Incidence of acquired immunodeficiency syndrome (AIDS)-related Kaposi's sarcoma in the Aquitaine Cohort, France, 1988-1996. Groupe d'Epidemiologie Clinique du SIDA en Aquitaine.
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OBJECTIVE: To assess secular trends of the incidence of Kaposi's sarcoma (KS) between 1988 and 1996 in the Aquitaine Cohort of human immunodeficiency virus type 1 (HIV1)-infected subjects (southwestern France). METHODS: Adults of both sexes of all HIV-transmission categories were included. We distinguished between incident and prevalent KS and in case of multiple acquired immunodeficiency syndrome (AIDS) defining illnesses between initial or subsequent KS. Only incident KS were considered for annual incidence rate calculation. RESULTS: Overall, 21.2% (356/1678) of homosexuals and 1.9% (58/3030) of the other patients were diagnosed with KS over time. Although there was a sharp decrease in 1996 for initial KS, the annual incidence rate of KS was stable over time in the overall cohort as well as in homosexuals (4.3% per year on the average for KS as an initial AIDS-defining illness and 2.1% per year for subsequent KS in homosexuals). The median CD4+ cell count at the time of diagnosis of KS was 56 per mm3 (78 for initial KS, 14 for subsequent KS), with no significant variation over time. CONCLUSION: In the Aquitaine Cohort, the annual incidence of KS has remained stable between 1988 and 1995 with a recent decline in 1996, only for initial KS, while case management of HIV-infected subjects changed drastically. (+info)
Detection of Kaposi's sarcoma herpesvirus DNA sequences in multiple myeloma bone marrow stromal cells.
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Whether Kaposi's sarcoma herpesvirus (KSHV) is associated with multiple myeloma (MM) remains controversial. We assayed for KSHV DNA sequences in long-term bone marrow stromal cells (BMSCs) from 26 patients with MM and 4 normal donors. Polymerase chain reaction (PCR) using primers which amplify a KSHV gene sequence to yield a 233-bp fragment (KS330233 within open reading frame 26) was negative in all cases. Aliquots of these PCR products were used as templates in subsequent nested PCR, with primers that amplify a 186-bp product internal to KS330233. BMSCs from 24 of 26 (92%) patients with MM and 1 of 4 normal donors were KSHV PCR+. DNA sequence analyses showed interpatient specific mutations (2 to 3 bp). Both Southern blot and sequence analyses confirmed the specificity of PCR results. The presence of the KSHV gene sequences was further confirmed by amplifying T 1.1 (open reading frame [ORF] K7) and viral cyclin D (ORF 72), two other domains within the KSHV genome. Immunohistochemical studies of KSHV PCR+ MM BMSCs demonstrate expression of dendritic cell (DC) lineage markers (CD68, CD83, and fascin). Serological studies for the presence of KSHV lytic or latent antibodies were performed using sera from 53 MM patients, 12 normal donors, and 5 human immunodeficiency virus (HIV)/KSHV+ patients. No lytic or latent antibodies were present in sera from either MM patients or normal donors. Taken together, these findings show that KSHV DNA sequences are detectable in BMSCs from the majority of MM patients, but that serologic responses to KSHV are not present. Ongoing studies are defining whether the lack of antibody response is caused by the absence of ongoing infection, the presence of a novel viral strain associated with MM, or underlying immunodeficiency in these patients. (+info)
Bone marrow and peripheral blood dendritic cells from patients with multiple myeloma are phenotypically and functionally normal despite the detection of Kaposi's sarcoma herpesvirus gene sequences.
(3/1749)
Multiple myeloma (MM) cells express idiotypic proteins and other tumor-associated antigens which make them ideal targets for novel immunotherapeutic approaches. However, recent reports show the presence of Kaposi's sarcoma herpesvirus (KSHV) gene sequences in bone marrow dendritic cells (BMDCs) in MM, raising concerns regarding their antigen-presenting cell (APC) function. In the present study, we sought to identify the ideal source of DCs from MM patients for use in vaccination approaches. We compared the relative frequency, phenotype, and function of BMDCs or peripheral blood dendritic cells (PBDCs) from MM patients versus normal donors. DCs were derived by culture of mononuclear cells in the presence of granulocyte-macrophage colony-stimulating factor and interleukin-4. The yield as well as the pattern and intensity of Ag (HLA-DR, CD40, CD54, CD80, and CD86) expression were equivalent on DCs from BM or PB of MM patients versus normal donors. Comparison of PBDCs versus BMDCs showed higher surface expression of HLA-DR (P =.01), CD86 (P =. 0003), and CD14 (P =.04) on PBDCs. APC function, assessed using an allogeneic mixed lymphocyte reaction (MLR), demonstrated equivalent T-cell proliferation triggered by MM versus normal DCs. Moreover, no differences in APC function were noted in BMDCs compared with PBDCs. Polymerase chain reaction (PCR) analysis of genomic DNA from both MM patient and normal donor DCs for the 233-bp KSHV gene sequence (KS330233) was negative, but nested PCR to yield a final product of 186 bp internal to KS330233 was positive in 16 of 18 (88.8%) MM BMDCs, 3 of 8 (37.5%) normal BMDCs, 1 of 5 (20%) MM PBDCs, and 2 of 6 (33.3%) normal donor PBDCs. Sequencing of 4 MM patient PCR products showed 96% to 98% homology to the published KSHV gene sequence, with patient specific mutations ruling out PCR artifacts or contamination. In addition, KHSV-specific viral cyclin D (open reading frame [ORF] 72) was amplified in 2 of 5 MM BMDCs, with sequencing of the ORF 72 amplicon revealing 91% and 92% homology to the KSHV viral cyclin D sequence. These sequences again demonstrated patient specific mutations, ruling out contamination. Therefore, our studies show that PB appears to be the preferred source of DCs for use in vaccination strategies due to the ready accessibility and phenotypic profile of PBDCs, as well as the comparable APC function and lower detection rate of KSHV gene sequences compared with BMDCs. Whether active KSHV infection is present and important in the pathophysiology of MM remains unclear; however, our study shows that MMDCs remain functional despite the detection of KSHV gene sequences. (+info)
Human serum antibodies to a major defined epitope of human herpesvirus 8 small viral capsid antigen.
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The major antibody-reactive epitope of the small viral capsid antigen (sVCA) of human herpesvirus 8 (HHV-8) was defined by use of overlapping peptides. Strong IgG reactivity was found among approximately 50% of 44 human immunodeficiency virus-positive or -negative patients with Kaposi's sarcoma and 13 subjects who were seropositive by immunofluorescence assay (IFA) for the latent HHV-8 nuclear antigen. Only 1 of 106 subjects seronegative for both lytic and latent HHV-8 antigens and 10 of 81 subjects IFA-seropositive only for the lytic HHV-8 antigen had strong IgG reactivity to this epitope. Among 534 healthy Swedish women, only 1.3% were strongly seropositive. Comparison of the peptide-based and purified sVCA protein-based ELISAs found 55% sensitivity and 98% specificity. However, only 1 of 452 serum samples from healthy women was positive in both tests. In conclusion, the defined sVCA epitope was a specific, but not very sensitive, serologic marker of active HHV-8 infection. Such infection appears to be rare among Swedish women, even with sexual risk-taking behavior. (+info)
High seroprevalence of antibodies to human herpesvirus-8 in Egyptian children: evidence of nonsexual transmission.
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BACKGROUND: In western countries, human herpesvirus-8 (HHV-8) appears to be transmitted mainly by sexual contact. To evaluate the role of other transmission routes, especially in developing countries, we estimated the seroprevalence of HHV-8 in Egyptian children, who, if seropositive, would have acquired the virus through a nonsexual route. METHODS: Sera from 196 children (<1-12 years of age), 20 adolescents (13-20 years of age), and 30 young adults (21-25 years of age) attending a vaccination program in Alexandria, Egypt, were studied. Immunofluorescence assays were used to detect antibodies against HHV-8 lytic-phase antigens (anti-lytic) and latent-phase antigens (anti-latent). Antibodies against Epstein-Barr virus viral cap antigen, cytomegalovirus, and HHV-6 were detected by enzyme-linked immunosorbent assays. Seroprevalence of these herpesviruses was calculated after stratifying the subjects by age. RESULTS: Anti-lytic and anti-latent HHV-8 antibodies were detected in 44.7% and 8.5% of the study participants, respectively. The prevalence of anti-lytic antibodies tended to increase with age, exceeding 50% in children older than 6 years; once children reached the age of 10 years, the prevalence tended to stabilize. The seroprevalence of other herpesviruses tended to be higher than that of HHV-8, ranging from approximately 83% to more than 97% in the 9- to 12-year age group. One- to 3-year-old children had higher titers of antilytic HHV-8 antibodies than children in the other age groups. Anti-latent antibodies were more frequently detected in individuals with high anti-lytic antibody titers. CONCLUSIONS: HHV-8 antibodies are highly prevalent in Egyptian children, suggesting that, in developing countries, HHV-8 infection may be acquired early in life through routes other than sexual transmission. The lower seroprevalence of HHV-8 relative to that of the other herpesviruses suggests that HHV-8 is less transmissible than other common herpesviruses. (+info)
Activation in vivo of retroperitoneal fibromatosis-associated herpesvirus, a simian homologue of human herpesvirus-8.
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Retroperitoneal fibromatosis-associated herpesvirus of rhesus macaques (RFHVMm) is a gammaherpesvirus closely related to human herpesvirus-8 (HHV-8), which is thought to be a necessary cofactor for the development of Kaposi's sarcoma (KS) in humans. Here, RFHVMm infection of rhesus macaques exposed to the D-type retrovirus simian retrovirus-2 (SRV-2) is described. Development of SRV-2 viraemia, infection with simian immunodeficiency virus or administration of cyclosporin A could result in persistent RFHVMm viraemia. From this, it is concluded that productive retrovirus infection or otherwise-induced immune suppression has the ability to activate this herpesvirus in vivo. Elevated levels of circulating interleukin-6, a cytokine that plays a central role in KS, were found in RFHVMm-viraemic animals. In viraemic animals, RFHVMm was found in tissues that are common sites for the development of AIDS-associated KS, especially the oral cavity. Together, these data suggest a common biology between RFHVMm infection of macaques and HHV-8 infection and pathogenesis in humans. (+info)
Sequence and genomic analysis of a Rhesus macaque rhadinovirus with similarity to Kaposi's sarcoma-associated herpesvirus/human herpesvirus 8.
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We have sequenced the long unique region (LUR) and characterized the terminal repeats of the genome of a rhesus rhadinovirus (RRV), strain 17577. The LUR as sequenced is 131,364 bp in length, with a G+C content of 52.2% and a CpG ratio of 1.11. The genome codes for 79 open reading frames (ORFs), with 67 of these ORFs similar to genes found in both Kaposi's sarcoma-associated herpesvirus (KSHV) (formal name, human herpesvirus 8) and herpesvirus saimiri. Eight of the 12 unique genes show similarity to genes found in KSHV, including genes for viral interleukin-6, viral macrophage inflammatory protein, and a family of viral interferon regulatory factors (vIRFs). Genomic organization is essentially colinear with KSHV, the primary differences being the number of cytokine and IRF genes and the location of the gene for dihydrofolate reductase. Highly repetitive sequences are located in positions corresponding to repetitive sequences found in KSHV. Phylogenetic analysis of several ORFs supports the similarity between RRV and KSHV. Overall, the sequence, structural, and phylogenetic data combine to provide strong evidence that RRV 17577 is the rhesus macaque homolog of KSHV. (+info)
Human herpesvirus 8 seroprevalence and evaluation of nonsexual transmission routes by detection of DNA in clinical specimens from human immunodeficiency virus-seronegative patients from central and southern Italy, with and without Kaposi's sarcoma.
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In order to investigate the seroprevalence of human herpesvirus 8 (HHV-8) infection in central and southern Italy, sera from human immunodeficiency virus (HIV)-seronegative subjects, with and without Kaposi's sarcoma (KS), were analyzed by immunofluorescence assay, using BC-3, a cell line latently infected with HHV-8. High titers of antibody against HHV-8 lytic and latent antigens were detected in all 50 KS patients studied, while in 50 HIV-seronegative subjects without KS, 32 (64%) were found positive for HHV-8 antibodies. Titers in the sera of these patients were lower than those for KS patients. This data suggests that HHV-8 infection is not restricted to KS patients and that the prevalence of HHV-8 infection in the general population may be correlated with differing rates of prevalence of KS in different parts of the world. In view of these findings, possible nonsexual transmission routes were evaluated. Nested PCR was used to test for the presence of HHV-8 DNA in saliva, urine, and tonsillar swabs from KS and non-KS patients. In KS patients, 14 out of 32 tonsillar swabs (43.7%), 11 out of 24 saliva samples (45.8%), and just 2 out of 24 urine samples (8.3%) tested positive for HHV-8 DNA. In the control group, on the contrary, none of the 20 saliva and 20 urine specimens was positive for HHV-8 DNA; only 1 out of 22 tonsillar swabs gave a positive result. This data supports the hypothesis that HHV-8 infects the general population in a latent form. The reactivation of viral infection may result in salivary shedding of HHV-8, contributing to viral spread by nonsexual transmission routes. (+info)