Progression Of Kaposi's Sarcoma Research Articles

Mortality and Associated Risk Factors Among People Living With HIV With Kaposi Sarcoma: A5263/AMC066 and A5264/AMC067.

AIDS-related Kaposi sarcoma (AIDS-KS) remains a leading cause of morbidity and mortality among people living with HIV in Africa. Mortality among people with AIDS-KS on antiretroviral therapy remains high compared with people on antiretroviral therapy who do not have AIDS-KS. People living with HIV with Kaposi sarcoma (KS) who participated in 2 randomized trials (A5263/AMC066 [advanced stage] and A5264/AMC067 [mild-to-moderate stage]) conducted by AIDS Clinical Trials Group/AIDS Malignancy Consortium in low- and middle-income countries. We estimated mortality rates over the trial period. Cox proportional hazards regressions were used to identify baseline characteristics associated with mortality and compared mortality rates between participants who had KS progression within 12 weeks of treatment initiation (early progression of KS [KS-PD]) and those who did not. Of the 329 and 189 eligible participants in A5263/AMC066 and A5264/AMC067, 71 (21.6%) and 24 (12.7%) died, respectively. In both trials, hypoalbuminemia was associated with increased hazards of death compared with normal albumin; A5263/AMC066: mild hypoalbuminemia (adjusted hazard ratio [aHR] = 3.01; 95% CI: 1.42 to 6.29), moderate hypoalbuminemia (aHR = 5.11; 95% CI: 2.54 to 10.29), and severe hypoalbuminemia (aHR = 14.58; 95% CI: 6.32 to 35.60), and A5264/AMC067: mild hypoalbuminemia (aHR = 5.66; 95% CI: 1.90 to 16.93) and moderate hypoalbuminemia (aHR = 7.02; 95% CI: 2.57 to 19.15). The rate of death was higher among participants who had early KS-PD than those without early KS-PD in A5263/AMC066 (HR = 5.09; 95% CI: 1.71 to 15.19) but not in A5264/AMC067 (HR = 1.74; 95% CI: 0.66 to 4.62). Albumin measurements may be used to identify individuals at higher risk of death after initiating KS treatment and for evaluation of interventions that can reduce AIDS-KS mortality.

Kaposi's sarcoma-associated herpes virus-derived microRNA K12-1 over-activates the PI3K/Akt pathway to facilitate cancer progression in HIV-related gastrointestinal Kaposi's sarcoma.

Kaposi's sarcoma-associated herpes virus (KSHV) initiate and accelerate the development of Kaposi's sarcoma (KS), and KSHV possesses many cancer-associated genes, including KSHV-derived microRNA miR-K12-1, which has been identified to be closely associated with KS progression. However, the detailed mechanisms by which miR-K12-1 facilitates HIV-related gastrointestinal KS development are still not fully delineated. This study strived to evaluate the effect of miR-K12-1 on the progression of HIV-related gastrointestinal KS. The expression levels of miR-K12-1 in HIV-related gastrointestinal KS tissues were determined by RT-qPCR. Proliferation and apoptosis were assessed by colony formation, CCK-8 and flow cytometry, respectively. The expression of all proteins was detected by Western blot. The in vivo effect of miR-K12-1 on the formation of a tumor was explored by using the mouse xenograft model. In this study, we uncovered that KSHV-miR-K12-1 was upregulated in HIV-related gastrointestinal KS tissues and associated with poor outcome in HIV-related gastrointestinal KS patients. Compared with the control group, after miR-K12-1 inhibitor transfection, BCBL-1 cell viability was decreased, and the cell apoptosis was significantly increased, whereas transfection of miR-K12-1 mimics promoted cell proliferation and mitosis. In addition, our rescuing experiments verified that miR-K12-1 promoted cell proliferation via activating the PI3K/Akt pathway, and inhibition of the PI3K/Akt pathway by LY294002 abrogated the tumor-promoting effects of miR-K12-1 in HIV-related gastrointestinal KS. In summary, we concluded that KSHV-derived miR-K12-1 activate the PI3K/Akt pathway to initiate and accelerate the development of KS, which convinces us that miR-K12-1 can be used as potential biomarkers for KS diagnosis, treatment and prognosis.

Switching from a Non-Protease inhibitor-Based Regimen To the Fixed Dose Combination of Darunavir/Cobicistat/Emtricitabine/Tenofovir Alafenamide in Clinical Practice.

BackgroundThe primary objective of this study was to estimate the proportion of people living with HIV (PLWH) who switched from a non-protease inhibitor (PI)-based regimen [integrase strand transfer inhibitor (InSTI)-based or non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimen] to darunavir, cobicistat, emtricitabine, tenofovir alafenamide (D/C/F/TAF).MethodsThis was a retrospective study on PLWH treated with a non-PI regimen in January 2017, who switched to D/C/F/TAF or to another antiretroviral therapy (ART) within November 2019. Follow-up was from the start date of D/C/F/TAF until the last available visit or discontinuation for any reason of this regimen. Virological failure (VF) was defined as 2 consecutive HIV-RNA values >50 copies/mL. Characteristics were reported as median (interquartile range) or frequency (%). A univariate Poisson regression model was used to measure the incidence rate of switch to D/C/F/TAF. Changes in laboratory parameters during D/C/F/TAF were assessed by univariate mixed linear models.ResultsOverall, 3076 PLWH were included; 83% were male, median age at ART switch was 50 (42–56) years and median time on ART was 5.2 (0.3–13.0) years. PLWH had a median follow-up of 4.76 (3.70–6.38) years; during 17,099 person-years of follow-up (PYFU), 423/3076 (14%) participants discontinued the non-PI-based regimen and 106/423 (25%) switched to D/C/F/TAF, with an overall incidence rate of switch to D/C/F/TAF of 6.2 per 1000-PYFU (95% CI: 5.0–7.4). Among PLWH who switched to D/C/F/TAF, the ongoing regimen was based on NNRTIs in 37 (35%) and on InSTIs in 69 (65%). Main reasons leading to switch to D/C/F/TAF included neuropsychiatric adverse events (37%), VF (26%) and Kaposi sarcoma progression (5%).ConclusionIn the last years, a non-negligible proportion of patients on an NNRTI- or an InSTI-based regimen switched to D/C/F/TAF.

Long-term outcomes for children and adolescents with Kaposi sarcoma.

Kaposi sarcoma (KS) is one of the most common childhood cancers in eastern and central Africa. It has become a treatable disease with increasing availability of antiretroviral therapy (ART) and chemotherapy. We aimed to fill the data gap in establishing whether long-term survival is achievable for children in low-income countries. We retrospectively analysed data for children and adolescents aged ≤18.9years diagnosed with HIV-related or endemic KS from 2006 to 2015 who received standardized institutional treatment regimens utilizing chemotherapy plus ART (if HIV-positive) at a tertiary care public hospital in Lilongwe, Malawi. Long-term survival was analysed and mortality was associated with KS for those with refractory/progressive disease at the time of death. There were 207 children/adolescents with KS (90.8% HIV-related); 36.7% were alive, 54.6% had died, and 8.7% had been lost to follow-up. The median follow-up time for survivors was 6.9years (range 4.2-13.9 years). Death occurred at a median of 5.3months after KS diagnosis (range 0.1-123 months). KS progression was associated with mortality for most (61%) early deaths (survival time of < 6months); conversely, KS was associated with a minority (31%) of late-onset deaths (after 24months). The 7-year overall survival was 37% [95% confidence interval (CI) 30-44%] and was higher for those diagnosed between 2011 and 2015 compared to 2006-2010: 42% (95% CI 33-51%) versus 29% (95% CI 20-39%), respectively (P=0.01). Among the 66 HIV-positive survivors, 58% were still on first-line ART. Long-term survival is possible for pediatric KS in low-resource settings. Despite better survival in more recent years, there remains room for improvement.

Antiretroviral Therapy for HIV-Associated Cutaneous Kaposi's Sarcoma: Clinical, HIV-Related, and Sociodemographic Predictors of Outcome.

Kaposi's sarcoma (KS) is an AIDS-defining malignancy that can improve or worsen with antiretroviral therapy (ART). We aimed at identifying clinical, HIV-related, and sociodemographic factors associated with either progression or nonprogression (regression or stable disease) of ART-treated HIV-associated KS in patients with limited cutaneous disease. We conducted a prospective cohort study of ART-treated HIV-associated KS cases. Clinical, HIV-related, and sociodemographic variables were collected at baseline, and patients were followed up to determine treatment outcomes. Cox regression, linear mixed effects model, and Spearman's rank correlation were used for analysis. Half (50%) of the study participants had KS regression or stable disease, whereas the other half (50%) had disease progression during the treatment and follow-up period. Among the data analyzed, presence of KS nodules at baseline (hazard ratio = 5.47; 95% confidence interval = 1.32–22.65; p = .02) was an independent predictor of poor treatment outcome. Progressors and nonprogressors were indistinguishable in the changes they experienced in the HIV plasma viral load and CD4 counts as a result of ART. Even when cutaneous presentation is limited, the presence of nodular morphotype KS lesions should be considered an indicator for combined ART plus chemotherapy. Temporal trends in CD4 counts and HIV viral loads did not correlate with treatment outcome in ART-treated HIV-associated KS.

Expression of CD40L on CD4+T cells distinguishes active versus inactive HIV-associated Kaposi's Sarcoma

Kaposi's sarcoma (KS) is a malignancy of vascular origin. It is caused by the Kaposi's sarcoma-associated herpes virus (KSHV). Immune dysregulation is a key feature in the development and progression of KS. The main aim of this study was to determine and compare circulating CD4+ and CD8+T cell subsets including their expression of CD40 ligand (CD40L) and programmed cell death protein 1 (PD1), natural killer (NK) cells, and NK T cells between individuals with active HIV-associated KS versus those in remission. We found that the proportion of CD4+T cells was significantly higher in individuals in remission compared to those with active KS (26.3% vs 13.9%; p = 0.01). We also observed that the proportion of CD4+T cells and central memory CD4+T cells expressing CD40L was significantly higher in individuals with active KS versus those in remission, (10.6% vs 5.4%; p = 0.03) and (14.8% vs 5.9%; p = 0.01) respectively. There was no significant difference in proportion of CD4+ and CD8+ naïve, central memory, effector memory, and terminal effector cells between the two groups. In addition, there was no difference in expression of PD1 on the T cell subsets between the two groups. Furthermore, the proportion of NK cells and NK T cells were not differential between individuals with active disease versus those in remission. CD40L expression is higher in individuals with active HIV-associated KS compared to those in remission. The proportion of CD4+T cells is higher in individuals in remission compared to those with active HIV-associated KS.

The Tat Protein of Human Immunodeficiency Virus Type-1 Promotes Vascular Cell Growth and Locomotion by Engaging the α5β1 and αvβ3 Integrins and by Mobilizing Sequestered Basic Fibroblast Growth Factor

AbstractThe Tat protein of human immunodeficiency virus type-1 (HIV-1) has been shown to be released during acute infection of T cells by HIV-1 and to promote angiogenesis and Kaposi's sarcoma (KS) development in infected individuals. In this study, we investigated the molecular mechanisms responsible for the angiogenic effects of Tat. The results shown herein indicate that two different Tat domains cooperate to induce these effects by different pathways. The arginine-glycine-aspartic acid (RGD) sequence present at the carboxyterminal of Tat mediates vascular cell migration and invasion by binding to the α5β1 and αvβ3 integrins. This interaction also provides endothelial cells with the adhesion signal they require to grow in response to mitogens. At the same time, the Tat basic sequence retrieves into a soluble form extracellular basic fibroblast growth factor (bFGF) bound to heparan sulfate proteoglycans by competing for heparin-binding sites. This soluble bFGF mediates Tat-induced vascular cell growth. These effects resemble those of extracellular matrix proteins, suggesting that Tat enhances angiogenesis and promotes KS progression by a molecular mimicry of these molecules.

The Presence of Antibody-Dependent Cell Cytotoxicity–Mediating Antibodies in Kaposi Sarcoma–Associated Herpesvirus–Seropositive Individuals Does Not Correlate with Disease Pathogenesis or Progression

Although the immune response is likely to play a pivotal role in controlling Kaposi sarcoma (KS)-associated herpesvirus (KSHV) and preventing disease development, the exact factors responsible for that control remain ill defined. T cell responses are weak and variable, and neutralizing Abs are more frequently detected in individuals with KS. This suggests a potential role for nonneutralizing Abs, which to date have been largely uninvestigated. Ab-dependent cell cytotoxicity (ADCC) is a common effector function for nonneutralizing Abs and is known to play a protective role in other herpesvirus infections; yet, ADCC has never been investigated in the context of KSHV infection. In this study, we provide, to our knowledge, the first evidence that anti-KSHV Abs are capable of mediating ADCC responses against infected human cells undergoing lytic reactivation. ADCC activity significantly higher than seronegative controls was detected in 24 of 68 KSHV-seropositive individuals tested. However, ADCC responses were not associated with KS development or progression. ADCC activity was also found to be independent of HIV status, sex, age, KSHV Ab titer, and KSHV-neutralizing activity. Nevertheless, additional investigations into effector cell function between KS and asymptomatic individuals are needed to determine whether ADCC has a role in preventing KS.

S2214 Unusual Initial Presentation of HIV With Disseminated Kaposi Sarcoma (KS) as Rectal Bleeding

INTRODUCTION: Kaposi's sarcoma (KS) is a cancer that develops from the cells that line lymph or blood vessels. It usually appears as tumors on the skin or on mucosal surfaces such as inside the mouth, but these tumors can also develop in other parts of the body, such as in the lymph nodes, the lungs or digestive tract. KS involvement of GI tract may remain asymptomatic in the beginning or may present with mild non-specific abdominal symptoms, unlikely to be diagnosed in late stage. Here we are presenting a case of disseminated KS presented with rectal bleed in homosexual undiagnosed HIV patient. CASE DESCRIPTION/METHODS: A 33 yr old male with no significant past medical history, presented with 3-month history of constipation and progressive unintentional weight loss (40 lbs in 3 months). Lately, patient noticed his stool mixed with blood and mucus, early satiety and fatigue. Patient has family history significant for breast cancer and biliary cancer in mother. Patient is sexually active with 5 male partners. On presentation, vitals were stable and physical examination revealed multiple purple non-blanchable lesions on his extremities and trunk, a mass on the hard palate, supraclavicular and inguinal lymphadenopathy, external hemorrhoids, and a palpable mass in the rectum. Labs showing normocytic anemia with Hb of 10.3, ESR of 95 and CRP of 9.88. Patient was found to be positive for HIV with viral load of 118,255 and CD4 count of 236. Patient also had high IgG titers for Chlamydia trachomatis and CT abdomen and pelvis showed rectosigmoid mass with perirectal lymphadenopathy, inguinal adenopathy, and mild retroperitoneal lymphadenopathy. CT chest showed pulmonary metastasis and colonoscopy showed mild non-specific ileitis, nodule in descending colon and neoplasm in the rectum. Biopsy from the descending colon and rectal mass showed ulcerated Kaposi’s sarcoma and positive immunostaining for human herpes virus -8 (HHV-8). Patient was diagnosed with disseminated KS and started on anti-retroviral therapy (ART) and systemic chemotherapy. DISCUSSION: AIDS-associated disseminated KS is a rare entity. ART has resulted in marked decline in the incidence of KS. Due to the rapid and progressive nature of AIDS related KS, early diagnosis and institution of ART is crucial to achieving favorable prognosis. In addition, co-infection of HHV-8 with HIV promotes the oncogenicity of HHV-8 leading to rapid onset and progression of KS. Above patient responding well to the ART and Chemo going for surveillance Colonoscopy.Figure 1.: Kaposi Sarcoma on Hard Palate.Figure 2Figure 3.: Kaposi Sarcoma in Rectum.

Interim monitoring in a treatment strategy trial with a composite primary endpoint

When a clinical trial has a composite endpoint and a comparison of treatment strategies with multiple intervention components, interim data reviews by a data safety and monitoring board (DSMB) can be challenging as the data evolve on multiple fronts. We illustrate with a study in the treatment of Kaposi sarcoma (KS), an HIV-associated cancer with a multi-faceted disease presentation. The study, ACTG-A5264/AMC-067, was a 1:1 randomized trial to compare two strategies: immediate initiation of etoposide with antiretroviral therapy (ART), or ART with delayed etoposide upon disease progression. The outcome was a composite endpoint that included the following events, ordered from worst to best in the following three categories: (1) KS progression at 48 weeks, death, initiation of alternate KS treatment, loss to study follow-up; (2) stable KS; and (3) partial or complete KS response at 48 weeks. We present the interim results on the composite endpoint and the individual components, where components favored different study arms at an interim review. To facilitate interim data monitoring for complex trials, we recommend clear communications between the study team and the DSMB prior to the initiation of the trial on the need for a composite endpoint, the intentions behind the defined strategies, and relative importance of individual components of the composite endpoint. We also recommend flexibility in the timing of data reviews by the DSMB to interpret emerging data in multiple dimensions.Clinicaltrials.govNCT01352117

Tumor-Associated Protein Profiles in Kaposi Sarcoma and Mimicking Vascular Tumors, and Their Pathological Implications

We investigated protein profiles specific to vascular lesions mimicking Kaposi sarcoma (KS), based on stepwise morphogenesis progression of KS. We surveyed 26 tumor-associated proteins in 130 cases, comprising 39 benign vascular lesions (BG), 14 hemangioendotheliomas (HE), 37 KS, and 40 angiosarcomas (AS), by immunohistochemistry. The dominant proteins in KS were HHV8, lymphatic markers, Rb, phosphorylated Rb, VEGF, and galectin-3. Aberrant expression of p53, inactivation of cell cycle inhibitors, loss of beta-catenin, and increased VEGFR1 were more frequent in AS. HE had the lowest Ki-67 index, and the inactivation rates of cell cycle inhibitors in HE were between those of AS and BG/KS. Protein expression patterns in BG and KS were similar. Clustering analysis showed that the 130 cases were divided into three clusters: AS-rich, BG-rich, and KS-rich clusters. The AS-rich cluster was characterized by high caveolin-1 positivity, abnormal p53, high Ki-67 index, and inactivated p27. The KS-rich cluster shared the features of KS, and the BG-rich group had high positive expression rates of galectin-3 and low bcl2 expression. In conclusion, although the rate was different, AS and HE tended to have less cell cycle marker expression than KS, and features of BG and activated KS cell signaling were similar.

The Hypoxia Inducible Factor 1 Alpha is Required for Optimal GammaHerpes Virus Lytic Replication and Reactivation from Latency

Lytic replication of Kaposi's Sarcoma Associated Herpes Virus (KSHV) exacerbates Kaposi's sarcoma (KS) progression, an angiogenic spindle‐cell sarcoma associated with AIDS. Current antiviral therapy targeting lytic replication can prevent KS in seropositive patients. KSHV lytic infection is not manifested in vitro, and currently there are no animal models that display pathogenic phenotypes. In this study, we employed a biological and genetically mouse pathogen similar to KSHV, the murine gammaherpes virus (gHV) 68 (MHV68), that readily infects laboratory mice providing a valuable small animal model. Moreover, MHV68 in vitro infection exhibits a default lytic infection. Several studies have shown that during infection KSHV employs several viral proteins to de‐regulate the host transcription factor hypoxia inducible factor 1 alpha (HIF1α) and KSHV‐induced activation of HIF1α is necessary for viral persistence and KS progression. However, little is known about the role of HIF1 α in gHV replication and pathogenesis. To further investigate the role of this host factor, we induced transcriptional inactivation of HIF1α in MHV68 virus‐specific cells in vivo. Conditional knock out of HIF1α was achieved by infecting transgenic mice with Cre‐recombinase (Cre) LoxP specific site within the functional domain of HIF1α gene using a recombinant MHV68 that expressing a CMV driven Cre expression.Our data demonstrated for the first time that HIF1α inactivation during gammaherpes virus infection in vivo affects viral gene transcription resulting in impaired virus expansion and early clearance of acute infection in a mouse model. In addition, our results from in vitro MHV68 lytic infection of mouse fibroblasts lacking HIF1α showed that lytic virus production and transcription is decreased. During latency establishment in vivo, the frequency of MHV68 latent splenocytes undergoing latent to lytic replication was largely decreased as well. Our data suggest that HIF1α is required for sustained acute infection since it's deletion in virus‐infected cells resulted in early clearance of productive infection and impairment in reactivation. Moreover, HIF1α is required for mRNA upregulation of glycolytic enzymes during MHV68 lytic infection suggesting a role for HIF1a as a modulator of cell energetics and viral gene expression. We conclude that gammaherpes viruses required the function of the cellular host factor HIF1α in order to effectively replicate and establish latency within its host.Support or Funding InformationNational Cancer Institute 3R01CA136387‐08S1This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

As-Needed Vs Immediate Etoposide Chemotherapy in Combination With Antiretroviral Therapy for Mild-to-Moderate AIDS-Associated Kaposi Sarcoma in Resource-Limited Settings: A5264/AMC-067 Randomized Clinical Trial.

Mild-to-moderate AIDS-associated Kaposi sarcoma (KS) often responds to antiretroviral therapy (ART) alone; the role of chemotherapy is unclear. We assessed the impact of immediate vs as-needed oral etoposide (ET) among human immunodeficiency virus (HIV)-infected individuals with mild-to-moderate KS initiating ART. Chemotherapy-naive, HIV type 1-infected adults with mild-to-moderate KS initiating ART in Africa and South America were randomized to ART (tenofovir/emtricitabine/efavirenz) alone (chemotherapy "as-needed" arm) vs ART plus up to 8 cycles of oral ET (immediate arm). Participants with KS progression on ART alone received ET as part of the as-needed strategy. Primary outcome was ordinal as follows: failure, stable, and response at 48 weeks. Secondary outcomes included time to initial KS progression, KS-associated immune reconstitution inflammatory syndrome (KS-IRIS), and KS response. Of 190 randomized participants (as-needed = 94, immediate = 96), the majority were men (71%) and African (93%). Failure (53.8% vs 56.6%), stable (16.3% vs 10.8%), and response (30% vs 32.5%) did not differ between arms (as-needed vs immediate) among those with week 48 data potential (N = 163, P = .91). Time to KS progression (P = .021), KS-IRIS (P = .003), and KS response (P = .003) favored the immediate arm. Twenty-five participants died (13%). Mortality, adverse events, CD4+ T-cell changes, and HIV RNA suppression were similar at 48 weeks. Among HIV-infected adults with mild-to-moderate KS, immediate ET provided early, nondurable clinical benefits. By 48 weeks, no clinical benefit was observed compared to use of ET as needed. Mortality was high and tumor response was low. NCT01352117.

Let-7 miRNA silencing promotes Kaposi's sarcoma-associated herpesvirus lytic replication via activating mitogen-activated protein kinase kinase kinase kinase 4 and its downstream factors

To explore the effect of let-7 miRNA silencing on Kaposi's sarcoma-associated herpesvirus (KSHV) lytic replication and the underling mechanism. The pEGFP-C2-let-7 sponge vector was transfected into BCBL-1 and 293T cells with Lipofectamine 2000 to silence the expression of let-7 miRNAs. Quantitative real-time PCR (qRT-PCR) was used to quantify the expression of let-7 miRNAs, the transcriptional levels of mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4), cyclooxygenase-2 (COX-2) and matrix metalloproteinase 13 (MMP-13), and the DNA copy numbers of KSHV open reading frame 50 (ORF50) and open reading frame 72 (ORF72). Western blot was used to detect the total and phosphorylated protein levels of MAP4K4, COX-2, extracellular regulated protein kinases (ERK1/2), c-Jun N-terminal kinase (JNK) and p38 MAPK. The expression of let-7 miRNAs was dramatically decreased in the let-7 sponge transfected BCBL-1 and 293T cells compared with that in the vector-transfected cells (P<0.05 for all). The gene copy number and mRNA transcriptional level of KSHV ORF50 were significantly increased in the let-7 sponge transfected BCBL-1 cells compared with that in the vector-transfected cells (1.00±0.10 vs. 2.33±0.18 and 1.08±0.48 vs 3.22±0.27, respectively,P<0.001 for both). The gene copy number and mRNA transcriptional level of KSHV ORF72 were also significantly increased in let-7 sponge transfected BCBL-1 cells compared with those in the vector-transfected cells(1.07±0.49 vs 1.67±0.45 and 1.01±0.19 vs 1.54±0.11, respectively,P<0.05 for both). Furthermore, the mRNA transcriptional levels of MAP4K4, COX-2 and MMP-13 were significantly increased in the let-7 sponge transfected BCBL-1 cells compared with those in the vector-transfected cells (1.00±0.05 vs 5.73±0.96, 1.00±0.05 vs 2.68±0.19, 1.00±0.02 vs 2.69±0.25, respectively,P<0.001 for all). Let-7 miRNAs silencing also increased the protein expression levels of MAP4K4, COX-2 and phospho-ERK1/2, while the phospho-JNK and phospho-p38 were not changed in the BCBL-1 and 293T cells. Let-7 silencing may activate the replication of KSHV, possibly through up-regulating MAP4K4 and its downstream molecules COX-2, MMP-13, and phosphorylation of ERK1/2, finally results in the progression of Kaposi sarcoma.

Relapse of Kaposi's Sarcoma and HHV-8 viremia in an HIV-infected patient switching from protease inhibitor to integrase inhibitor-based antiretroviral therapy

Combination antiretroviral therapy (cART) reduced the incidence of Kaposi's Sarcoma (KS), mainly mediated by the suppression of HIV replication and the recovery of the immune system. The effect of specific classes of antiretrovirals on KS remains unclear. However, both in vitro and clinical studies provided evidences that protease inhibitors (PI) can inhibit Human Herpesvirus 8 (HHV-8) replication and reduce KS risk and progression. Moreover, relapses of KS in HIV-infected patients switching from a PI to a non-nucleoside reverse transcriptase inhibitor-based cART have been reported. We describe here the case of a patient who experienced a relapse of KS and a rebound of HHV-8 viremia two months after switching from a PI to an integrase inhibitor-based cART.

Kaposi sarcoma-associated herpesvirus promotes tumorigenesis by modulating the Hippo pathway.

Kaposi sarcoma-associated herpesvirus (KSHV) is an oncogenic virus and the culprit behind the human disease Kaposi sarcoma (KS), an AIDS-defining malignancy. KSHV encodes a viral G-protein-coupled receptor (vGPCR) critical for the initiation and progression of KS. In this study, we identified that YAP/TAZ, two homologous oncoproteins inhibited by the Hippo tumor suppressor pathway, are activated in KSHV-infected cells in vitro, KS-like mouse tumors and clinical human KS specimens. The KSHV-encoded vGPCR acts through Gq/11 and G12/13 to inhibit the Hippo pathway kinases Lats1/2, promoting the activation of YAP/TAZ. Furthermore, depletion of YAP/TAZ blocks vGPCR-induced cell proliferation and tumorigenesis in a xenograft mouse model. The vGPCR-transformed cells are sensitive to pharmacologic inhibition of YAP. Our study establishes a pivotal role of the Hippo pathway in mediating the oncogenic activity of KSHV and development of KS, and also suggests a potential of using YAP inhibitors for KS intervention.

A MATHEMATICAL MODEL FOR THE TREATMENT OF AIDS-RELATED KAPOSI'S SARCOMA

We formulate a mathematical model to study the dynamics of HIV-1 related Kaposi's Sarcoma (KS) pathogenesis. KS progression is modeled as a dual process involving the primary infection of B cells, which sustains HHV-8 replication and the secondary infection of progenitor cells by HHV-8, which sustains the KS cell replication. We incorporate the pharmacodynamics of highly active antiretroviral therapy (HAART), or combination therapy (HAART plus KS therapy) and consider how each treatment strategy alters the disease progression. Our results indicate that administration of HAART to individuals co-infected with the HIV-1 and HHV-8 viruses can greatly amplify the therapeutic response of low-dose KS therapies. We have found that adherence levels above 85% can significantly reduce the risk of KS and HIV for a treatment periods under 1 year. For longer treatment periods, however, at least 90% adherence level is recommended.

ERK-dependent downregulation of the atypical chemokine receptor D6 drives tumor aggressiveness in Kaposi sarcoma.

D6 is an atypical chemokine receptor acting as a decoy and scavenger for inflammatory CC chemokines expressed in lymphatic endothelial cells. Here, we report that D6 is expressed in Kaposi sarcoma (KS), a tumor ontogenetically related to the lymphatic endothelium. Both in human tumors and in an experimental model, D6 expression levels were inversely correlated with tumor aggressiveness and increased infiltration of proangiogenic macrophages. Inhibition of monocyte recruitment reduced the growth of tumors, while adoptive transfer of wild-type, but not CCR2(-/-) macrophages, increased the growth rate of D6-competent neoplasms. In the KS model with the B-Raf V600E-activating mutation, inhibition of B-Raf or the downstream ERK pathway induced D6 expression; in progressing human KS tumors, the activation of ERK correlates with reduced levels of D6 expression. These results indicate that activation of the K-Ras-B-Raf-ERK pathway during KS progression downregulates D6 expression, which unleashes chemokine-mediated macrophage recruitment and their acquisition of an M2-like phenotype supporting angiogenesis and tumor growth. Combined targeting of CCR2 and the ERK pathway should be considered as a therapeutic option for patients with KS.

Phase II Trial of Imatinib in AIDS-Associated Kaposi's Sarcoma: AIDS Malignancy Consortium Protocol 042

Kaposi's sarcoma (KS) is a disease of multifocal vascular proliferation that requires infection with KS herpes virus (KSHV/HHV-8). Activation of the c-kit and platelet-derived growth factor (PDGF) receptors by autocrine/paracrine mechanisms follows endothelial cell KSHV infection. In a pilot study, imatinib, a c-kit/PDGF-receptor inhibitor, induced partial regression of AIDS-associated KS (AIDS-KS) in five of 10 patients. This multicenter phase II study was designed to estimate the response rate to imatinib in AIDS-KS. Secondary objectives included investigation of predictors of response and imatinib pharmacokinetics in patients on antiretrovirals. Patients received imatinib 400 mg/day by mouth for up to 12 months with dose escalation up to 600 mg/day at 3 months if their disease was stable. Thirty patients were treated at 12 AIDS Malignancy Consortium sites. Ten patients (33.3%) achieved partial response, six (20%) had stable disease, and seven (23.3%) exhibited KS progression. Nine patients completed 52 weeks of imatinib therapy. The median treatment duration was 22.5 weeks. Only five patients (16.7%) discontinued therapy owing to adverse events. Antiretroviral regimens did not significantly alter imatinib metabolism. Activating mutations in PDGF-R and c-kit were not found at baseline or at disease progression. We found no correlation with response with changes in any of the candidate cytokines. Imatinib has activity in AIDS-KS. Pharmacokinetic interactions with antiretroviral drugs did not correlate with toxicity. Thirty percent of patients showed long-term clinical benefit and remained on imatinib for the entire year. These results suggest imatinib is well tolerated and may be an alternative therapy for some patients with AIDS-KS.

Prospective Stage-Stratified Approach to AIDS-Related Kaposi's Sarcoma

Combination antiretroviral therapy (cART) is standard of care for patients with HIV diagnosed with Kaposi's sarcoma (KS), but the current role of systemic chemotherapy is undefined. Since 1998, a prospective stage-stratified approach has been adopted for 469 patients with HIV with KS. Patients with early-stage (T0) KS are treated with cART alone; patients with advanced-stage (T1) KS receive cART plus liposomal anthracycline chemotherapy. Clinical characteristics, overall survival, and KS progression-free survival were analyzed according to stage at presentation and treatment received. A total of 303 patients presented with T0 stage KS, including 237 who were not receiving cART, and 166 patients had T1 stage KS. Patients with T0 KS had higher CD4 cell counts (P < .001); 90% of patients with T0 KS who were not receiving cART and 84% of those with T1 KS were treated in accordance with the stage-stratified approach. Median follow-up was 4.6 years, and 5-year overall survival was 89%; 54 patients have died, 15 as a result of KS. Overall 5-year survival was 92% for T0 KS and 83% to T1 KS (P = .0024). On-treatment analysis of 213 cART-naive patients with T0 KS treated with cART alone revealed 5-year overall survival of 95% and progression-free survival of 77%. For 140 patients with T1 disease treated with cART and liposomal anthracycline chemotherapy, 5-year overall survival was 85%. This stage-stratified approach to the management of KS achieves high survival in patients with advanced KS and reduces exposure to chemotherapy in patients with early-stage KS.