Cancer burden in women with HIV on Medicaid: A nationwide analysis.

BACKGROUND: Cancer is the leading cause of death in people living with HIV. In the United States, nearly 1 in 4 people living with HIV are women, more than half of whom rely on Medicaid for healthcare coverage. OBJECTIVE: The objective of this study is to evaluate the cancer burden of women living with HIV on Medicaid. DESIGN: We conducted a cross-sectional study of women 18-64 years of age enrolled in Medicaid during 2012, using data from Medicaid Analytic eXtract files. METHODS: Using International Classification of Diseases, Ninth Revision, Clinical Modification diagnosis codes, we identified women living with HIV (n = 72,508) and women without HIV (n = 17,353,963), flagging the presence of 15 types of cancer and differentiating between AIDS-defining cancers and non-AIDS-defining cancers. We obtained adjusted prevalence ratios and 95% confidence intervals for each cancer and for all cancers combined, using multivariable log-binomial models, and additionally stratifying by age and race/ethnicity. RESULTS: The highest adjusted prevalence ratios were observed for Kaposi's sarcoma (81.79 (95% confidence interval: 57.11-117.22)) and non-Hodgkin's lymphoma (27.69 (21.67-35.39)). The adjusted prevalence ratios for anal and cervical cancer, both of which were human papillomavirus-associated cancers, were 19.31 (17.33-21.51) and 4.20 (3.90-4.52), respectively. Among women living with HIV, the adjusted prevalence ratio for all cancer types combined was about two-fold higher (1.99 (1.86-2.14)) in women 45-64 years of age than in women 18-44 years of age. For non-AIDS-defining cancers but not for AIDS-defining cancers, the adjusted prevalence ratios were higher in older than in younger women. There was no significant difference in the adjusted prevalence ratios for all cancer types combined in the race/ethnicity-stratified analyses of the women living with HIV cohort. However, in cancer type-specific sub-analyses, differences in adjusted prevalence ratios between Hispanic versus non-Hispanic women were observed. For example, the adjusted prevalence ratio for Hispanic women for non-Hodgkin's lymphoma was 2.00 (1.30-3.07) and 0.73 (0.58-0.92), respectively, for breast cancer. CONCLUSION: Compared to their counterparts without HIV, women living with HIV on Medicaid have excess prevalence of cervical and anal cancers, both of which are human papillomavirus related, as well as Kaposi's sarcoma and lymphoma. Older age is also associated with increased burden of non-AIDS-defining cancers in women living with HIV. Our findings emphasize the need for not only cancer screening among women living with HIV but also for efforts to increase human papillomavirus vaccination among all eligible individuals.

A novel mathematical model of AIDS-associated Kaposi's sarcoma: Analysis and optimal control.

Kaposi's sarcoma (KS) has been the most common HHV-8 virus-induced neoplasm associated with HIV-1 infection. Although the standard KS therapy has not changed in 20 years, not all cases of KS will respond to the same therapy. The goal of current AIDS-KS treatment modalities is to reconstitute the immune system and suppress HIV-1 replication, but newer treatment modalities are on horizon. There are very few mathematical models that have included HIV-1 viral load (VL) measures, despite VL being a key determinant of treatment outcome. Here we introduce a mathematical model that consolidates the effect of both HIV-1 and HHV-8 VL on KS tumor progression by incorporating low or high VLs into the proliferation terms of the immune cell populations. Regulation of HIV-1/HHV-8 VL and viral reservoir cells is crucial for restoring a patient to an asymptomatic stage. Therefore, an optimal control strategy given by a combined antiretroviral therapy (cART) is derived. The results indicate that the drug treatment strategies are capable of removing the viral reservoirs faster and consequently, the HIV-1 and KS tumor burden is reduced. The predictions of the mathematical model have the potential to offer more effective therapeutic interventions based on viral and virus-infected cell load and support new studies addressing the superiority of VL over CD4+ T-cell count in HIV-1 pathogenesis.

Designing a multi-epitope based vaccine to combat Kaposi Sarcoma utilizing immunoinformatics approach.

Kaposi's sarcoma-associated herpesvirus (KSHV) responsible for causing Kaposi sarcoma (KS), an opportunistic angioproliferative neoplasm is emerging rapidly. Despite this there is no permanent cure for this disease. The present study was aimed to design a multi-epitope based vaccine targeting the major glycoproteins of KSHV which plays an important role in the virus entry. After the application of rigorous immunoinformatics analysis and several immune filters, the multi-epitope vaccine was constructed, consisting of CD4, CD8 and IFN-γ inducing epitopes. Several physiochemical characteristics, allergenicity and antigenicity of the multi-epitope vaccine were analyzed in order to ensure its safety and immunogenicity. Further, the binding affinity and stability of the vaccine with Toll like receptor -9 (TLR-9) was analyzed by molecular docking and dynamics simulation studies. In addition, an in silico cloning was performed to ensure the expression and translation efficiency of the vaccine, utilizing pET-28a (+) vector. Such T-cell-based immunotherapies which leverage this mechanism could prove their potential against cancer. Further, the authors propose to test the present findings in the lab settings to ensure the safety, immunogenicity and efficacy of the presented vaccine which may help in controlling KSHV infection.

Kaposi sarcoma herpesvirus pathogenesis.

Kaposi sarcoma herpesvirus (KSHV), taxonomical name human gammaherpesvirus 8, is a phylogenetically old human virus that co-evolved with human populations, but is now only common (seroprevalence greater than 10%) in sub-Saharan Africa, around the Mediterranean Sea, parts of South America and in a few ethnic communities. KSHV causes three human malignancies, Kaposi sarcoma, primary effusion lymphoma, and many cases of the plasmablastic form of multicentric Castleman's disease (MCD) as well as occasional cases of plasmablastic lymphoma arising from MCD; it has also been linked to rare cases of bone marrow failure and hepatitis. As it has colonized humans physiologically for many thousand years, cofactors are needed to allow it to unfold its pathogenic potential. In most cases, these include immune defects of genetic, iatrogenic or infectious origin, and inflammation appears to play an important role in disease development. Our much improved understanding of its life cycle and its role in pathogenesis should now allow us to develop new therapeutic strategies directed against key viral proteins or intracellular pathways that are crucial for virus replication or persistence. Likewise, its limited (for a herpesvirus) distribution and transmission should offer an opportunity for the development and use of a vaccine to prevent transmission.This article is part of the themed issue 'Human oncogenic viruses'.

Cancer risk in HIV-infected people in the USA from 1996 to 2012: a population-based, registry-linkage study.

BACKGROUND: Monitoring cancer risk among HIV-infected people in the modern antiretroviral therapy (ART) era is essential given their elevated risk for many cancers and prolonged survival with immunosuppression, ART exposure, and ageing. We aimed to examine cancer risk in HIV-infected people in the USA as compared with that in the general population. METHODS: We did a registry-linkage study with data from population-based HIV and cancer registries in the USA (the HIV/AIDS Cancer Match Study). We assessed a cohort of HIV-infected people identified in HIV registries in Colorado, Connecticut, Georgia, Maryland, Michigan, New Jersey, New York, Puerto Rico, and Texas from 1996 to 2012. Follow-up started 3 months after either the latest of the beginning of systematic name-based state HIV registration, HIV report date (or AIDS diagnosis, if this was earlier), start of cancer registration, or Jan 1, 1996, and ended at the earliest of either death, end of cancer-registry coverage, or Dec 31, 2012. We identified diagnoses of cancer in this population through linkage with corresponding cancer registries and calculated standardised incidence ratios (SIRs) to measure cancer risk in people with HIV compared with the USA general population, by dividing the observed number of cases in people with HIV by the expected number (estimated by applying general population cancer-incidence rates to person-time in the HIV population based on sex, age, race or ethnic group, calendar year, and registry). We tested SIR differences by AIDS status and over time using Poisson regression. FINDINGS: Among 448 258 people with HIV (who contributed 3 093 033 person-years), 21 294 incident cancers were diagnosed during 1996-2012. In these people, compared with the general population, risk was elevated (p<0·0001 for all) for cancer overall (SIR 1·69, 95% CI 1·67-1·72), AIDS-defining cancers (Kaposi's sarcoma [498·11, 477·82-519·03], non-Hodgkin lymphoma [11·51, 11·14-11·89], and cervix [3·24, 2·94-3·56]), most other virus-related cancers (eg, anus [19·06, 18·13-20·03], liver [3·21, 3·02-3·41], and Hodgkin's lymphoma [7·70, 7·20-8·23]), and some virus-unrelated cancers (eg, lung [1·97, 1·89-2·05]), but not for other common cancers. Risk for several cancers was higher after AIDS onset and declined across calendar periods. After multivariable adjustment, SIRs decreased significantly across 1996-2012 for Kaposi's sarcoma, two subtypes of non-Hodgkin lymphoma, and cancer of the anus, liver, and lung, but remained elevated. SIRs did not increase over time for any cancer. INTERPRETATION: For several virus-related cancers and lung cancer, declining risks over time in HIV-infected people probably reflect the expansion of ART since 1996. Additional efforts aimed at cancer prevention and screening in people with HIV are warranted. FUNDING: National Cancer Institute.

Nonmelanoma Skin Cancers After Kidney Transplant: Our 15 Years of Experience With Mammalian Target of Rapamycin Inhibitors.

OBJECTIVES: We evaluated patients with nonmelanoma skin cancer after kidney transplant and the effects of immunosuppression reduction and switching to a mammalian target of rapamycin inhibitor drugs. MATERIALS AND METHODS: Kidney transplant recipients were evaluated retrospectively from patient medical records (between January 2000 and December 2014). A 30% increase in serum creatinine was accepted as indicating renal failure progression. RESULTS: Of 18 patients included (mean follow-up 98 ± 66 mo), 7 (38.8%) had squamous cell carcinoma, 7 (38.8%) had Kaposi sarcoma, and 4 (22.2%) had basal cell carcinoma. At cancer diagnosis, average serum creatinine was 1.6 ± 0.7 mg/dL and proteinuria was 410 ± 766 mg/d. Immunosuppression regimen was changed in 15 patients (83.3%), with new regimen being a single-drug (only prednisolone) in 4 patients, double-drug in 6 patients, and triple-drug protocol in 8 patients. Eight patients were switched to a mammalian target of rapamycin inhibitor-based double (4 patients) or triple (4 patients) regimen. During follow-up after starting new treatment (average 46 ± 50 mo), 6 patients (33.3%) had progressive kidney failure (0 were receiving triple regimen). Those that progressed were using mammalian target of rapamycin inhibitor-based drugs relatively less (33% vs 50%), although often receiving a single-drug immunosuppression treatment (50% vs 8.3%). Three patients (33.3%) had acute rejection (2 receiving double and 1 receiving single immunosuppression treatment). Five patients (27.7%) had local recurrence of the primary tumor. Mammalian target of rapamycin inhibitor use was relatively less common in patients with tumor relapse (20% vs 46%). One patient died (heart failure), and 1 with chronic rejection returned to dialysis. CONCLUSIONS: Mammalian target of rapamycin inhibitorbased drugs could reduce local recurrence rate in kidney transplant recipients with nonmelanoma skin cancers. Aggressive reduction and/or cessation of immunosuppressive drugs after skin cancer can lead to graft rejection.

Genipin Enhances Kaposi's Sarcoma-Associated Herpesvirus Genome Maintenance.

Kaposi's sarcoma-associated herpesvirus (KSHV) is a Gammaherpesvirus that causes acute infection and establishes life-long latency. KSHV causes several human cancers, including Kaposi's sarcoma, an acquired immune deficiency syndrome (AIDS)-related form of non-Hodgkin lymphoma. Genipin, an aglycone derived from geniposide found in Gardenia jasminoides, is known to be an excellent natural cross-linker, strong apoptosis inducer, and antiviral agent. Although evidence suggests antiviral activity of genipin in several in vitro viral infection systems, no inhibitory effect of genipin on KSHV infection has been reported. Thus, our aim was to determine, using the iSLK-BAC16 KSHV infection system, whether genipin has inhibitory effects on KSHV infection. For this purpose, we evaluated biological effects of genipin on KSHV infection and finally determined the underlying mechanisms responsible for the bioactive effects of genipin. A cytotoxicity assay revealed that genipin caused 50% cytotoxicity at 49.5 µM in iSLK-puro (KSHV-negative) cells and at 72.5 µM in iSLK-BAC16 (KSHV-positive) cells. Caspase 3/7 activities were slightly suppressed by genipin treatment in iSLK-BAC16 cells while significantly induced in iSLK-puro cells. Production of the KSHV latency-associated nuclear antigen (LANA), but not that of the R-transactivator (RTA) protein, was significantly induced by genipin treatment at lower concentration. Consistent with the LANA upregulation, KSHV LANA transcripts, but not RTA transcripts, were expressed at a higher level. Furthermore, KSHV intracellular copy numbers were slightly increased at lower concentration of genipin, while KSHV extracellular copy numbers were significantly increased at higher concentration of genipin. Interestingly, genipin treatment at a lower concentration did induce the expression of DNA (cytosine-5)-methyltransferase 1 (DNMT1); however, a co-immunoprecipitation assay showed that the DNMT1 and LANA induced by genipin did not co-precipitate from iSLK-BAC16 cells. Moreover, a chromatin immunoprecipitation assay demonstrated that genipin treatment enhanced the binding of CCCTC-binding factor (CTCF) to the CTCF-binding site in the KSHV latency control region but suppressed the binding of structural maintenance of chromosomes protein 3 (SMC3) to this site. Genipin treatment also led to the recruitment of additional RNA polymerase to the majority of binding sites of some interesting proteins in the KSHV latency control region, which might be related to the extension of S phase in iSLK-BAC16 cells by genipin treatment. Finally, genipin treatment at lower concentration could promote the KSHV latent replication. In contrast, the treatment at higher concentration could induce the KSHV lytic replication. In conclusion, genipin was shown to be an interesting reagent, which we used to manipulate KSHV life cycle in KSHV latently infected cells.

Ecografía cutánea en el sarcoma de Kaposi / Skin Ultrasound in Kaposi Sarcoma

Recientemente ha aumentado el uso de la ecografía cutánea en múltiples enfermedades dermatológicas. Se trata de una técnica no invasiva, que nos proporciona más detalles acerca de la estructura y vascularización de las lesiones cutáneas. El sarcoma de Kaposi es un tumor vascular, que se localiza principalmente en la piel y las mucosas, pudiendo afectar los ganglios linfáticos y los órganos internos. Presentamos 3 pacientes con diagnóstico de sarcoma de Kaposi, sospechado clínicamente, y confirmado histológicamente, a los cuales realizamos exploración ecográfica en modo B y modo Doppler color. Encontramos diferencias en el patrón ecográfico, tanto en modo B como en modo Doppler color, entre las lesiones que clínicamente correspondían a nódulos frente a las que eran placas. Consideramos que la ecografía cutánea podría ser útil como prueba complementaria, en el estudio de las lesiones cutáneas del sarcoma de Kaposi, proporcionándonos más información acerca de sus características estructurales y vasculares

The use of ultrasound imaging has recently been increasing in numerous dermatologic diseases. This noninvasive technique provides additional details on the structure and vascularization of skin lesions. Kaposi sarcoma is a vascular tumor that typically arises in the skin and mucosas. It can spread to lymph nodes and internal organs. We performed B-mode and color Doppler ultrasound studies in 3 patients with a clinical diagnosis of Kaposi sarcoma confirmed by histological examination. We found differences in the ultrasound pattern between nodular and plaque lesions, in both B-mode and color Doppler. We believe that skin ultrasound imaging could be a useful technique for studying cutaneous Kaposi sarcoma, providing additional information on the structural and vascular characteristics of the lesion

Effects of Antiretroviral Therapy on Kaposi's Sarcoma-Associated Herpesvirus (KSHV) Transmission Among HIV-Infected Zambian Children.

BACKGROUND: The risk of Kaposi's sarcoma-associated herpesvirus (KSHV) acquisition among children is increased by HIV infection. Antiretroviral therapy (ART) was recently made widely available to HIV-infected children in Zambia. However, the impact of early ART on KSHV transmission to HIV-infected children is unknown. METHODS: We enrolled and followed a cohort of 287 HIV-exposed, KSHV-negative children under 12 months of age from Lusaka, Zambia, to identify KSHV seroconversion events. Potential factors associated with KSHV infection-with an emphasis on HIV, ART, and immunological measures-were assessed through structured questionnaires and blood analyses. Incidence rate, Kaplan-Meier, and multivariable Cox regression models were used to assess differences in time to event (KSHV seroconversion) between groups. All statistical tests were two-sided. RESULTS: During follow-up, 151 (52.6%) children underwent KSHV seroconversion. Based on 3552 months of follow-up, we observed similar KSHV incidence rates between HIV-infected and uninfected children. Among HIV-infected children, ART-naïve children had statistically significantly increased risk of KSHV acquisition (adjusted hazard ratio [AHR] = 5.04, 95% confidence interval [CI] = 2.36 to 10.80, P < .001). Time-updated CD4(+) T-cell percentage was also statistically significantly associated with risk of KSHV acquisition (AHR = 0.82, 95% CI = 0.74 to 0.92, P < .001), such that each 5% increase of CD4(+) T-cells represented an 18% decrease in risk of acquiring KSHV. CONCLUSIONS: Our data suggest that early ART and prevention of immune suppression reduce the risk of KSHV acquisition among HIV-infected children in an area where both viruses are highly endemic. This study highlights the importance of programs in Africa to provide children with ART immediately after HIV infection is diagnosed.

Different impact of anti-retroviral regimen containing protease inhibitors on development of HIV-related Kaposi sarcoma.

BACKGROUND: The incidence of Kaposi's sarcoma (KS), an AIDS-related malignancy, has dramatically decreased in the Highly Active Anti-retroviral Therapy (HAART) era. However, KS remains the second most frequent tumor in HIV-infected patients worldwide and has become the most common cancer in the sub-Saharan Africa. Experimental studies have demonstrated a direct anti-neoplastic effect of HAART, and overall of protease inhibitors (PIs), on KS. CASE REPORT: We describe five cases of KS in HIV-infected patients on HAART regimen, containing PIs as atazanavir/r (ATV/r), darunavir/r (DRV/r), lopinavir/r (LPV/r) and fosamprenavir (fAMP/r). CONCLUSION: Clinical and experimental observations support the hypothesis that PIs may play an important role in prevention and treatment of KS. In our study, the treatment with PIs of recent generation was not protective against the development of KS. Therefore, it could be necessary to re-evaluate the therapeutic effects of PIs and their role in the development and treatment of KS in HIV-infected patients.

Prospective study of human herpesvirus type 8 serostatus and prostate cancer risk in the placebo arm of the Prostate Cancer Prevention Trial.

BACKGROUND: Human herpesvirus type 8 (HHV-8), a gamma herpesvirus associated with Kaposi's sarcoma, has been proposed as a candidate risk factor for prostate cancer (PCa) because of its detection in benign and malignant prostate specimens, and its relation with histologic prostatic inflammation. We investigated the possible relation between pre-diagnostic HHV-8 infection and PCa risk in a case-control study sampled from the placebo arm of the Prostate Cancer Prevention Trial. METHODS: We defined cases as men with a confirmed diagnosis of PCa after visit 2 (n = 315) and controls as men not diagnosed with PCa during the trial who also had a negative end-of-study prostate biopsy (n = 315). We tested sera from visit 2 for IgG antibodies against HHV-8 using a monoclonal antibody-enhanced immunofluorescence assay against multiple lytic HHV-8 antigens. RESULTS: The adjusted seroprevalence of HHV-8 infection was 11.6 % for cases and 11.0 % for controls (p = 0.81). No association was observed between HHV-8 seropositivity and PCa risk (OR 1.06, 95 % CI 0.65-1.76). CONCLUSION: Our findings of a null association between HHV-8 seropositivity and PCa risk do not support an association between HHV-8 infection and PCa development, consistent with the general tendency of the epidemiologic literature to date.

mTOR inhibitors block Kaposi sarcoma growth by inhibiting essential autocrine growth factors and tumor angiogenesis.

Kaposi sarcoma originates from endothelial cells and it is one of the most overt angiogenic tumors. In Sub-Saharan Africa, where HIV and the Kaposi sarcoma-associated herpesvirus (KSHV) are endemic, Kaposi sarcoma is the most common cancer overall, but model systems for disease study are insufficient. Here, we report the development of a novel mouse model of Kaposi sarcoma, where KSHV is retained stably and tumors are elicited rapidly. Tumor growth was sensitive to specific allosteric inhibitors (rapamycin, CCI-779, and RAD001) of the pivotal cell growth regulator mTOR. Inhibition of tumor growth was durable up to 130 days and reversible. mTOR blockade reduced VEGF secretion and formation of tumor vasculature. Together, the results show that mTOR inhibitors exert a direct anti-Kaposi sarcoma effect by inhibiting angiogenesis and paracrine effectors, suggesting their application as a new treatment modality for Kaposi sarcoma and other cancers of endothelial origin.

A role for virally induced reactive oxygen species in Kaposi's sarcoma herpesvirus tumorigenesis.

AIMS: Kaposi's sarcoma (KS), caused by the Kaposi's sarcoma herpesvirus (KSHV), is an AIDS-associated cancer characterized by angiogenesis and proliferation of spindle cells. Rac1-activated reactive oxygen species (ROS) production has been implicated in KS tumorigenesis. We used an animal model of KSHV-induced Kaposi's sarcomagenesis (mECK36) to study the role of ROS in KS and the efficacy of N-acetyl l-cysteine (NAC) in inhibiting or preventing KS. RESULTS: Signaling by the KSHV early lytic gene viral G protein-coupled receptor (vGPCR) activated ROS production in mECK36 cells via a Rac1-NADPH oxidase pathway. Induction of the lytic cycle in KSHV-infected KS spindle cells upregulated ROS along with upregulation of vGPCR expression. We also found that expression of the major latent transcript in 293 cells increased ROS levels. ROS scavenging with NAC halted mECK36 tumor growth in a KSHV-specific manner. NAC inhibited KSHV latent gene expression as well as tumor angiogenesis and lymphangiogenesis. These effects correlated with the reduction of vascular endothelial growth factor (VEGF), c-myc, and cyclin D1, and could be explained on the basis of inhibition of STAT3 tyrosine phosphorylation. NAC prevented mECK36 de novo tumor formation. Molecular analysis of NAC-resistant tumors revealed a strong upregulation of Rac1 and p40(PHOX). INNOVATION AND CONCLUSION: Our results demonstrate that ROS-induction by KSHV plays a causal role in KS oncogenesis by promoting proliferation and angiogenesis. Our results show that both ROS and their molecular sources can be targeted therapeutically using NAC or other Food and Drug Administration (FDA)-approved inhibitors for prevention and treatment of AIDS-KS.

Incidence, risk factors, and preventative management of skin cancers in organ transplant recipients: a review of single- and multicenter retrospective studies from 2006 to 2010.

BACKGROUND: Organ transplant recipients (OTRs) taking immunosuppressants are at high risk of skin cancer, which is the most common malignant condition in OTRs, so dermatologic surveillance is important for OTRs. OBJECTIVES: To characterize the most common skin cancers arising from chronic immunosuppression in OTRs. METHODS: A PubMed search for retrospective single- and multicenter studies reporting skin cancer incidence from 2006 to 2010 was undertaken. Data regarding each study's immunosuppressive regimen, affected skin cancer cohort, and associated risk factors were extracted. RESULTS: Thirty-six articles that met our inclusion criteria reported incidences of nonmelanoma skin cancer (NMSC), Kaposi's sarcoma, melanoma, and Merkel cell carcinoma. NMSC was the most commonly reported cancer of all skin cancers after transplantation. Common risk factors were sex, age, sunlight exposure, and immunosuppressive agent-related (duration, type). CONCLUSION: Sun education programs and frequent screenings in organ transplant clinics have provided the best preventative strategies after transplantation, although the characteristics of the immunosuppressive regimen also play an important role. Thus, the adjuvant strategy of modifying immunosuppression may be effective when confronting severe transplant-associated skin cancer. Although the decision-making process for curbing levels of immunosuppression is difficult, further long-term, randomized controlled studies should assess the effect of using less immunosuppressant medication while preserving graft function.

Vaccine prospect of Kaposi sarcoma-associated herpesvirus.

Infection of Kaposi sarcoma-associated herpesvirus (KSHV) or human herpesvirus-8 (HHV-8) is estimated to account for 34,000 new cancer cases globally. Unlike other herpesviruses, KSHV is not ubiquitous but is highly prevalent in some areas, such as sub-Saharan Africa where Kaposi sarcoma is the leading cancer among adults. While latent infection of KSHV plays a major and direct role in tumorigenesis, viral lytic replication also makes significant contributions to this process. Efforts to develop a KSHV vaccine are limited, but studies with EBV have provided important lessons. Informative vaccine research has been conducted in the mouse infection model of a closely related rodent virus, murine gammaherpesvirus-68 (MHV-68 or γHV-68). This mouse model has generated fundamental principles for an effective vaccination strategy. KSHV vaccines designed to prevent a naïve host from infection and to boost the immune control of KSHV in persistently infected people will have major impact on individuals who are at a high risk of developing KSHV-associated diseases.