Kaposi's Sarcoma-associated Herpesvirus Transmission Research Articles

Transmission of Kaposi Sarcoma-Associated Herpesvirus Between Mothers and Children in a South African Population

To assess whether Kaposi sarcoma-associated herpesvirus (KSHV) with or without HIV coinfection in South African mothers is associated with higher KSHV seropositivity in their children. We tested sera from 1287 South African children and 1179 mothers using assays for KSHV lytic K8.1 and latent ORF73 antigens. We computed odds ratios (ORs) and 95% confidence intervals (CIs) to assess associations between KSHV serostatus and risk factors. KSHV seroprevalence was 15.9% (204 of 1287 subjects) in children and 29.7% (350 of 1179 subjects) in mothers. The risk of KSHV seropositivity was significantly higher in children of KSHV-seropositive mothers compared with those of KSHV-seronegative mothers. The HIV status of mothers was marginally associated with an increased risk of KSHV seropositivity in their children (OR = 1.6, 95% CI: 1.0 to 2.6; P = 0.07). KSHV seroprevalence was significantly higher in HIV-infected subjects (P = 0.0005), and HIV-infected subjects had significantly higher lytic and latent KSHV antibody levels than HIV-negative subjects. The risk of acquisition of KSHV was higher among children of KSHV-seropositive mothers. Although KSHV seroprevalence was significantly higher in children and mothers who were infected with HIV, the HIV status of the mother was only marginally associated with an increased risk of KSHV seropositivity in the child.

Delta (9)-Tetrahydrocannabinol Contributes to the Development of Kaposi's Sarcoma.

Kaposi's sarcoma-associated herpesvirus (KSHV), a DNA tumor virus, appears to be necessary but not sufficient for the development of Kaposi's sarcoma (KS). This is highlighted by the observation that most KSHV infections are asymptomatic, and more than 95% of persons who become infected never develop KS or other KSHV-related cancers. In addition to KSHV, a variety of factors, including HIV-1 Tat protein, may contribute to the pathogenesis of KS. These cofactors usually induce immunosuppression, enhance susceptibility to infection, modulate the viral life cycle, and/or stimulate angiogenesis and tumorigenesis either individually or in combination.Delta (9)-Tetrahydrocannabinol (THC), the major active component of marijuana, has been prescribed for medicinal use and has also been reported to induce immunosuppression. To date, contradictory observations have been made about its effects on viral infection/replication and on tumor cell growth. This prompted us to study the biological effect of Δ9-THC on KSHV, and obtain more evidence to assess the potential risks versus benefits of THC administration among KSHV-positive populations. We found an increased efficiency of KSHV infection (40% vs 15%) in human dermal microvascular endothelial cells (HMVEC) in the presence of low concentrations of Δ9-THC (10–100 nM). THC enhanced endocytosis and cell-cell adhesion by 30–60%, which may account for this increase in infection efficiency. Using real-time DNA PCR technology, the number of copies of the KSHV latent gene, LANA-1, was quantitated and correlated with the viral load in endothelial cells. We found that Δ9-THC increased the viral load 20–100 fold in KSHV-infected endothelial cells as compared to treatment with the vehicle control. We then quantitated expression of the KSHV lytic switch gene ORF50 (RTA) by real-time RT-PCR, in the presence or absence of Δ9-THC. ORF50 expression was shown to be up-regulated by Δ9-THC, leading to increased KSHV loads. We also observed that comparable concentrations of Δ9-THC up-regulated vGPCR expression, thereby fostering endothelial transformation and inducing significantly more colony-formation (1.5 fold) in soft agar. Our results indicate that Δ9-THC may enhance KSHV infection, transmission, replication, and viral-mediated endothelial transformation. Thus, THC administration may put individuals at greater risk for the development and growth of Kaposi's sarcoma.

Neoplastic Conditions in the Context of HIV-1 Infection

HIV-1 infection predisposes to the development of specific types of cancer. Most cancers seen in the AIDS setting are related to oncogenic virus infections, such as Epstein-Barr virus (EBV), Kaposi's sarcoma (KS)-associated herpesvirus (KSHV) and human papillomavirus (HPV). It is generally assumed that HIV-1 infection play a passive role in cancer development by impairing the host immune surveillance and increasing the risk of oncogenic virus infection. Recent insights, however, indicate that HIV-1 infection more actively promotes cancer growth. Experimental evidence has shown that HIV-1-encoded proteins can directly induce tumor angiogenesis and enhance KSHV transmission to target cells. Clinical evidence suggests that the oncogenicity of HPV is altered by the presence of HIV-1 infection irrespective of host immune status. The introduction of highly active antiretroviral therapy (HAART) has dramatically decreased the incidence of KS whereas the impact of HAART is variable in EBV-related lymphoma and HPV-related cervical cancer, suggesting that additional factors are involved in the pathogenesis of these cancers. Understanding the direct and indirect roles of HIV-1 in the pathogenesis of neoplastic conditions could provide the rationale for prevention and development of new treatments for AIDS-associated malignancies.

Quantification of Kaposi's sarcoma-associated herpesvirus in blood, oral mucosa, and saliva in patients with Kaposi's sarcoma.

The aims of this study were to measure Kaposi's sarcoma-associated herpesvirus (KSHV) load in oral mucosa and blood and to determine their relationship with clinical activity of KS in both AIDS-Kaposi's sarcoma (KS) and HIV-unrelated KS patients. Among AIDS patients, KSHV viral load in peripheral blood mononuclear cells (PBMCs) was higher in patients with active KS than in patients with KS in complete remission. In HIV-unrelated KS patients, KSHV viral load in PBMCs was not correlated with clinical stage. Thus, monitoring KSHV viral load in PBMCs could be useful, particularly in the context of HIV infection. In patients with HIV-unrelated KS, KSHV viral load in oral compartments can be very high even in patients with nonactive KS, implying that patients with nonactive KS are still a potential source of transmission of KSHV through oral contact.

Wild-type Kaposi's sarcoma-associated herpesvirus isolated from the oropharynx of immune-competent individuals has tropism for cultured oral epithelial cells.

Based on the observation that wild-type Kaposi's sarcoma-associated herpesvirus (KSHV) DNA can be detected in the oral cavity of healthy, immunocompetent individuals, we hypothesized that epithelial cells could be infected in vitro by wild-type (WT) KSHV isolated from immunocompetent individuals. Primary oral epithelial (P-EPI) cells and telomerase-immortalized oral epithelial cells were generated from human gingival tissue and were then infected in vitro with WT KSHV isolated from throat wash samples. Markers of lytic and latent KSHV infection were detected in cultures by 24 h postinfection by immunofluorescence confocal microscopic assays. The infectivity of the WT and BCBL virus was blocked by neutralizing antibodies against KSHV gB. The presence of KSHV DNA in these cells was confirmed by real-time PCR amplification of different regions of the viral genome. The significant in vitro viral replication that had occurred was inhibited by ganciclovir and by neutralizing antibodies against gB. When infected cultures were examined by scanning electron microscopy, thousands of KSHV particles were clearly visible across the surfaces of P-EPI cells. The detection of enveloped particles indicated that the infectious cycle had proceeded through assembly and egress. We thus demonstrated that oral WT KSHV isolated from immunocompetent individuals was able to infect and replicate in vitro in a relevant primary cell type. Furthermore, our results provide compelling evidence for KSHV transmission within infected oral epithelial cells derived from healthy, immunocompetent populations.

Transmission and disease association of Kaposi's sarcoma-associated herpesvirus: recent developments.

Kaposi's sarcoma-associated herpesvirus or human herpesvirus 8, common in sub-Saharan Africa and around the Mediterranean Sea but rare in most other countries, is known to be transmitted in childhood within families in endemic regions, and through sexual contacts among high-risk groups in Western countries. Nevertheless recent developments on other modes of transmission of the virus have been made during the last years and are summarized in this review. Furthermore, recent published disease associations are discussed. The last year has seen research addressing the question of parenteral transmission, sexual transmission through heterosexual contact, transmission of Kaposi's sarcoma-associated herpesvirus-infected cells from organ donors to recipient, as well as the first suggestion that host genetic factors may facilitate infection in childhood. Additional clinical manifestations of infection with the virus such as primary pulmonary hypertension and germinotropic lymphoproliferative disorder have been identified. Evidence of Kaposi's sarcoma-associated herpesvirus transmission other than between homosexual adults and during childhood - namely transmission through heterosexual contact or injection drug use - is growing although these issues are still incompletely analysed and far away from being fully understood. Despite our increasing knowledge on transmission and disease associations of the virus, implications on the clinical management of associated diseases and public health have to be further evaluated in the coming years.

Risk factors for Kaposi's sarcoma-associated herpesvirus infection among HIV-1-infected pregnant women in the USA

We sought to identify risk factors for infection with the Kaposi's Sarcoma-associated herpesvirus (KSHV) among pregnant women and to examine a reported association of KSHV with injecting drug use (IDU) and hepatitis C virus (HCV) infection. Cross-sectional evaluation of questionnaire data and KSHV and HCV seroprevalence in the Women and Infants Transmission Study. In sera collected from HIV-1-infected pregnant women (n = 887) and, at age 12 months, their offspring (n = 900) at six sites in the USA and Puerto Rico, KSHV and HCV antibodies were detected with sensitive and specific enzyme immunoassays. Risk of KSHV was estimated by the unadjusted and adjusted odds ratio (OR(adj)) and 95% confidence interval (CI). The geographic referent sites were Chicago and Boston. Forty-seven (5.3%) of the women and three (0.3%) of the infants were KSHV seropositive. In univariate and multivariate analyses, KSHV in the women was associated with enrollment in Puerto Rico, Houston or Brooklyn (OR(adj), 4.3; 95% CI, 1.8-10.4) or Manhattan (OR(adj), 9.8; 95% CI, 3.7-25.6); non-completion of high school (OR(adj), 1.8; 95% CI, 0.9-3.4); the number of sexually transmitted diseases (OR(adj), 1.4; 95% CI, 1.0-1.9 per disease); and especially with IDU and HCV infection (OR(adj), 3.5; 95% CI, 1.5-7.9). Transmission of KSHV by blood inoculation may be highly inefficient, but our data support the hypothesis that it does occur. Large formal studies to evaluate whether KSHV transmission occurs via transfusion are needed to inform decisions regarding screening volunteer blood donors to protect the blood supply.

Prevalence of Kaposi sarcoma-associated herpesvirus infection in homosexual men at beginning of and during the HIV epidemic.

Some studies have inferred that an epidemic of Kaposi sarcoma-associated herpesvirus (KSHV) infection in homosexual men in the United States occurred concurrently with that of human immunodeficiency virus (HIV), but there have been no direct measurements of KSHV prevalence at the beginning of the HIV epidemic. To determine the prevalence of KSHV infection in homosexual men in San Francisco, Calif, at the beginning of the HIV epidemic in 1978 and 1979 and to examine changes in prevalence of KSHV at time points from 1978 through 1996 in light of changes in sexual behavior. Analysis of a clinic-based sample (n = 398) derived from the San Francisco City Clinic Cohort (ages 18-66 years) (n = 2666 for analyses herein) and from population-based samples from the San Francisco Men's Health Study (MHS) (ages 25-54 years) (n = 825 and 252) and the San Francisco Young Men's Health Study (YMHS) (ages 18-29 years) (n = 428-976, and 557); behavioral studies were longitudinal and KSHV prevalence studies were cross-sectional. Antibodies against KSHV and HIV; sexual behaviors. The prevalence of KSHV infection in 1978 and 1979 was 26.5% of 235 (a random sample) overall (weighted for HIV infection) vs 6.9% (128/1842) for HIV in the San Francisco City Clinic Cohort sample. The prevalence of KSHV infection remained essentially unchanged between an MHS sample of 252 in 1984 and 1985 (29.6%) and a YMHS sample of 557 in 1995 and 1996 (26.4%), while HIV prevalence dropped from 49.5% of 825 in 1984 and 1985 (MHS) to 17.6% of 428 in 1992 and 1993 (YMHS). The proportion of men practicing unprotected receptive anal intercourse with 1 or more partners declined from 54% to 11% during the 1984 through 1993 period (MHS) with similar though slightly higher values in the YMHS in 1992 and 1993; whereas for unprotected oral intercourse it ranged between 60% and 90% in the 1984 through 1996 period (MHS and YMHS). Infection with KSHV was already highly prevalent in homosexual men when the HIV epidemic began in San Francisco, and its prevalence has been maintained at a nearly constant level. Any declines in the incidence of Kaposi sarcoma do not appear to be caused by a decline in KSHV transmission.

Prevalence of Kaposi's sarcoma-associated herpesvirus infection in sex workers and women from the general population in Spain.

Transmission routes of Kaposi's sarcoma-associated herpesvirus (KSHV) in the general population are poorly understood. Whereas sexual transmission appears to be common in homosexual men, the evidence for heterosexual transmission is less convincing. In our study, prevalence of KSHV infection was examined among women in the Spanish general population and among sex workers. Subjects consisted of 100 prostitutes and 100 women randomly sampled from the general population and age-matched to the prostitutes. Women had a personal interview and gynecologic examinations in which a blood sample, cervical cells and oral cells were obtained. Peripheral blood mononuclear cells (PBMC), oral and cervical samples were tested for KSHV DNA by quantitative real-time PCR. Sera were tested for antibodies against human immunodeficiency virus (HIV) by ELISA and against KSHV by latent IFA and K8.1 ELISA. Women who were positive in either serologic assay or PCR were considered infected by KSHV. Human papillomavirus (HPV) DNA in cervical scrapes were evaluated using the Hybrid Capture System. The study population had an average age of 30 years and were HIV-negative. Women from the general population were largely of Spanish nationality, and 61% reported lifetime monogamy. The majority of the prostitutes (76%) were immigrants, primarily from South America. Sex workers were twice as likely to be infected with KSHV than women in the general population (16% vs. 8%, prevalence odds ratio [OR] = 2.2). KSHV was more prevalent among HPV DNA-positive women (OR = 2.5) and among women with an early age at first sexual intercourse (OR = 2.7, p < 0.05). KSHV DNA was detected by PCR in 3% of the oral cavity samples, in 2% of the cervical samples of the prostitutes and in 1% of the cervical samples of women in the general population. All PBMC samples were negative. These results suggest that in low-risk countries for KSHV, oral shedding and heterosexual contacts are potential pathways for KSHV transmission.

Seroprevalence of Kaposi's Sarcoma-Associated Herpesvirus Infection among Blood Donors from Texas

PURPOSE: Kaposi's sarcoma-associated herpesvirus (KSHV), a gammaherpesvirus recently discovered among AIDS patients with Kaposi's sarcoma, is a potential candidate for screening in blood and plasma donors. While a number of studies have assessed KSHV infection among U.S. blood donors, larger-scale population-based studies would be necessary to develop more refined estimates of the magnitude and variation of KSHV infection across different geographic regions of the U.S. blood supply. The goal of the present study, therefore, was to determine the seroprevalence of KSHV infection and to assess demographic correlates of KSHV infection among south Texas blood donors. METHODS: KSHV infection was determined using specific serologic assays that measure antibodies to KSHV latent and lytic antigens. RESULTS: The overall seroprevalence of KSHV in Texas blood donors (15.0%) is substantially higher than previously reported among blood donor and general population samples in the United States. This high rate of KSHV infection persisted across most of the sociodemographic subgroups under study but was particularly elevated among participants with less than a high school education. The infection rate also increased linearly with age. CONCLUSIONS: The elevated infection rate reported in the present study suggests that screening methods to detect KSHV infection in blood donors should be considered. In view of the etiologic role of KSHV for several malignancies, it would be important for future studies to directly assess the risk of KSHV transmission via blood transfusion.

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.

Detection of Kaposi's sarcoma-associated herpesvirus in oral and genital secretions of Zimbabwean women.

Kaposi's sarcoma-associated herpesvirus (KSHV) in oral and genital secretions of women may be involved in horizontal and vertical transmission in endemic regions. Nested polymerase chain reaction assays were used to detect KSHV DNA sequences in one-third of oral, vaginal, and cervical specimens and in 42% of peripheral blood mononuclear cell (PBMC) specimens collected from 41 women infected with human immunodeficiency virus type 1 who had Kaposi's sarcoma (KS). KSHV DNA was not detected in specimens from 100 women without KS, 9 of whom were seropositive for KSHV. A positive association was observed between KSHV DNA detection in oral and genital mucosa, neither of which was associated with KSHV DNA detection in PBMC. These data suggest that KSHV replicates in preferred anatomic sites at levels independent of PBMC viremia. Detection of genital-tract KSHV only among relatively immunosuppressed women may provide an explanation for infrequent perinatal transmission of KSHV.

Kaposi's sarcoma-associated herpesvirus (human herpesvirus 8): epidemiology and pathogenesis.

Kaposi's sarcoma-associated herpesvirus (KSHV), or human herpesvirus type 8 (HHV-8), is a gamma2 herpesvirus (rhadinovirus) and the most recently discovered human tumour virus. It is involved in the pathogenesis of Kaposi's sarcoma (KS), primary effusion lymphoma and the plasma cell variant of multicentric Castleman's disease. KSHV is not pathogenic in most otherwise healthy individuals but is highly oncogenic in HIV-1-infected and iatrogenically immunosuppressed individuals. It establishes a latent infection in most KS spindle (endothelial tumour) cells and in the neoplastic B cells of primary effusion lymphomas. The KSHV genome contains several homologues of cellular genes known to regulate cell growth and differentiation. Although some of these have transforming properties in vitro, their precise role in oncogenesis is still under investigation. Other co-factors may be involved in the pathogenesis of KS in HIV-uninfected, immunocompetent individuals, e.g. in African endemic KS, but none have been identified yet. Transmission of KSHV among homosexual men appears to occur through sexual contact, but in endemic countries transmission is frequent in childhood and may occur through close contact within families. Four major variants of KSHV have been defined, on the basis of variability in the K1 gene; they may have co-evolved with certain human populations. In addition, some KSHV strains may have resulted from a recombination event with a related, but not yet identified, gamma2 herpesvirus.

Increasing Kaposi's sarcoma-associated herpesvirus seroprevalence with age in a highly Kaposi's sarcoma endemic region, Zambia in 1985.

Kaposi's sarcoma (KS)-associated herpesvirus (KSHV) is a newly discovered virus found in all forms of KS. In the United States, KSHV infection appears to be most common amongst individuals at high-risk for KS. Preliminary data from Africa suggest that KSHV infection may be much more common in the general population. To examine the KSHV seroprevalence and age-specific patterns of infection in an African country with high rates of KS. Cross-sectional seroprevalence study. Sera were taken for a hospital-based HIV seroprevalence study conducted in August 1985 in Lusaka, Zambia at a time when HIV was just becoming epidemic in this area. A total of 251 sera were randomly sampled and examined for antibodies against latent and lytic antigens to KSHV. KSHV seroprevalence was compared with demographic and clinical variables using chi2 test for linear trend and odds ratios and 95% confidence intervals. Overall, 58% of persons aged 14-84 years were KSHV-seropositive. KSHV seroprevalence increased linearly with age (P = 0.04) and was inversely related to years of education (P = 0.015). In contrast, HIV infection peaked in those aged 20-29 years and was positively related to years of education (P = 0.01 5). No association between KSHV and gender, marital status, or HIV serostatus was seen. KSHV infection was significantly more common in this region of Zambia in 1985 than it currently is in the United States. Our data are consistent with KSHV being well-established in this region prior to 1985 and that continued adult transmission of the virus was occurring. The high seroprevalence in the adolescent age-group and the relatively linear increase in prevalence with age suggest that non-sexual modes of transmission may be important for KSHV transmission in Africa.