Risk Of Kaposi's Sarcoma Research Articles

Kaposi's sarcoma, oncogenic viruses, and iron

Iron is required for many cellular processes, but it is also toxic in excess quantities. Therefore, iron homeostasis and utilization must be strictly maintained, and defects in iron absorption or transport result in iron depletion or accumulation. Most research has been directed to enteral and placental transfer of iron, but little is known about iron entry through the skin. We present evidence that exposure to wet clay soils in Africa is an important risk factor for Kaposi's sarcoma (KS) and speculate that iron may be responsible for soil toxicity contributing to the pathogenesis of KS. Evidence gathered from case control studies and related investigations in Uganda between 1995 and 1998 are summarized. A large case control study of KS in HIV-infected adults disclosed affluence and mobility that suggest enhanced sexual exposure to human herpesvirus-8, the putative aetiologic agent of KS. Another study in endemic KS (HIV-negative) also showed affluence and mobility as risk factors. In addition, barefoot exposure to wet soil was an important risk factor for men with endemic KS. Other studies point to diminish delayed hypersensitivity in the lower limbs of KS patients. Geographic similarities of KS to podoconiosis (non-filarial elephantiasis) in Africa implicate soil absorbtion through the skin in the pathogenesis of KS and podoconiosis. The hypothesis of soil exposure as a risk for endemic KS has been strengthened by recent investigation. Particulate soil exposure may cause localized microtrauma and inflammation, predisposing to KS on the extremities in HHV-8 infected men. A role for iron toxicity is yet to be determined.

Incidence and trends in Kaposi's sarcoma in the era of effective antiretroviral therapy.

To evaluate the impact of antiretroviral and antiherpesvirus therapies on the incidence of KS and assess trends in incidence of Kaposi's sarcoma (KS) in a large multicenter HIV/AIDS surveillance system between 1990 and 1998. Incidence was calculated per 100 person-years (py); the effects of therapies on risk for KS were calculated by using multivariate Poisson regression controlling for gender, race/ethnicity, age, HIV exposure mode, CD4+ cell count, and calendar year. Antiretroviral therapy was defined as monotherapy, dual therapy, or triple therapy (95% of triple therapy regimens contained a protease inhibitor). Acyclovir, ganciclovir, and foscarnet were the antiherpesvirus therapies evaluated. There were 37,303 HIV-infected people in the study contributing 70,238 py. Those prescribed triple antiretroviral therapy had a 50% reduction in the incidence of KS (95% confidence interval, 20%-70%) compared with those who were not prescribed antiretroviral therapy and there was a reduction in risk for KS among persons prescribed foscarnet (p =.05). Overall, KS incidence declined an estimated 8.8% per year (observed incidence 4. 1 per 100 py in 1990 to 0.7 per 100 py in 1998; p <.001). Incidence of KS is declining in this large U.S. population and may continue to decline as new, more effective antiretroviral agents are developed and used widely.

Incidence of Kaposi's sarcoma and HHV-8 seroprevalence among homosexual men with known dates of HIV seroconversion. Italian Seroconversion Study.

To evaluate temporal trends of Kaposi's sarcoma (KS) and of the KS-related human herpesvirus (HHV-8) among homosexual men who seroconverted for HIV between 1984 and 1997. The study participants were 387 homosexual men. Changes over a period of time were assessed by estimating KS incidence rates per 1000 person-years for the periods 1984-1989, 1990-1992, 1993-1995, and 1996-1997. The proportional incidence of KS as the AIDS-defining disease for the same periods was also calculated. To evaluate a cohort effect of calendar period, Kaplan-Meier curves were used to estimate the risk of KS by period of HIV seroconversion [i.e. before 1990 (median year of seroconversion) versus later]. Relative hazards for the four periods were estimated using competitive-risks models. We also estimated HHV-8 seroprevalence over the study period. Forty-eight participants developed KS. Between 1984 and 1995, the incidence rate of KS per 1000 person-years increased from 3.9 to 32.8, whereas the proportional incidence decreased from 33.3 to 24.3%. The risk of developing KS after HIV seroconversion did not change when comparing the seroconversion periods (i.e. before 1990 versus later). HHV-8 seroprevalence also remained stable. The rates of KS and the relative hazards dramatically decreased after 1995. Although KS incidence rates increased up to 1995, the proportional incidence decreased, due to the higher increase in rates of other AIDS-defining diseases. The finding that the risk of developing KS after HIV seroconversion remained stable over time is consistent with the stable trend of HHV-8 seroprevalence. The dramatic decrease in KS incidence rates after 1995 coincides with combined antiretroviral therapy.

Interaction of human immunodeficiency virus type 1 and human herpesvirus type 8 infections on the incidence of Kaposi's sarcoma.

To determine Kaposi's sarcoma (KS) risk related to timing of human immunodeficiency virus type 1 (HIV-1) and human herpesvirus type 8 (HHV-8) infections, stored longitudinal sera from 400 homosexual men with known dates of HIV-1 seroconversion (+/-4.5 months) were tested for HHV-8 antibody. Times from HHV-8 seroconversion to KS were compared for the 69 men who became infected with HHV-8 after acquiring HIV-1 to the 182 men who were HHV-8 seropositive before their HIV-1 infection. None developed KS before coinfection. HHV-8 seroconversion after HIV-1 infection increased the risk of KS (risk ratio, 2.55; 95% confidence interval, 1.06-6.10) compared with those infected with HHV-8 before HIV-1. The KS hazards in HHV-8-infected men increased by 60% (P<.001) for each year of HIV-1 infection. Faster CD4 cell loss and higher HIV-1 RNA levels significantly predicted KS. The quicker development of KS in men acquiring HHV-8 after HIV-1 and its association with CD4 slope argues that KS is more likely if HHV-8 infection occurs in an immunocompromised person.

Detection of antibodies to human herpesvirus 8 in Italian children: evidence for horizontal transmission.

Human herpesvirus 8 (HHV-8), also known as Kaposi's sarcoma associated herpesvirus (KSHV), has been shown to be the causative agent for Kaposi's sarcoma (KS) and to be more prevalent in populations or risk groups at increased risk for KS. HHV-8 infection is rare in children from the US and the UK, but has been reported in African children. In this study we examine HHV-8 infection in children from Italy, a country with an elevated prevalence of HHV-8 in adults and high socio-economic conditions. © 2000 Cancer Research Campaign

Is volcanic soil a cofactor for classic Kaposi's sarcoma?

Sir, Following the hypothesis formulated by Ziegler in 1993 [1] on the relationship between exposure to volcanic soil and occurrence of the African form of Kaposi's sarcoma (KS), our group evaluated, in 1996, such potential association in the Campania region, Southern Italy, among the population living in the flanks of Mount Vesuvius (an area characterised by active volcanism and by the presence of basaltic lava). In 1996, information on 70 cases of classic KS and on a hospital-based series of 280 controls was analysed, and a nearly twofold increase in KS risk turned out to be associated with birth or residence in areas with

Human herpesvirus 8: is it a tumor virus?

Human herpesvirus 8 (HHV-8), also termed Kaposi's sarcoma-associated herpesvirus, was identified in Kaposi's sarcoma (KS) biopsy specimens in 1994. The epidemiological data available to date indicate a strong association of HHV-8 with KS. It appears that HHV-8 is necessary for KS development. HHV-8 DNA is invariably found in all epidemiological forms of KS and primary effusion lymphomas. In contrast, HHV-8 DNA is rarely found in various tumor and nontumor tissues from patient groups not at risk of KS. Although current serology does not allow us to assess the HHV-8 prevalence in the general population, high titers of HHV-8 antibodies are almost exclusively found in KS risk groups. In addition, HHV-8 seroconversion has been shown to precede KS development. The mechanisms and genes involved in HHV-8 pathogenesis are less clear. HHV-8 belongs to a family of transforming viruses, and several candidate oncogenes have been identified by using rodent fibroblast transformation assays. However, expression of most of these genes could not be shown in latently infected tumor cells. As the HHV-8 genome encodes several cytokines and cytokine receptor homologues, HHV-8 may also promote KS pathogenesis through paraendocrine mechanisms.

Treatment Options for Cytomegalovirus Retinitis

THE NEW ENGLAND JOURNAL OF MEDICINE Oral Ganciclovir for Patients With Cytomegalovirus Retinitis Treated With a Ganciclovir Implant Daniel F. Martin, MD; Baruch D. Kuppermann, MD, PhD; Richard A. Wolitz, MD; Alan G. Palestine, MD; Hong Li, MS; Charles A. Robinson, MD; and the Roche Ganciclovir Study Group Background The intraocular ganciclovir implant is effective for local treatment of cytomegalovirus retinitis in patients with the acquired immunodeficiency syndrome (AIDS), but it does not treat or prevent other systemic manifestations of cytomegalovirus infection. Methods Three hundred seventy-seven patients with AIDS and unilateral cytomegalovirus retinitis were randomly assigned to 1 of 3 treatments: a ganciclovir implant plus oral ganciclovir (4.5 g daily), a ganciclovir implant plus oral placebo, or intravenous ganciclovir alone. The primary outcome measure was the development of new cytomegalovirus disease, either contralateral retinitis or biopsy-proved extraocular disease. Results The incidence of new cytomegalovirus disease at 6 months was 44.3% in the group assigned to the ganciclovir implant plus placebo, as compared with 24.3% in the group assigned to the ganciclovir implant plus oral ganciclovir ( P = .002) and 19.6% in the group assigned to intravenous ganciclovir alone ( P P = .02). However, in the subgroup of 103 patients who took protease inhibitors, the rates of new cytomegalovirus disease were low and of similar magnitude, regardless of treatment assignment. Progression of retinitis in the eye that initially received an implant was delayed by the addition of oral ganciclovir, as compared with placebo ( P = .03). Treatment with oral or intravenous ganciclovir reduced the risk of Kaposi sarcoma by 75% ( P = .008) and 93% ( P Conclusions In patients with AIDS and cytomegalovirus retinitis, oral ganciclovir in conjunction with a ganciclovir implant reduces the incidence of new cytomegalovirus disease and delays progression of the retinitis. Treatment with oral or intravenous ganciclovir also reduces the risk of Kaposi sarcoma. 1999;340:1063-1070.

Human herpesvirus 8 cellular immune responses in homosexual men.

Little is known about cellular immunity to human herpesvirus 8 (HHV-8), the virus associated with Kaposi's sarcoma (KS). T cell proliferative responses to purified HHV-8 were measured in homosexual men, a group with elevated HHV-8 seroprevalence and high risk of KS. None of 20 blood donor controls had T cell responses to HHV-8. Among human immunodeficiency virus (HIV)-negative homosexual men, 8 (42%) of 19 HHV-8 seropositive men responded as did 4 (16%) of 25 HHV-8 seronegative men. Among HIV-positive homosexual men, however, none of 21 HHV-8 seropositives had T cell responses to HHV-8, even though most responded to common recall antigens, and 10 had >/=400 CD4 cells/mm3. The results suggest that HHV-8 T cell proliferative responses are common in HIV-negative homosexual men and that HIV infection may be associated with diminished HHV-8 cellular immunity, possibly before there is substantial depletion of CD4 cells. If correct, this could explain why KS occurs relatively early in HIV infection/AIDS.

Evidence for concurrent epidemics of human herpesvirus 8 and human immunodeficiency virus type 1 in US homosexual men: rates, risk factors, and relationship to Kaposi's sarcoma.

We examined human herpesvirus 8 (HHV-8) seroprevalence and seroincidence among 245 homosexual men from New York City (NYC) and Washington, DC (DC) who have been followed since 1982. An immunofluorescence assay measured antibodies to a latent HHV-8 nuclear antigen. Seroprevalence was 20.4% in 1982; seroincidence was approximately 15%/year during 1982-1983 but fell sharply thereafter. NYC men had a higher seroprevalence (odds ratio, 3.43; P<.001) and seroincidence (rate ratio, 2.13; P=.01) than DC men. Risk of Kaposi's sarcoma (KS) was increased in seropositive men (adjusted relative hazard, 3.58; P=.02). Among men who were seropositive for both human immunodeficiency virus type 1 and HHV-8, the 10-year cumulative risk of KS was 39%; time from coinfection to KS diagnosis ranged from 15 to 154 months (median, 63.5 months). This study shows an epidemic of HHV-8 among US homosexual men in the early 1980s that was associated with a high risk of developing KS.

Human herpesvirus 8 seropositivity and risk of Kaposi's sarcoma and other acquired immunodeficiency syndrome-related diseases.

The incidence of Kaposi's sarcoma (KS) is increased severalfold in individuals infected with human immunodeficiency virus-1 (HIV). Human herpesvirus 8 (HHV8) has also been implicated in KS. We investigated several factors that may determine the onset of KS, particularly HHV8 infection in individuals after becoming seropositive for HIV. We studied 366 individuals belonging to different HIV-exposure categories (i.e., homosexual activity, intravenous drug use, and heterosexual contact) for whom a negative HIV serologic test and then a positive HIV serologic test were available within a 2-year period. HHV8 antibody testing was performed by use of an immunofluorescence assay on the first serum sample available after the first positive HIV test. Actuarial rates of progression of KS and of other acquired immunodeficiency syndrome (AIDS)-defining diseases were estimated by use of time-to-event statistical methods. All statistical tests were two-sided. Twenty-one of the 366 study participants developed AIDS-related KS, and 83 developed AIDS without KS. One hundred forty (38.3%) participants had detectable anti-HHV8 antibodies. The actuarial progression rate to KS among persons co-infected with HIV/HHV8 was nearly 30% by 10 years after HIV seroconversion. Increasing HHV8 antibody titers increased the risk of developing KS (for seronegative versus highest titer [1:125 serum dilution], adjusted relative hazard [RH] = 51.82; 95% confidence interval [CI] = 6.08-441.33) but not of other AIDS-defining diseases (adjusted RH = 1.14; 95% CI = 0.72-1.80). HHV8-seropositive homosexual men compared with HHV8-seropositive participants from other HIV-exposure categories showed an increased risk of KS that approached statistical significance (adjusted RH = 6.93; 95% CI = 0.88-54.84). Approximately one third of individuals co-infected with HIV/HHV8 developed KS within 10 years after HIV seroconversion. Progression to KS increased with time after HIV seroconversion. Higher antibody titers to HHV8 appear to be related to faster progression to KS but not to other AIDS-defining diseases.

The role of HHV-8 in Kaposi's sarcoma

The epidemiology of Kaposi's sarcoma (KS) amongst North American and Northern European patients with AIDS suggests that an infectious agent other than HIV is involved in its pathogenesis. Several lines of evidence indicate that human herpesvirus 8 (HHV–8), also termed Kaposi's sarcoma associated herpesvirus, is the sought after agent. DNA of HHV–8 is invariably found in all forms of KS where the virus is present in the KS spindle cell. In contrast, HHV–8 DNA is not regularly detected in most other malignancies. Antibodies against HHV–8 are more frequently found in groups at risk of KS, and HHV–8 seroconversion precedes KS development. Several HHV–8 genes have been identified that exhibit transforming potential in cell culture systems. In addition, the virus encodes and induces several cytokines and angiogenic factors. This is of particular interest as models of KS pathogenesis developed before the discovery of HHV-8 emphasized the importance of inflammatory cytokines. Although the expression pattern of viral genes in KS is not certain yet, it appears likely that the pathogenetic role of HHV–8 in KS may be rather complex and differs from other virus-induced malignancies.@9cBackground: Kaposi's sarcoma among AIDS patients—evidence for a sexually transmitted infection@21K aposi's sarcoma (ks) was—and outside of the HIV-infected population still is—a rare disease in Europe and the United States. In its `classical' form it afflicts elderly men of Mediterranean or Eastern European origin, where it may progress slowly over several years. The unusual occurrence of a more aggressive variant of KS in young homosexual men was one of the first signs of the beginning of AIDS epidemic.1Out of the 90,990 persons with AIDS that were reported to the Centers for Disease Control until March 1989, 13,616 or 15% suffered from Kaposi's sarcoma.2KS was thus at least 20,000 times more common in persons with AIDS than expected in the general population. The peculiar epidemiology of KS in different HIV-transmission groups clearly indicated that an environmental or transmis- sible agent other than HIV must be involved in KS pathogenesis.2Most notably, whereas approximately 20% of homo- and bisexual AIDS-patients developed KS, only 1% of age- and sex-matched men with hemophilia suffered from this uncommon tumor (Figure 1). This triggered a broad search for behavioral factors3and infectious agents associated with increased risk for KS. Several known human viruses were identified in KS tissues by PCR, including human cytomegalovirus,4human herpesvirus 6,5human papilloma viruses 16/186and BK virus.7However, none of these factors or viruses was found to be linked consistently to KS.8–10Representational difference analysis, a PCR-based method targeted at the identification of differences between two complex genomes, was published in 1993.11Application of this technique to Kaposi's sarcoma resulted in the identification of two short DNA fragments from a new herpesvirus by Yuan Chang, Patrick Moore and their colleagues.12This virus, now termed human herpesvirus 8 (HHV-8) or Kaposi's sarcoma-associated herpesvirus (KSHV), is the first known human member of the genus Rhadinovirus or γ2-herpesviruses.<fig 1>

Human herpes virus-8 and other risk factors for Kaposi's sarcoma in kidney transplant recipients. Groupe Cooperatif de Transplantation d' Ile de France (GCIF).

The exact reasons for the high incidence of Kaposi's sarcoma (KS) after kidney transplantation are still unknown. Immunosuppression is classically considered as the main risk factor, but the relative risk contributed by the patient's geographic origin and by human herpes virus (HHV)-8 infection still has to be determined. We carried out a retrospective and a prospective study among kidney transplant recipients (TP) to identify the risk factors for posttransplantation KS. Each of 30 KS patients was matched with two controls to investigate the association with geographic origin, immunosuppressive regimen, HHV-8 antibodies before and after transplantation, and other infections. Among TP with new onset of KS, we prospectively evaluated HHV-8 serology and viremia in response to decreased immunosuppression. African and Middle East origins, past infection with hepatitis B, hemoglobin level <12 g/dl, lymphocyte count <750/mm3 at the time of diagnosis and initial use of polyclonal antilymphocyte sera were risk factors for KS. After multivariate analysis, origin in Africa or Middle East and use of antilymphocyte sera for induction remained as independent risk factors. Sixty-eight percent (17/25) of TP with HHV-8 antibodies before or after transplantation developed KS compared with 3% (1/33) of seronegative TP (P<0.00001). HHV-8 DNA was detectable in seven of nine peripheral blood mononuclear cells (PBMC) and in six of six KS lesions at diagnosis; it became negative in PBMC in three of five patients in parallel with tumor regression. African and Middle East geographic origins, HHV-8 infection before and after kidney transplantation, and initial use of polyclonal antilymphocyte sera were independent risk factors for KS. The presence of HHV-8 antibodies before or after transplantation was highly predictive of the emergence of posttransplantation KS and conferred a 28-fold increased risk of KS (odds ratio=28.4; 95% confidence interval: 4.9-279). Detection of HHV-8 DNA within PBMC and KS lesions seems related to tumor burden and evolution.

Effect of antiviral drugs used to treat cytomegalovirus end-organ disease on subsequent course of previously diagnosed Kaposi's sarcoma in patients with AIDS.

To evaluate the association of ganciclovir (GCV) and foscarnet (PFA) therapy with the outcome of previously diagnosed Kaposi's sarcoma (KS) after initiating antiviral therapy for cytomegalovirus (CMV) end-organ disease. Retrospective study. KS progression was defined as a clinically obvious increase in size of baseline cutaneous or mucosal lesions, a new diagnosis of visceral KS, or initiation of a new systemic antineoplastic regimen or radiation therapy to treat KS. Multivariate analyses of risk of KS progression were calculated for prior duration of KS before initiating CMV treatment, treatment with PFA or GCV, number of weeks treated with PFA or GCV, absolute CD4 lymphocyte count at time of CMV-related disease diagnosis, diagnosis of KS prior to 1991, visceral KS, prior systemic chemotherapy, and prior radiation therapy. Among 66 patients who received > or = 14 days PFA (N=20) or only GCV (N=46), median time to progression of KS was 211 days (95% confidence interval [CI], 46-578) for patients who received PFA versus 22 days (95% CI, 15-41) for those who received only GCV (p < .001). In the stepwise multivariate analysis, only prior visceral KS (rate ratio [RR]=2.80; 95% CI, 1.07-7.35) and foscarnet therapy (RR = 0.24; 95% CI, 0.11-0.53) were significantly associated with risk of KS progression. PFA may be an effective therapy for AIDS-related KS; prospective trials are indicated.

Molecular Pathogenesis of AIDS-Associated Kaposi's Sarcoma: Growth and Apoptosis

Kaposi's sarcoma (KS) is a multicentral, multiorgan tumor, with individual lesions characterized by proliferating spindle-shaped cells, ongoing angiogenesis, infiltration of inflammatory mononuclear cells, extravasated erythrocytes, and edema. KS is common in patients seropositive for human immunodeficiency virus (HIV). This chapter outlines recent advances in the molecular pathogenesis of KS. The symptoms of KS include lesions that are widespread in skin and oral mucosa and involve lymph nodes and internal organs. The lesions vary from patches to plaques to nodules that occur at any site of the body. Examinations of cell surface antigens showed that most KS cells express endothelial cell markers but some cells express characteristic antigens of smooth muscle cells, macrophages, or dermal dendritic cells. Flow cytometry analysis of cellular DNA content showed that most KS lesions are normal diploid. KS has a variable clinical course, ranging from limited, asymptomatic cutaneous disease to a widespread, explosively progressive disease with visceral involvement and edema. Some clinical observations revealed that glucocorticoid use is a possible risk factor in KS. The chapter describes the molecular mechanisms of Kaposi's sarcoma cell growth. Immunosuppression induced by HIV may relate to the risk of KS. Apoptosis in Kaposi's sarcoma cells is prevented due to resistance of KS cells to anticancer drugs, expression of antiapoptotic molecules in KS cells, death receptor-mediated apoptosis, and human Herpesvirus-8-encoded antiapoptotic molecules. Existing chemotherapeutic treatments and radiation therapy for KS are only partially effective and often cause significant adverse effects; therefore, cure or long-term remission cannot be achieved with currently available treatments.

Sexual Transmission of HHV-8 and the Risk of Kaposi's Sarcoma

A recently discovered virus, human herpesvirus 8 (HHV-8), appears to be the cause of Kaposi's sarcoma. Epidemiologic information suggests the virus is

THE IMMUNOGENIC GLYCOPROTEIN GP35/37 OF HUMAN HERPESVIRUS 8 IS ENCODED BY OPEN READING FRAME K8.1

60 Background: Human herpesvirus 8 (HHV-8) is likely to be involved in the pathogenesis of Kaposi's sarcoma (KS) and body-cavity based lymphomas (BCBLs). The HHV-8 genome is primarily in a latent state in the BCBL derived cell lines like BCBL-1, but lytic replication can be induced by phorbol esters {Renne 1996}. Methods: A 35- to 37-kDa glycoprotein (gp35-37) is the polypeptide most frequently recognized by KS patient sera on Western blots with induced BCBL-1 cells. Its apparent molecular weight is reduced to 30-kDa by digestion with protein-N-glycosidase F (PNGase F). By searching the HHV-8 sequence for open reading frames (ORF) with the potential to encode this glycoprotein, a new reading frame was identified adjacent to ORF K8. This ORF, termed K8.1, was predicted to encode glycoprotein of 229 amino acids translated from a spliced mRNA. Recombinant K8.1 was regularly recognized by KS-patient sera in Western blots, and immunoaffinity purified antibodies to recombinant K8.1 reacted with gp35-37. Results: The immunogenic gp35-37 is encoded by HHV-8 reading frame K8.1. Recombinant K8.1 (rK8.1) expressed in E. coli is currently used for studies of HHV-8 epidemiology in children and adolescents, healty blood donors, and different groups at risk for KS. In this study antibodies against rK8.1 were detectable in 3.3% (4/118) of blood donors and 90.5% (19/21) of AIDS-KS patients. Antibodies against rK8.1 were not detectable in children below the age of 10 (0/400), whereas 3/100 adolescents aged 10 - 14 and 6/100 aged 15 - 19 were anti-rK8.1 positive. Conclusions: Although antibodies against only one protein are unlikely to reveal the complete epidemiology of HHV-8, the age distribution observed would be compatible with an agent which is transmitted in the context of sexual activity.

HHV-8 Infection in Homosexual Men From New York City (NYC) and Washington (DC): Frequency, Risk Factors, and Relationship to Kaposi's Sarcoma (KS)

57 Background: The observations that HHV-8 is etiologically linked to KS and that KS is much commoner in homosexual men than in other HIV-1 risk groups suggest that HHV-8 is a non-ubiquitous, sexually transmitted infection. To clarify the epidemiology of HHV-8 and its relationship to KS, we measured antibodies to HHV-8 longitudinally in homosexual men from two U.S. cities. Methods: In 1982, 245 homosexual men without evidence of AIDS were enrolled in a prospective study of AIDS incidence. We collected blood specimens and sexual behavior information anually; follow-up of HIV-1-uninfected men ceased in 1991. Antibodies to latent HHV-8 antigens were measured in all serum specimens of sufficient volume by an immunofluorescence assay. We used X2 tests for statistical testing and Kaplan-Meier methods to examine the risk of KS after infection with both HIV-1 and HHV-8. Results: The prevalence of HHV-8 at study entry was 40% among NYC subjects and 14.5% among DC subjects (RR, 2.8; p=0.001). HHV-8 prevalence was also associated with HIV-1 infection (RR 3.4; p=0.001) and number of sex partners (p=0.001, X2 for trend), but the higher prevalence in NYC men persisted after considering these variables. DC men with one or more sex partners from NYC were 3.1-fold more likely to be infected with HHV-8 at study entry (p=0.01) than were DC men with no NYC partners. The incidence of HHV-8 infection subsequent to study entry was similar regardless of residence (NYC, 0.04/person-year; DC, 0.03/person-year; p=0.5), but was strongly associated with the number of sex partners (p=0.001, X2 for trend). Among 60 men infected with both HHV-8 and HIV-1, 15 have developed KS at a median of 45 months (range, 12 to 154 months); the ten-year KS-free survival among these dually-infected men was 62%. Conclusions: 1) HHV-8 infection was common among these homosexual men in the early 1980's, especially those residing in or having sex partners from NYC. This geographic difference in HHV-8 prevalence is consistent with differences in the KS risk reported among homosexual men from these cities. 2) HHV-8 prevalence and incidence were strongly associated with the number of sex partners in this population. 3) Persons infected with both HHV-8 and HIV-1 are at high risk of developing KS; the time from dual infection with these viruses to the diagnosis of KS varies widely and may exceed a decade.

Human Herpesvirus 8 (HHV-8) in the Pathogenesis of Kaposi's Sarcoma and Other Diseases

The discovery of Kaposi's Sarcoma-associated herpesvirus/human herpesvirus-8 (KSHV/HHV-8) and subsequent studies of this virus have provided a body of evidence that support the concept that this is an etiologic agent for Kaposi's sarcoma (KS). Several studies have indicated that this virus may also be a causal agent for primary effusion lymphoma (PEL) and Castleman's disease as well. First generation serologic assays for HHV-8 have now been developed. The preponderance of data suggest that the incidence of HHV-8 infection is highest in populations at risk for KS: male homosexuals, immunosuppressed patients, and those who live in endemic regions. HHV-8 encodes for functional homologs of human proteins that may play a role in the development of disease. As we learn more about the steps by which this virus can lead to KS and/or other diseases, rational therapies and preventative strategies may be possible.

Geography of AIDS-associated Kaposi's sarcoma in Europe.

Classical Kaposi's sarcoma (KS) is about four times more common in southern Europeans than in northern Europeans. To describe the epidemiology of AIDS-associated KS (AIDS-KS) in Europe and to determine whether it occurs with increased frequency in southern Europe. Analysis of the 'European non-aggregate AIDS data set', as of September 1995. Countries with a cumulative total of > or = 50 KS cases as the presenting manifestation of AIDS were included. Homosexual men were excluded from south versus non-south comparisons because of possible confounding effects due to their route of HIV transmission. KS was the presenting manifestation of AIDS for 13.3% (16,367 out of 122,679) of men and 2% (491 out of 24,826) of women. In all countries, the risk for KS was higher in individuals who acquired HIV infection via sexual rather than parenteral transmission. Among AIDS patients, there is little difference by sex in the risk of KS in injecting drug users (IDU) or transfusion recipients. The percentage with KS increased with age among homosexual and bisexual men, from 10% in the age group 15-19 years to 23% in the age group 30-39 years. In all countries, the percentage with KS declined over time. The risk of KS was not significantly higher in southern Europe. The percentage with KS in southern Europe was slightly lower than in northern Europe (P > 0.1) in male IDU (1.8% versus 2.1%), and only slightly higher (P > 0.1) in female IDU (1.5% versus 1.1%), in male transfusion recipients (3.5% versus 3.0%), in female transfusion recipients (2.4% versus 2.3%), and in both heterosexual men (7.5% versus 6.2%) and women (2.0% versus 1.6%) excluding those originating from countries where heterosexual HIV transmission is frequent. The strong geographic predilection described for classical KS in southern Europe was not seen for AIDS-KS. If KS is caused by a viral infection in an immunodeficient host, our findings suggest the geographical variations in classical KS are not due to variation in prevalence of the causative virus but may be due to geographical variations in the prevalence of a form of mild immunodeficiency.