Thomas F. Schulz

Kaposi's Sarcoma‐associated Herpesvirus (Human Herpesvirus 8)

As epidemiologic evidence accumulates, it is becoming increasingly clear that Kaposis sarcoma (KS)-associated herpesvirus (KSHV) (or human herpesvirus 8 [HHV-8]) is the likely infectious cause of KS and related neoplastic disorders. Immunosuppression is an important cofactor in KS pathogenesis, as shown by the occurrence of KS in post-transplant patients and its occasional regression after the reduction of iatrogenic immunosuppression. Whether KS is a hyperplastic process driven by cytokine dysregulation or represents the oligo-or monoclonal-expansion of virus-transformed endothelial cells remains controversial. Near-universal detection of KSKSHV DNA in all of the histologically indistinguishable forms of KS suggests that they share a common etiology. In addition to studies suggesting persistence of KSHV in prostate tissues from KS patients, one study has found that dorsal root ganglia may harbor viral DNA in patients with AIDS-KS. Cultivation of the virus in cells uninfected with Epstein-Barr virus (EBV) has led to the development of serologic tests and studies of KSHV gene expression during latency and lytic replication. The close correspondence between signal pathways activated by EBV infection and those activated by virus-encoded homologs during KSHV infection is seen for interleukin-6 (IL-6) signal transduction. DNA tumor viruses have been essential tools in dissecting out transformation pathways, and KSHV promises to provide a unique model for investigating virus-induced transformation. The unique epidemiology of KSHV and its public health importance, especially to parts of sub-Saharan Africa, suggest that this virus be accorded an important priority in the development of techniques for its control and treatment.

Kaposi's-sarcoma-associated herpesvirus in HIV-negative Kaposi's sarcoma

events involving, to various degrees, microorganisms such as herpesviruses, hepatitis B virus, HIV, and Mycoplasma penetrans.H Chang and colleagues5 have identified herpesvirus-like DNA sequence in biopsy samples from patients with AIDS-associated KS. This DNA sequence was found exclusively in KS biopsy specimens but not in several other tested tissues. We report our results of screening DNA samples from isolated peripheral blood mononuclear cells (PBMCs). DNA was directly purified from uncultured PBMCs that

Prevalence and transmission of Kaposi's sarcoma‐associated herpesvirus (human herpesvirus 8) in Ugandan children and adolescents

We studied the seroprevalence and transmission of Kaposis sarcoma‐associated herpesvirus (KSHV/HHV8), among 215 Ugandan children, adolescents and young adults. We measured antibodies to a latent nuclear antigen (LANA) and a lytic cycle protein encoded by open reading frame (orf) 65. Infection with KSHV/HHV8 occurred during early childhood and reached adult levels (approx. 50%) before the age of puberty. In children younger than 12 years of age, antibodies to LANA and the orf65 protein were independently associated with hepatitis B infection (p < 0.005). KSHV/HHV8 infection was not associated with antibodies to hepatitis A virus and hepatitis C virus, nor with the quality of the water supply, household size, previous blood transfusions, number of boy/girl friends or marital status. Antibodies to the orf65 protein, but not LANA, were weakly associated with a history of i.v. injections. Our results show that, in contrast to its sexual mode of transmission among homo/bisexual men and sexually transmitted diseases clinic attendees of Northern Europe and the US, transmission of KSHV in Uganda occurs largely before puberty. Among Ugandan children, KSHV transmission follows a horizontal pattern similar to other herpesviruses, in particular the related γ herpesvirus, Epstein‐Barr virus. Transmission of KSHV may be facilitated by living conditions that also promote infection with hepatitis B virus. Int. J. Cancer 77:817–820, 1998.© 1998 Wiley‐Liss, Inc.

HIV-associated lymphomas and gamma-herpesviruses.

Among the most common HIV-associated lymphomas are Burkitt lymphoma (BL) and diffuse large B-cell lymphoma (DLBCL) with immunoblastic-plasmacytoid differentiation (also involving the central nervous system). Lymphomas occurring specifically in HIV-positive patients include primary effusion lymphoma (PEL) and its solid variants, plasmablastic lymphoma of the oral cavity type and large B-cell lymphoma arising in Kaposi sarcoma herpesvirus (KSHV)-associated multicentric Castleman disease. These lymphomas together with BL and DLBCL with immunoblastic-plasmacytoid differentiation frequently carry EBV infection and display a phenotype related to plasma cells. EBV infection occurs at different rates in different lymphoma types, whereas KSHV is specifically associated with PEL, which usually occurs in the setting of profound immunosuppression. The current knowledge about HIV-associated lymphomas can be summarized in the following key points: (1) lymphomas specifically occurring in patients with HIV infection are closely linked to other viral diseases; (2) AIDS lymphomas fall in a spectrum of B-cell differentiation where those associated with EBV or KSHV commonly exhibit plasmablastic differentiation; and (3) prognosis for patients with lymphomas and concomitant HIV infection could be improved using better combined chemotherapy protocols incorporating anticancer treatments and antiretroviral drugs.

Seroconversion for human herpesvirus 8 during HIV infection is highly predictive of Kaposi's sarcoma.

Background:The finding of antibodies against human herpesvirus 8 (HHV-8) is associated with the occurrence of Kaposis sarcoma in persons infected with HIV. However, the predictive value of HHV-8 antibodies for Kaposis sarcoma in HIV infection is unknown. Methods:The Amsterdam Cohort Studies on HIV infection and AIDS started in 1984 for homosexual men and in 1985 for injecting drug users. Serum samples from 1459 homosexual men and 1167 drug users were tested for antibodies to recombinant HHV-8 lytic-phase capsid (ORF65) antigen and latent-phase nuclear (ORF73) antigen. Individuals were retrospectively identified as HHV-8-positive or HHV-8-negative at enrolment or HHV-8 seroconverter during the study. Kaposis sarcoma-free survival time was compared between HIV-infected men who were positive for HHV-8 at enrolment and those who later seroconverted for HHV-8. Hazard ratios were estimated for Kaposis sarcoma, lymphoma, and opportunistic infection according to the HHV-8 serostatus. Results:The incidence of HHV-8 seroconversion among drugs users was 0.7 per 100 person-years based on 31 seroconversions, whereas an incidence of 3.6 was found among homosexual men based on 215 seroconversions. The hazard ratio for Kaposis sarcoma was 3.15 (95% CI: 1.89–5.25) in HIV-infected individuals if HHV-8 antibodies were present either at enrolment or at HIV seroconversion. In HIV-infected persons who later seroconverted to HHV-8, Kaposis sarcoma developed more rapidly: hazard ratio of 5.04 (95% CI: 2.94–8.64), an additional risk of 1.60 (95% CI: 1.01–2.53; P = 0.04). Time-dependent adjustment for CD4+ cell count and HIV RNA had no impact on the additional risk, although the CD4+ cell count was an independent risk factor for Kaposis sarcoma. HHV-8 infection did not increase the risk of AIDS-related lymphoma or opportunistic infections. Conclusions:The incidence of HHV-8 infection is higher in homosexual men than in drug users. The presence of HHV-8 antibodies in HIV-infected persons increases the risk of Kaposis sarcoma. Among HIV-infected persons, those who subsequently seroconvert for HHV-8 are at highest risk. These results strongly confirm the causal role of HHV-8 in Kaposis sarcoma and emphasize the clinical relevance of HHV-8 seroconversion before and after the HIV infection.

Interassay Correlation of Human Herpesvirus 8 Serologic Tests

To standardize human herpesvirus 8 (HHV-8) antibody assays for application to asymptomatic infection, a blinded comparison was done of seven immunofluorescence assays and ELISAs. Five experienced laboratories tested a serum panel from 143 subjects in 4 diagnostic groups. Except for a minor capsid protein ELISA, the other six tests detected HHV-8 antibodies most frequently in classic (80%-100%) and AIDS-related (67%-91%) Kaposis sarcoma, followed by human immunodeficiency virus-seropositive patients (27%-60%), and least frequently in healthy blood donors (0-29%). However, these six assays frequently disagreed on individual sera, particularly for blood donor samples. Current HHV-8 antibody tests have uncertain accuracy in asymptomatic HHV-8 infection and may require correlation with viral protein or nucleic acid detection. Antibody assays are useful for epidemiologic investigations, but the absolute prevalence of HHV-8 infection in the United States cannot yet be determined.

Post-transplant Kaposi sarcoma originates from the seeding of donor-derived progenitors.

Kaposi sarcoma (KS) is a vascular tumor that can develop in recipients of solid tissue transplants as a result of either primary infection or reactivation of a gammaherpesvirus, the KS- associated herpesvirus, also known as human herpesvirus-8 (HHV-8). We studied whether HHV-8 and the elusive KS progenitor cells could be transmitted from the donor through the grafts. We used a variety of molecular, cytogenetic, immunohistochemical and immunofluorescence methods to show that the HHV-8–infected neoplastic cells in post-transplant KS from five of eight renal transplant patients harbored either genetic or antigenic markers of their matched donors. These data suggest the use of donor-derived HHV-8–specific T cells for the control of post-transplant KS.

The pleiotropic effects of Kaposi's sarcoma herpesvirus.

Kaposis sarcoma herpesvirus (KSHV), or human herpesvirus 8 (HHV8), is an essential factor in the pathogenesis of Kaposis sarcoma (KS), multicentric Castlemans disease (MCD), and primary effusion lymphoma (PEL). Case reports suggest an occasional involvement in bone marrow hypoplasia and haemophagocytic syndrome, but other disease associations are unconfirmed or controversial. KSHV‐associated disease is of particular importance in immunosuppressed individuals, in particular in patients with HIV infection and transplant recipients. KSHV establishes a latent infection in the majority of infected cells in KS, MCD, and PEL, but lytic replication occurs in a small fraction of infected cells. Viral proteins expressed during both the latent and the lytic phase of the viral life cycle contribute to the pathogenesis of KSHV‐associated diseases. Copyright

Neuropsychiatric disease relevance of circulating anti-NMDA receptor autoantibodies depends on blood-brain barrier integrity.

In 2007, a multifaceted syndrome, associated with anti-NMDA receptor autoantibodies (NMDAR-AB) of immunoglobulin-G isotype, has been described, which variably consists of psychosis, epilepsy, cognitive decline and extrapyramidal symptoms. Prevalence and significance of NMDAR-AB in complex neuropsychiatric disease versus health, however, have remained unclear. We tested sera of 2817 subjects (1325 healthy, 1081 schizophrenic, 263 Parkinson and 148 affective-disorder subjects) for presence of NMDAR-AB, conducted a genome-wide genetic association study, comparing AB carriers versus non-carriers, and assessed their influenza AB status. For mechanistic insight and documentation of AB functionality, in vivo experiments involving mice with deficient blood–brain barrier (ApoE−/−) and in vitro endocytosis assays in primary cortical neurons were performed. In 10.5% of subjects, NMDAR-AB (NR1 subunit) of any immunoglobulin isotype were detected, with no difference in seroprevalence, titer or in vitro functionality between patients and healthy controls. Administration of extracted human serum to mice influenced basal and MK-801-induced activity in the open field only in ApoE−/− mice injected with NMDAR-AB-positive serum but not in respective controls. Seropositive schizophrenic patients with a history of neurotrauma or birth complications, indicating an at least temporarily compromised blood–brain barrier, had more neurological abnormalities than seronegative patients with comparable history. A common genetic variant (rs524991, P=6.15E−08) as well as past influenza A (P=0.024) or B (P=0.006) infection were identified as predisposing factors for NMDAR-AB seropositivity. The >10% overall seroprevalence of NMDAR-AB of both healthy individuals and patients is unexpectedly high. Clinical significance, however, apparently depends on association with past or present perturbations of blood–brain barrier function.

Epidemiology of Kaposi's sarcoma-associated herpesvirus/human herpesvirus 8.

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