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Human herpesvirus 8 and Kaposi's sarcoma in the Amsterdam cohort studies.
Disease association, transmission and natural history
Renwick, N.M.
Publication date
2001
Link to publication
Citation for published version (APA):
Renwick, N. M. (2001). Human herpesvirus 8 and Kaposi's sarcoma in the Amsterdam cohort
studies. Disease association, transmission and natural history.
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Introduction n
AA groundbreaking study on the distribution of KS in per-sonss with AIDS changed the focus of research on this vas-cularr tumor from a "cvtokine-driven" proliferation to a dis-easee caused bv an unidentified infection (1). Four vcars later,, D N A sequences from a novel herpesvirus, named Humann Herpesvirus 8 or Kaposi's sarcoma-associated herpesvirus,, were detected in A1DS-KS tissue (2). These D N AA sequences were shown to be present in all KS vari-ants,, however a debate arose as to whether HHV8 was the
Diseasee causation is usefully considered in terms of criteria thatt describe a cause and effect relationship; (i) exposure to thee cause should be more common in those with the disease andd the prevalence and incidence of the disease should be higherr in those exposed to the proposed cause (ii) exposure too the cause should precede the appearance of the disease (iii)) the association should be observed in different places andd times (iv) a dose response relationship may be seen be-tweenn the severity of exposure and severity of outcome and preventionn or elimination of the risk factor or modification ott the host response should produce identical trends in dis-easee expression (v) the relationship mav be specific in that a singlee cause produces a single effect (vi) the relationship shouldd be biologically plausible (vii) and experimental evi-dencee should support the association (6,7).
Wee demonstrated some of the criteria that HHV8 causes AIDS-KSS in our cohort of homosexual men; the seroprevalencee of HHV8 was highest among persons with AIDS-KSS and the seroincidence of HHV8 was highest in HIV-11 infected homosexual men (5). The prevalence and
causativee agent or a "passenger virus" in KS tissue (3,4). Manyy serological and nucleic acid based assays were de-signedd to examine the association between HHV8 and KS. VC'ee designed an HI A using recombinant HHV8 h tic-phase capsidd (ORF65) and latent-phase nuclear (ORF73) antigens too investigate this association in the homosexual and drug userr cohorts of the Amsterdam Cohort Studies on HIY-1 infectionn and AIDS (5).
incidencee of AIDS-KS were higher among HIV-1 infected homosexuall men than among HIV-1 uninfected homosex-uall men and HIV-1 infected and uninfected drug users (8). HHV88 antibodies preceded the appearance of KS in HIV-1 infectedd men and were shown to be a strong risk factor for KSS in a time-dependent Cox proportional Hazards model; fortyy percent of HIV-1 and HHV8 co-infected individuals developedd KS within 10 years of follow-up (5). In this study,, modification of the host response, using antiretrovirall therapy, reduced the risk of KS in HIV-1 in-fectedd individuals by approximately two thirds however it waswas not clear whether this was due to a direct effect of the medicationn on HHV8 or an indirect effect of immune resto-ration. .
Resultss from prospective cohort studies in differing loca-tionss have provided the most convincing argument to date thatt HHV8 is the cause of KS in the context of HIV-1 in-fectionn (5,9-13). Not only are the associations between HHV88 and AIDS-KS consistently strong but also HHV8 antibodiess are usually detected before the appearance of
clinicall KS lesions. These features have also been demon-stratedd using PCR to detect HHV8 DNA in the peripheral bloodd of HIV-1 infected individuals (14). HHV8 DNA is presentt in all variants of KS and each variant is strongly as-sociatedd with HHV8 antibodies (see Introduction).
Thee remaining causation criteria have been considered in otherr studies; the dose-response criterion can be inter-pretedd as the host response to inoculation with a known dosee of virus however these studies can not be performed in humanss and HHV8 has not yet been successfully transmit-tedd to animals. This criterion can alternatively be inter-pretedd as the more frequent detection of HHV8 in KS le-sionss than in unaffected tissues; viral transcripts are more frequendyy detected in KS than in control tissue (15,16). The decreasee in KS incidence that occurs when ganciclovir is ad-ministeredd to persons with AIDS is also consistent with a dose-responsee relationship (17). A substantial volume of experimentall data on HHV8 supports a causative role in KS however,, pathogenetic mechanisms are often disputed and somee notable studies, such as the transformation of human endotheliall cells by HHV8, require confirmation (15,18). Biologicall plausibility7 provides strong support for the role
off HHV8 in KS however specificity is a weak criterion for causationn as HHV8 causes two other diseases (see below).
Numerouss studies have been published on the association orr lack of association between HHV8 and an extensive list off dermatologie, haematologic, neurologic and oncologic diseases,, infectious disease syndromes and systemic disor-ders.. HHV8 is consistently detected in B cell primary effu-sionn lymphomas / body-cavity-based lymphomas (2,19)
andd some forms of the B cell lymphoproliferative disorder, multicentricc Castieman's disease (20). A controversial asso-ciationn involving HHV8 resulted from an in vitro finding thatt vMIP-II prevents HIV-1 entry into cells that express CCR33 such as microglia (21). This finding led to the hy-pothesiss that HHV8 infection and/or KS could protect HIV-11 infected individuals from AIDS Dementia Complex (ADC)) however we found no such protective effect be-tweenn H H V 8 / K S and ADC in our cohort of HIV-1 in-fectedd homosexual men (22). The most controversial re-portss to date are those that concern HHV8 as the cause of sarcoidosiss and multiple myeloma (23,24). Serological stud-iess have not supported a causative role for HHV8 in these diseasess (25,26).
Reportss are starting to emerge on the symptoms that are as-sociatedd with primary HHV8 infection (27,28). Wang et al. showedd that primary HHV8 infection has distinct clinical, immunologicall and virological components and reported thee occurrence of non-specific symptoms, such as diarrhea, fatigue,, localized rash and lymphadenopathy, during acute infectionn (27). We also investigated the symptoms that were experiencedd by HIV-1 infected and uninfected homosexual menn during primary HHV8 infection; significant increases inn the incidences of cough, sore throat, and muscle ache weree observed in HIV-1 uninfected participants whereas no significantt increases in symptom incidences were observed inn HIV-1 infected participants (28). In our opinion, primary HHV88 infection should be considered as a flu-like illness andd further studies are necessary to delineate the range of syndromess produced by HHV8 infection (28).
Transmission n
Thee distribution of Kaposi's sarcoma in persons with AIDS alsoo provided insights into the transmission of the "Kaposi agent",, namely HHV8. The predominance of KS in HIV-1 infectedd homosexual men in comparison to all other missionn groups such as drug users, hemophiliacs and trans-fusionn recipients suggests that HHV8 is primarily sexually transmittedd with rare transmission through clotting factors andd blood transfusion (1).
Studiess on HHV8 transmission have been facilitated by pre-existingg cross-sectional and prospective cohort studies onn HIV-1 infection and AIDS. The majority of transmis-sionn studies have examined risk factors for HHV8 seropositivityy in cross-sectional studies and may not accu-ratelyy reflect the association between recent infection and thee risk factor under investigation (29). Two studies have examinedd the association between risk factors and HHV8 seroconversionn (11, 29). In a study of Danish homosexual men,, H H V 8 seroconversion was associated with HIV-1 in-fectionn and visits to homosexual communities in the United Statess of America. In our cohort of homosexual men, H H V 88 seroconversion was associated with oro-genital sex, olderr age and preceding HIV-1 infection (29). Despite gen-erall agreement that HHV8 is sexually transmitted among homosexuall men, the precise sexual technique(s) remains to bee confirmed (30). Transmission through oro-genital con-tactt is supported by the presence of HHV8 in saliva and se-menn and mucosal shedding from the oro-pharynx however transmissionn through other sexual behaviours remains pos-siblee (31,32).
Blood-bornee transmission of HHV8 in HIV-1 transmission groupss is controversial; daily-injection drug use was shown
too be associated with HHV8 seropositivity in a cross-sec-tionall study of women with or at risk for HIV-1 infection in Northh America (33). We investigated a cohort of drug users inn the Netherlands for III IV8-associated risk factors how-everr we were unable to assess recent behaviour due to the loww number of seroincident cases (34). In our study, HHV8 seropositivityy at study entry was associated with homosex-uall contact and a Mediterranean nationality for men and a historyy of sexual contact with a bisexual man, absence of a steadyy partner and commercial unprotected sex for women. N oo associations were seen between HHV8 seropositivity andd injection-drug use or Hepatitis B, Hepatitis C or HIV-1 infections.. The discrepant risk factor associations may re-flectt differences between the study populations such as the prevalencee of HIV-1 infection or may be due to method-ologicall differences; we improved the positive predictive valuee of our serology by adding a confirmation step to the protocoll however our serological assay was less sensitive thann that employed by Cannon et al. (33,34). The infre-quencyy of bloodborne transmission is supported by a study off persons who received blood from HIV-1 and HHV8 coinfectedd donors; all 14 recipients developed HIV-1 anti-bodiess whereas none developed HHV8 antibodies (35).
Non-sexuall transmission of HHV8 is probable as KS af-fectss transplant recipients and African children (30). HHV8 appearss to be transmitted in childhood in countries where HHV88 is endemic and the appearance of HHV8 antibodies inn patients after organ transplantation indicates that trans-missionn may occur through infected blood products or do-norr grafts (30). Elucidation of the modes of HHV8 trans-missionn is important as simple precautions may lessen the impactt of HHV8 infection on human health.
Naturall History of Human Herpesvirus 8
HHV88 belongs to the rhadinovirus subfamily of the gammaherpesvirinaee and is thought to have evolved from a mammaliann herpesviral ancestor that existed over 200 mil-lionn years ago (36,37). The gammaherpesvirinae are well knownn for their association with lymphoproliferative disor-derss and cancer; Herpesvirus Saimiri can induce malignant lymphomass in owl monkeys and marmosets (Aotus and Saguinuss sp.) and Epstein-Barr virus infection is linked to a fatall B-cell proliferation in young males with X-linked lymphoproliferativee disease, posttransplant lymphomas, immunobtasticc lymphomas in AIDS patients, Burkitt's Lymphoma,, Nasopharyngeal carcinoma and Hodgkin's Diseasee (38,39). This relationship between gammaherpes-virinaee and cancer fulfils the biological plausibility require-mentt of the causation criteria (see above).
Rhadinovirusess are found in many species and several ex-ampless have been identified in non-human primates; HVS
Althoughh HHV8 infection is the necessary cause of KS, otherr factors appear to be required to produce the disease; HIV-11 infection and immunosuppressive therapy are con-ditionall for AIDS-KS and Transplant KS respectively. The rolee of immunosuppression, immunoactivation and/or otherr co-factors remains to be established for Classic and Endemicc KS. It is reasonable to speculate that malaria is a co-factorr for Endemic KS on the basis of its role in EBV-relatedd Burkitt's lymphoma (39). Classic KS may re-sultt from superinfection or circulation of a more virulent strainn of HHV8 in countries where HHV8 is endemic or mayy be due to age-dependent decline of cell mediated
im-inn Saimiri sciureus, ateline herpesviruses (HVA) in Ateles geoffroyi,, rhesus rhadinovirus (RRV) in macaques and retroperitoneall fibromatosis herpesvirus in both Macaca mulattaa (RFHVMm) and Macaca nemestrina (RFHVMn) (40-44).. Two distinct rhadinoviral sequences from African greenn monkeys have also been identified and these viruses aree termed Chlorocebus rhadinovirus (ChRV) 1 and 2 (45). Phylogeneticc analysis of the DNA polymerase gene se-quencess from these primates show that there may be two distinctt rhadinoviral lineages in Old World primates com-prisingg respectively HHV8/RFHV/ChRVl and RRV/ChRV22 and raises the possibility that there is a ninth humann herpesvirus (45). Of these animal rhadinoviruses, onlyy the New World representatives (HVS, ateline herpesvirus)) and RRV grow well in tissue culture and can thereforee be used in animal models.
munity,, genetic susceptibility of the affected population or ann unidentified environmental co-factor.
Factorss that are necessary for KS development can be de-terminedd in prospective cohort studies and pre-existing studiess on HIV-1 infection have facilitated the study of the naturall history of HHV8 infection and AIDS-KS. HHV8 antibodiess and declining CD4+ cell counts were shown to bee independent predictors for KS in our cohort of HIV-1 infectedd homosexual men (5). Antibody levels of both lytic-phasee capsid and latent-phase nuclear antigens are higherr in HIV-1 infected men compared to uninfected men.
Thesee levels rise with declining C D 4 + cell counts and peak att the time of KS however, it remains to be determined if thiss is due to continuing and increasing viral replication (8). Cohortt studies will play a significant role in elucidating the pathogenesiss of KS.
Intriguingly,, HHV8 seroconversion in the course of HIV-1 infectionn confers a significantly higher risk for KS than the conversee situation (5). This finding was confirmed by Ja-cobsonn et al. who attributed the shortened length of the KS-freee period to the immunocompromised state of the hostt (46). We found that the increased risk for KS due to the timingg of infections was independent of the CD4+ cell countt and speculated that HIV-1 infection facilitated the spreadd of HHV8 to endothelial cells or increased the titer of HHV88 (5). This timing phenomenon results in "short" and "long"" KS-free periods and may have fundamental implica-tions;; the bi-modal age distribution of herpesvirus-related tumors,, such as nasopharyngeal carcinoma, could be ex-plainedd by "short" and "long" tumor-free periods from a fixedd moment of infection (47).
Itt is not yet possible to describe the molecular events that resultt in Kaposi's sarcoma however the functions of HHV8-encodedd proteins provide valuable insights into KS pathogenesiss (15). The survival of HHV8 in the human host iss dependent on its ability to escape innate and adaptive im-munee responses; immunomodulatory proteins such as vIRF-11 regulate the cellular actions of interferon and K3
Continuedd epidemiological and clinical surveillance of KS is requiredd and this thesis highlights a pressing need to opti-misee serological and nucleic-acid based assays for the
accu-andd K5 inhibit the expression of MHC class I antigens. HHV88 also encodes the anti-apoptotic proteins, vBcI-2, vFLIP,, vIL-6 and LANA-1, which may limit the threat that programmedd cell death poses to viral infection and replica-tion.tion. HHV8 also encodes proteins that regulate the cell-cyclee such as v-cyclin and experimental data supports a rolee in cellular transformation for v-IRF-1, K12, immunoreceptorr signalling protein (ORFK1), vIL-6 (ORFK9),, and cytokine receptor vGPCR (ORF74). In ad-ditionn the vMIPs, vIL-6 and vGPCR are angiogenic (see In-troduction). .
HHV88 latently infects most KS spindle cells and only the anti-apoptoticc v-FLIP and LANA-1, cell cycle regulator)-, v-cyclin,, and transforming proteins kaposin are expressed (seee Introduction). A few spindle cells express lytic genes, suchh as vGPCR, which may contribute to pathogenesis throughh cellular transformation and/or the release of vas-cularr endothelial growth factor (VEGF) (48). We investi-gatedd the role of V E G F in AIDS-KS by measuring serum concentrationss of this growth factor but found no differ-encee between healthy individuals and those with AIDS-KS (49).. Systemic V E G F concentrations may not accurately re-flectt the concentration or activity of this growth factor in thee KS lesion. The role that HHV8-encoded proteins and inflammatoryy cytokines play in Kaposi's sarcoma and the synergisticc relationship between HHV8 and HIV-1 infec-tionss to produce AIDS-KS requires further investigation.
ratee detection of HHV8 infection. The availability of a cell culturee system and/or an animal model will extend the stud-iess that can be done on KS pathogenesis and also aid in the
evaluationn of therapeutic agents. HHV8 is likely to prove an instructivee tool for examining fundamental cellular path-waysways that are involved in tumorigenesis and angiogenesis and,, in addition, should shed further light on human innate andd adaptive immune responses. More fanciful ideas for HHV88 research involve modifying the genome to express
HIV-11 antigens as a vaccine against HIV-1 infection. HHV88 has opened and extended many research fields but wee should not forget that the main directions are to prevent, treatt and/or eradicate this disease.
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