KSHV) is a lymphotropic human herpesvirus with oncogenic potential. KSHV infects endothelial and B cells where it can cause malignancies of these cell types, namely, Kaposi sarcoma (KS) and primary effusion lymphoma (PEL), respectively, 1 and it is associated with the B-cell pathology multicentric Castleman disease (MCD). The HIV epidemic has made these diseases significantly more prevalent, with KS being the most frequently reported HIV-associated malignancy.An important finding from studying KS patients either with HIV, or those immunosuppressed after solid organ transplantation, is that this malignancy can resolve on restoration of immune function through the administration of highly active antiretroviral therapy (HAART) 2 or relaxation of immunosuppression, 3 respectively. These findings and the increased incidence of PEL and MCD in HIV patients 4 suggest that T-cell immunity is critical for control of KSHV infection and disease. Potential immune targets in KS include the latent antigens, namely, the genome maintenance protein LANA that is expressed in all infected cells and malignancies, the viral cyclin vCyclin, the antiapoptotic multifunctional protein vFLIP, and Kaposin. PELs and infected cells in MCD also express at least 2 other proteins, the viral IL-6 and the immunomodulatory and antiapoptotic protein vIRF3.Relatively low T-cell responses to LANA and Kaposin have been described in healthy immunocompetent donors; 5,6 however, most studies have been undertaken using donors with a disrupted immune system or in disease settings, focusing on responses to LANA and Kaposin. Thus, HIV-infected patients on HAART who control KSHV have been found to make T-cell responses to LANA, MCD patients make responses comparable to HIV patients on HAART, but patients with KS disease have very weak or no detectable responses. [7][8][9][10][11] The administration of HAART to HIVassociated KS patients has been associated with the detection and increase in KSHV-specific responses over time. 2,12 Little is known, however, about the size of responses made to the potential tumor antigens vFLIP or vCyclin in healthy donors or patients with disease.How T-cell control is exercised over KSHV-associated malignancies is unclear, particularly in view of the immune evasion mechanisms used by the virus. Thus, LANA encodes an extensive acidic repeat sequence that inhibits efficient synthesis and proteasomal degradation of itself. 13 This strategy, also used by the Epstein-Barr virus (EBV) homolog EBNA1, 14 limits the supply of peptides for presentation to CD8 ϩ T cells. 15 KSHV-specific T-cell killing of infected endothelial cells has not been tested; however, such in vitro infected cells transiently express K5 16 that functions to down-regulate surface HLA class I and other costimulatory molecules. No studies have been performed on the ability of T cells to recognize KSHV-infected cells fro...

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Kaposi's sarcoma-associated herpesvirus-specific immune reconstitution and antiviral effect of combined HAART/chemotherapy in HIV clade C-infected individuals with Kaposi's sarcoma

Abstract: The data show a temporal association between the clinical improvement of KS and the re-appearance of KSHV-specific cellular immunity, and demonstrate an effective suppression of KSHV viral replication using combination therapy.

Cited by 75 publications

References 35 publications

Pomalidomide for Symptomatic Kaposi's Sarcoma in People With and Without HIV Infection: A Phase I/II Study

Pomalidomide for Symptomatic Kaposi's Sarcoma in People With and Without HIV Infection: A Phase I/II Study

AIDS-Related Kaposi’s sarcoma and Associated Immune Reconstitution Inflammatory Syndrome

T-cell immunity to Kaposi sarcoma–associated herpesvirus: recognition of primary effusion lymphoma by LANA-specific CD4+ T cells

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