Kaposi's sarcoma-associated herpes virus and acquired immunodeficiency syndrome-related malignancy

Kaposi's sarcoma-associated herpes virus (KSHV), also known as human herpes virus-8 (HHV-8), is a recently described gamma-herpes virus that has been etiologically linked to two different acquired immunodeficiency syndrome (AIDS)-related malignancies by strong epidemiologic and pathologic evidence. Infection been shown to precede and predict the development of Kapasi's sarcoma (KS) in human immunodeficiency virus (HIV)-infected patients, and viral DNA has been found in KS lesions of all types and stages. Furthermore, KSHV is a lymphotropic virus and is present in nearly all cases of primary effusion lymphoma, a rare malignancy disproportionately affecting HIV-infected individuals. KSHV is also thought to dramatically affect the incidence, type, and course of multicentric Castleman's disease, another lymphoproliferative disorder over-represented in people with AIDS. KSHV encodes many potentially oncogenic products, including several apparently pirated from the human genome. These include various chemokines, cell cycle regulatory proteins, and survival and proliferation factors. Knowledge is rapidly accumulating concerning the viral pathogenic mechanisms and host cofactors necessary for KSHV-mediated disease.     

Antibodies against lytic and latent Kaposi's sarcoma-associated herpes virus antigens and lymphoma in the European EpiLymph case-control study

Background:

Kaposi''s sarcoma-associated herpes virus is associated with primary effusion lymphoma and multicentric Castleman''s disease.

Methods:

Seropositivity to lytic and latent Kaposi''s sarcoma herpes virus (KSHV) antigens were examined in 2083 lymphomas and 2013 controls from six European countries.

Results:

Antibodies against KSHV latent and lytic antigens were detectable in 4.5% and 3.4% of controls, respectively, and 3.6% of cases (P>0.05). The KSHV seropositivity was associated with splenic marginal zone lymphoma (SMZL) (odds ratio (OR)=4.11, 95% confidence interval (CI)=1.57–10.83) and multiple myeloma (OR=0.31, 95% CI=0.11–0.85).

Conclusion:

The KSHV is unlikely to contribute importantly to lymphomagenesis among immunocompetent subjects. However, the observed association with SMZL may underline a chronic antigen mechanism in its aetiology.     

Targeted therapy for Kaposi's sarcoma and Kaposi's sarcoma-associated herpesvirus

PURPOSE OF REVIEW: To summarize major recent findings on the biology of human herpesvirus-8, i.e. Kaposi's sarcoma-associated herpesvirus, and the implications of these findings for Kaposi's sarcoma treatment. RECENT FINDINGS: Although reduced in incidence in developed countries since the introduction of highly active antiretroviral therapy, Kaposi's sarcoma incidence is still markedly increased in HIV-infected patients in resource-rich areas of the world and is a major complication among HIV-infected individuals in sub-Saharan Africa. The Akt/mammalian target of rapamycin pathway has emerged as a major driving force in Kaposi's sarcoma. In addition, the roles of p53, the Kaposi's sarcoma-associated herpesvirus viral cyclin and nuclear factor-kappaB in the development and progression of Kaposi's sarcoma are being further clarified, and therapeutic agents are being developed that may target these pathogenetic mechanisms. New Kaposi's sarcoma treatments should be considered that target the molecular interface between virus and host. SUMMARY: The growing knowledge of Kaposi's sarcoma biology provides multiple opportunities for rational targeted therapies. Further research is needed to better understand the mechanisms by which Kaposi's sarcoma develops and to develop therapeutic strategies that prevent resistance to treatment.     

Immune reconstitution inflammatory syndrome associated with Kaposi's sarcoma.

PURPOSE: A proportion of patients with HIV infection who subsequently receive highly active antiretroviral therapy (HAART) exhibit a deterioration in their clinical status, despite control of virologic and immunologic parameters. This clinical response, known as the immune reconstitution inflammatory syndrome (IRIS), occurs secondary to an immune response against previously diagnosed pathogens. PATIENTS AND METHODS: From our cohort of 5,832 patients treated in the HAART era, we identified 150 therapy-naive patients with a first presentation of Kaposi's sarcoma (KS). Their clinicopathologic features and progress were recorded prospectively. RESULTS: After commencing HAART, ten patients (6.6%) developed progressive KS, which we identify as IRIS-associated KS. In a comparison of these individuals with those whose KS did not progress, we found that IRIS-KS occurred in patients with higher CD4 counts (P = .03), KS-associated edema (P = .01), and therapy with both protease inhibitors and non-nucleosides together (P = .03). Time to treatment failure was similar for both groups, although the CD4 count declined more rapidly at first, in those patients with IRIS-associated KS. Despite this initial decline, in our clinical experience HAART could be successfully continued in those with IRIS-associated KS. CONCLUSION: We have identified IRIS-KS in a cohort of HIV patients with KS who start HAART.     

Vertical transmission of Kaposi's sarcoma-associated herpesvirus.

Little is presently known about the specific routes of transmission of Kaposi's sarcoma-associated herpesvirus (KSHV) or human herpesvirus-8 (HHV-8). To investigate whether this agent might be transmitted vertically from mother to infant, we conducted a study on 89 KSHV seropositive mothers and their newborn infants. Thirteen mothers (14.6%) had KSHV DNA detected in their peripheral blood mononuclear cells (PBMC). Two of 89 samples drawn at birth from infants born to KSHV seropositive mothers had KSHV DNA detectable within their PBMC. These findings suggest that KSHV can be transmitted perinatally, but infrequently. Other routes of transmission such as horizontal transmission remain the most likely means of KSHV transmission.     

Seroepidemiology of Kaposi's sarcoma-associated herpesvirus (KSHV).

Since the Kaposi's sarcoma-associated herpesvirus (KSHV also referred to as HHV-8, human herpesvirus-8) was discovered it has been shown that the virus is associated with all cases of Kaposi's sarcoma (KS) classical, endemic, or AIDS associated. In the numerous countries where the seroprevalence of this virus has been studied, data demonstrate that the virus is not ubiquitous in general healthy human populations as is the case with other human herpesviruses. Many seroprevalence studies to detect antibodies to HHV-8 have now been conducted using a variety of immunologic techniques. While these assays are not in total agreement and may overstate or understate the positivity of sera in the general population, they all show similar general antibody trends. For general populations the seroprevalence in sub-Saharan Africa is the highest, approximately 40% positive; in Mediterranean countries the seroprevalence is approximately 10%; whereas northern European, southeast Asian, and Caribbean countries have seroprevalence rates in the 2-4% range. In the United States, a 'mixing bowl' country the seroprevalence is in the range of 5-20%. In people with KS whether AIDS associated, classical, or endemic and other HHV-8 associated diseases such as multicentric Castleman's disease and certain body cavity lymphomas (BCL), also called primary effusion lymphoma (PEL) the seroprevalency rates are >90%. In populations with HIV-1 infection but no diagnosis of KS, the seroprevalency rates are elevated (20-50%) above those in the general population except in southeast Asia and the Caribbean where no AIDS associated KS has been reported. No correlation has been found between the presence of KSHV antibodies and other malignancies.     

A prospective study of Kaposi's sarcoma-associated herpesvirus and Epstein-Barr virus in adults with human immunodeficiency virus-1

Antibody titres against Kaposi's sarcoma associated herpesvirus (KSHV or human herpesvirus 8 (HHV-8)) and Epstein-Barr virus (EBV) were examined in people who subsequently developed Kaposi's sarcoma and non-Hodgkin's lymphoma, within randomised controlled trials of antiretroviral therapy in adults infected with the human immunodeficiency virus-1 (HIV). For each case of Kaposi's sarcoma (n=189) and each case of non-Hodgkin's lymphoma (n=67), which developed after randomisation, one control was randomly selected from other trial participants, after matching for age, sex, ethnicity, mode of HIV transmission, type of treatment received and period of follow-up. Using sera taken an average of two and a half years before the diagnosis of cancer, titres of antibodies against KSHV latent (LANA) and lytic (K8.1) antigens and against EBV (VCA) antigens were investigated in relation to subsequent risks of cancer by calculating odds ratios (OR) using conditional logistic regression. Latent antibodies against KSHV were detectable among 38% (72 out of 189) of Kaposi's sarcoma cases and 12% (23 out of 189) of their controls (OR=4.4, 95% confidence intervals (CI) 2.3-8.3, P<0.001). The OR for Kaposi's sarcoma increased with increasing antilatent KSHV antibody titre (chi(2)(1) for trend=32.2, P<0.001). Lytic antibodies against KSHV were detectable among 33% (61 out of 187) of Kaposi's sarcoma cases and 19% (36 out of 187) of their controls (OR=2.0, 95% CI 1.2-3.4, P=0.003) and the OR for Kaposi's sarcoma increased with increasing antilytic KSHV antibody titre (chi(2)(1) for trend=6.2, P=0.02). Virtually, all cases and controls had anti-EBV antibodies detected and the OR for non-Hodgkin's lymphoma associated with a doubling of the anti-EBV antibody titre was estimated to increase by a multiplicative factor of 1.3 (95% CI 0.9-1.7, P=0.1). Kaposi's sarcoma was not associated with antibody levels against EBV (P=0.4) and non-Hodgkin's lymphoma was not associated with antibodies against KSHV (latent P=0.3; lytic P=0.5). Adjustment for CD4 count at the time of sample collection made no material difference to any of the results. In conclusion, among human immunodeficiency virus infected people, high levels of antibodies against KSHV latent and lytic antigens are strongly associated with subsequent risk of Kaposi's sarcoma but not non-Hodgkin's lymphoma. Antibody titre to EBV does not appear to be strongly associated with subsequent risk of Kaposi's sarcoma or non-Hodgkin's lymphoma in HIV infected people.     

Immune evasion in human papillomavirus-associated cervical cancer

Tumour-associated viruses produce antigens that, on the face of it, are ideal targets for immunotherapy. Unfortunately, these viruses are experts at avoiding or subverting the host immune response. Cervical-cancer-associated human papillomavirus (HPV) has a battery of immune-evasion mechanisms at its disposal that could confound attempts at HPV-directed immunotherapy. Other virally associated human cancers might prove similarly refractive to immuno-intervention unless we learn how to circumvent their strategies for immune evasion.     

Cannabinoid modulation of Kaposi's sarcoma-associated herpesvirus infection and transformation

Kaposi's sarcoma-associated herpesvirus (KSHV; also named human herpesvirus 8) is necessary but not sufficient for the development of Kaposi's sarcoma. A variety of factors may contribute to the pathogenesis of Kaposi's sarcoma in addition to KSHV. Marijuana is a widely used recreational agent, and Delta(9)-tetrahydrocannabinol (Delta(9)-THC), the major active component of marijuana, is prescribed for medicinal use. To evaluate how cannabinoids may affect the pathogenesis of Kaposi's sarcoma, we studied primary human dermal microvascular endothelial cells (HMVEC) exposed to KSHV. There was an increased efficiency of KSHV infection in the presence of low doses of Delta(9)-THC. We also found that Delta(9)-THC increased the viral load in KSHV-infected HMVEC through activation of the KSHV lytic switch gene, the open reading frame 50. Furthermore, we observed that Delta(9)-THC stimulated expression of the KSHV-encoded viral G protein-coupled receptor and Kaposi's sarcoma cell proliferation. Our results indicate that Delta(9)-THC can enhance KSHV infection and replication and foster KSHV-mediated endothelial transformation. Thus, use of cannabinoids may place individuals at greater risk for the development and progression of Kaposi's sarcoma.     

Kaposi sarcoma-associated herpesvirus (KSHV): Molecular biology and oncogenesis

Kaposi sarcoma-associated herpesvirus (KSHV) is a double-stranded DNA herpesvirus belonging to the γ-herpesvirinae subfamily. KSHV has been associated with the development of three neoplastic diseases: Kaposi sarcoma (KS), primary effusion lymphoma (PEL), and multicentric Castleman disease (MCD). In this review, we discuss the three KSHV-associated malignancies, KSHV genome, latent and lytic aspects of the viral lifecycle, putative viral oncogenes, as well as therapeutic regimens used for the treatment of KS, PEL, and MCD.     

Kaposi's sarcoma-associated herpesvirus and sexual transmission of cancer risk.

The epidemiology of AIDS-related Kaposi's sarcoma (KS) predicted that a nonubiquitous sexually transmitted agent was central to its etiology. An assessment of Hill's criteria for causality reveals there is now sufficient evidence to declare Kaposi's sarcoma-associated herpesvirus (KSHV), or human herpesvirus 8, a necessary, albeit not sufficient, cause of KS. The most compelling evidence comes from longitudinal studies presented in the past year that demonstrate that KSHV infection temporally precedes and is independently associated with AIDS-related KS even after adjustment for other potential etiologic factors. In the United States and Northern Europe, many studies have now shown that KSHV can be sexually transmitted among homosexual men, but determining specific routes of sexual transmission is methodologically challenging, and initial results are conflicting. Data are also emerging that demonstrate nonsexual modes of transmission. Spread via renal allograft appears to occur, and in endemic areas of Europe and Africa, nonsexual horizontal and perhaps vertical spread are the dominant modes of transmission.