Transfer Factor as an Option for Managing the COVID-19 Pandemic.

Covid-19 or SARS-CoV-2, a new RNA virus with high infectivity, and seemingly low mutability, which appeared in 2019 in the Wuhan province of China, has created a pandemic with dire consequences. At the end of May 2020, it became the first cause of mortality. As no treatment or vaccine may become available before many months, and because occurrence of similar pandemics is only a matter of time, arguments are presented here for testing the effect of transfer factor (TF), an immunomodulator devoid of toxicity, which has been extensively studied in the past for the treatment and prevention of viral infections.

KIR2DL4-HLAG interaction at human NK cell-oligodendrocyte interfaces regulates IFN-γ-mediated effects.

Interactions between germline-encoded natural killer (NK) cell receptors and their respective ligands on tumorigenic or virus-infected cells determine NK cell cytotoxic activity and/or cytokine secretion. NK cell cytokine responses can be augmented in and can potentially contribute to multiple sclerosis (MS), an inflammatory disease of the central nervous system focused upon the oligodendrocytes (OLs). To investigate mechanisms by which NK cells may contribute to MS pathogenesis, we developed an in vitro human model of OL-NK cell interaction. We found that activated, but not resting human NK cells form conjugates with, and mediate cytotoxicity against, human oligodendrocytes. NK cells, when in conjugate with OLs, rapidly synthesize and polarize IFN-γ toward the OLs. IFN-γ is capable of reducing myelin oligodendrocyte and myelin associated glycoproteins (MOG and MAG) content. This activity is independent of MHC class-I mediated inhibition via KIR2DL1, but dependent upon the interaction between NK cell-expressed KIR2DL4 and its oligodendrocyte-expressed ligand, HLA-G. NK cells from patients with MS express higher levels of IFN-γ following conjugation to OLs, more actively promote in vitro reduction of MOG and MAG and have higher frequencies of the KIR2DL4 positive population. These data collectively suggest a mechanism by which NK cells can promote pathogenic effects upon OLs.

Transfer factor: an overlooked potential for the prevention and treatment of infectious diseases.

Transfer factor (TF) is a low-molecular-weight lymphocyte extract capable of transferring antigen-specific cell-mediated immunity (CMI) to T lymphocytes. It has been used successfully as an adjuvant or primary therapy for viral, parasitic, fungal, and some bacterial infections, as well as immunodeficiencies, neoplasias, allergies and autoimmune diseases. From the list of infections that seem to respond noticeably to transfer factor, those due to viruses of the herpes family are particularly remarkable. Indeed, for these viruses it was shown that TF can prevent infection or relapse, acting as a CMI vaccine. Data also suggest its possible use for adjuvant treatment and probably prevention of two currently widespread infections: tuberculosis and AIDS. Furthermore, TF has an interesting potential: answering the challenge from unknown pathogenic agents, a black box effect permitting production of antigen-specific TF to a new pathogen, even before its identification. It thus seems that the preventative potential of transfer factor is as important as its therapeutic one, both discussed in this review.

Quantitative HHV-6B antigenemia test for the monitoring of transplant patients.

Human herpesvirus-6 (HHV-6) infection, mostly caused by variant B, is common after transplantation. Here, we report a new modified method using an HHV-6B glycoprotein IgG antibody, OHV-3, and attempt to quantify the HHV-6 antigenemia after liver transplantation. Twenty-four liver transplant recipients were frequently monitored by the HHV-6 antigenemia test, which detects the HHV-6B virion protein in peripheral blood mononuclear cells (PBMC). HHV-6B antigens were now retrospectively demonstrated using a glycoprotein OHV-3 IgG antibody in the immunoperoxidase staining from the same specimens and quantified as positive cells/10,000 PBMC. The results were confirmed and quantified by DNA hybridization in situ. Altogether, 206 blood specimens were analyzed. During the first six months, HHV-6 antigenemia was detected in 17/24 (71%) recipients by using the HHV-6B virion antibody. In total, 37% (77/206) of specimens were positive with the virion antibody and 39% (78/201) by the OHV-3 antibody. The peak number of OHV-3-positive cells in the PBMC varied from 5 to 750/10,000 (mean 140/10,000). The OHV-3 antibody was useful to quantify the HHV-6B antigenemia. The findings of the HHV-6B quantitative antigenemia using the OHV-3 antibody correlated well with the previous qualitative HHV-6 antigenemia assay, and can be used as an alternative quantitative method in the monitoring of HHV-6 in transplant patients.

A randomized clinical trial of valacyclovir in multiple sclerosis.

OBJECTIVE: The human Herpesvirus type-6 (HHV-6) has been implicated in multiple sclerosis (MS). Valacyclovir is an antiviral agent with an excellent safety profile. A two-year placebo-controlled, double-blind study was conducted to (1) ascertain if high-dose, prolonged treatment with valacyclovir would be safe and (2) observe if valacyclovir would delay the progression of MS clinically or by magnetic resonance imaging (MRI). DESIGN/METHODS: Fifty-eight patients were stratified as to severity and randomly assigned to receive valacyclovir (3000 mg/day) or placebo for a period of two years. Patients were followed clinically over the two-year period by means of the Expanded Disability Status Scale (EDSS), the Ambulation Index (AI) and brain MRI scans. Patients underwent routine lab studies every three months. Patients continued on the medication for two years unless they had a sustained progression or repeated exacerbations. RESULTS: No patient discontinued the study due to side effects or toxicity. In Relative Ranking of Progression, time to first attack, attack rate, and time to withdrawal there were trends (but not statistically significant) toward drug effect over placebo in the Severe clinical category. MRI evaluation showed no significant drug effect. CONCLUSIONS: Although not statistically significant, positive trends were detected for acyclovir by clinical measures, but not by MRI.

Multicenter comparison of serologic assays and estimation of human herpesvirus 8 seroprevalence among US blood donors.

BACKGROUND: As part of assessing the possibility of transfusion transmission of human herpesvirus 8 (HHV-8 or Kaposi's sarcoma-associated herpesvirus), HHV-8 seroprevalence was estimated among US blood donors, the performance of HHV-8 serologic tests was compared, and the presence of HHV-8 DNA was tested for in donated blood. STUDY DESIGN AND METHODS: Replicate panels of 1040 plasma specimens prepared from 1000 US blood donors (collected in 1994 and 1995) and 21 Kaposi's sarcoma patients were tested for antibodies to HHV-8 in six laboratories. HHV-8 PCR was performed on blood samples from 138 donors, including all 33 who tested seropositive in at least two laboratories and 22 who tested positive in at least one. RESULTS: The estimated HHV-8 seroprevalence among US blood donors was 3.5 percent (95% CI, 1.2%-9.8%) by a conditional dependence latent-class model, 3.0 percent (95% CI, 2.0%-4.6%) by a conditional independence latent-class model, and 3.3 percent (95% CI, 2.3%-4.6%) by use of a consensus-derived gold standard (specimens positive in two or more laboratories); the conditional dependence model best fit the data. In this model, laboratory specificities ranged from 96.6 to 100 percent. Sensitivities ranged widely, but with overlapping 95 percent CIs. HHV-8 DNA was detected in blood from none of 138 donors evaluated. CONCLUSIONS: Medical and behavioral screening does not eliminate HHV-8-seropositive persons from the US blood donor pool, but no viral DNA was found in donor blood. Further studies of much larger numbers of seropositive individuals will be required to more completely assess the rate of viremia and possibility of HHV-8 transfusion transmission. Current data do not indicate a need to screen US blood donors for HHV-8.

Dynamics of infection with human herpesvirus-6 in EBV-negative infectious mononucleosis: data acquisition for computer modeling.

Ten adult patients with active HHV-6 variant A infections and clinical infectious mononucleosis-like disease (IM) were studied over a period of 32 weeks after onset of disease for their viral DNA load, changes in peripheral blood T-lymphocytes and subpopulations and frequency of cell death in peripheral blood cells. The data were collected as the basis for an advanced computer simulation study for which available data in the literature were too varied. Since the exact time of primary infection of the patients was not known and thus no time relationship of viral effects at cellular level were determined, we supplemented such data from separate tissue culture studies using HHV-6 alpha infection of HSB2 cells. Patients with IM demonstrate an increase in-HHV-6 DNA copies from 0 to 8.2 log 10/5 microL blood within 4 weeks return to normal by 16 weeks. Total T-lymphocytes follow infection with a 20-fold increase above normal peaking at 8-10 weeks and then return to normal by 24-28 weeks. Coincidently, less mature lymphoid cells carrying markers for stem cells, thymic cortical and medullary cells increase 8-10-fold indicating an enhanced mobilization of such cells from premature cell compartments. Cell death in peripheral mononuclear cells peaked with 30% at 8 weeks after onset of clinical disease and normalized by 24 weeks. HHV-6 replication in cell culture as determined by antigen expression, electron microscopy and harvest of infectious virus indicated a complete cycle of virus infection and replication of at least 6 days. The presented data compare well with others from the literature and will serve for testing in a computer simulation model, which is the subject of a forthcoming paper.

Antibodies to human herpesvirus 8 latent and lytic antigens in blood donors and potential high-risk groups in Sweden: variable frequencies found in a multicenter serological study.

Human herpesvirus 8 (HHV-8) is a herpesvirus associated with Kaposi's sarcoma (KS). An immunofluorescence assay was used for detection of IgG, IgM, and IgA antibodies against lytic and latent HHV-8 antigens to analyse samples from KS patients (n = 8), healthy blood donors (n = 162), individuals with a high risk sexual behaviour (n = 114), and bone marrow transplant patients (with high risk for bloodborne infections) (n = 34) in Sweden. Of the KS patients, 88% had IgG antibodies to both lytic and latent antigens by immunofluorescence. In all other groups, antilatent antibodies were rare (0-2.6%). IgG antibodies to the lytic antigens were found, by immunofluorescence, in 20% of the blood donors, 31% of the high risk patients, and in 24 and 29% of the bone marrow transplant patients (pre- and post-transplant samples, respectively). For verification of the specificity of the anti-lytic antibodies, 170 of the samples were also tested blindly at different laboratories world-wide with five other assays shown previously to detect HHV-8 antibodies in most KS patients. By using two recombinant HHV-8 proteins (ORF65/vp17 and K8.1/gp 35-37) in ELISA, a whole-virion ELISA and two immunofluorescence assays confirmation of the reactivity against lytic viral antigens was sought. The comparison of the different methods suggested the K8.1 ELISA to be highly specific and also showed a good agreement between two of the immunofluorescence assays. However, generally there was a poor correlation for positive results, indicating the need of further methodological development.

Lack of serologic association of human herpesvirus-8 (KSHV) in patients with monoclonal gammopathy of undetermined significance with and without progression to multiple myeloma.

Because human herpesvirus-8 (HHV-8) DNA has been found in multiple myeloma (MM) patients by polymerase chain reaction, it was suggested that HHV-8 may play a role in the transformation of monoclonal gammopathy of undetermined significance (MGUS) to MM. Therefore, 362 MGUS sera with and without progression to MM were tested for IgG antibody to HHV-8. Only 7.8% of the MGUS sera contained HHV-8 antibody to lytic proteins, and IgG antibody to HHV-8 latent antigen was even lower than lytic antibody (2.9%). No differences were observed in the distribution of antibody to HHV-8 in sera from MGUS patients who progressed to MM. The seroprevalences of HHV-8 in MGUS (7.8%), MM (5.4%), and healthy donors (5.9%) were similar, thus arguing for the lack of epidemiologic evidence of HHV-8 participation in the pathogenesis of MM. MGUS patients were immune competent in response to Epstein-Barr virus (EBV) infection because 97% contained antibody to EBV virus capsid antigen.

Human herpesvirus type 8 in HIV-infected patients with interstitial pneumonitis.

OBJECTIVES: The new human herpesvirus type 8 (HHV-8) has been detected in all types of Kaposi's sarcomas, as well as in body-cavity lymphomas and Castleman's disease. Recently, HHV-8 has also been associated with encephalitis in HIV-positive and HIV-negative patients. Interstitial pneumonitis, combined with detection of HHV-8 in non HIV-infected patients, indicates a pathogenetic role of HHV-8 in unexplained lung diseases. We have studied two HIV-infected patients, with otherwise unexplained interstitial pneumonitis for the presence of HHV-8. METHODS: Lung biopsies of both patients were investigated for HHV-8 sequences. A nested PCR method was used for amplification of HHV-8 DNA fragments, and the nature of the amplification products was confirmed by Southern blot hybridization. In addition, we used an in situ hybridization technique and immunohistochemical staining for detection of HHV-8 infected cells. RESULTS: Amplification of HHV-8 DNA fragments was seen with template DNA from lung biopsies of both cases and the appropriate positive controls, but not with negative controls. In situ hybridization and immunohistochemical staining demonstrated HHV-8 infected lymphoid cells and alveolar macrophages in both patients as well. CONCLUSIONS: HHV-8 was found in HIV-infected patients with otherwise unexplained interstitial pneumonitis, but the pathogenic role of HHV-8 in patients with interstitial pneumonia remains unclear.

Frequent HHV-6 reactivation in multiple sclerosis (MS) and chronic fatigue syndrome (CFS) patients.

BACKGROUND: HHV-6 is a ubiquitous virus and its infection usually occurs in childhood and then becomes a latent infection. HHV-6 reactivation has been shown to play a role in the pathogenesis of AIDS and several other diseases. OBJECTIVES: To determine what role HHV-6 infection or reactivation plays in the pathogenesis of multiple sclerosis (MS) and chronic fatigue syndrome (CFS). RESULTS: Twenty-one MS and 35 CFS patients were studied and followed clinically. In these patients, we measured HHV-6 IgG and IgM antibody levels and also analyzed their peripheral blood mononuclear cells (PBMCs) for the presence of HHV-6, using a short term culture assay. In both MS and CFS patients, we found higher levels of HHV-6 IgM antibody and elevated levels of IgG antibody when compared to healthy controls. Seventy percent of the MS patients studied contained IgM antibodies for HHV-6 late antigens (capsid), while only 15% of the healthy donors (HD) and 20% of the patients with other neurological disorders (OND) had HHV-6 IgM antibodies. Higher frequency of IgM antibody was also detected in CFS patients (57.1%) compared to HD (16%). Moreover, 54% of CFS patients exhibited antibody to HHV-6 early protein (p41/38) compared to only 8.0% of the HD. Elevated IgG antibody titers were detected in both the MS and the CFS patients. PBMCs from MS, CFS and HD were analyzed in a short term culture assay in order to detect HHV-6 antigen expressing cells and to characterize the viral isolates obtained as either Variant A or B. Fifty-four percent of MS patients contained HHV-6 early and late antigen producing cells and 87% of HHV-6 isolates were Variant B. Isolates from CFS, patients were predominately Variant A (70%) and isolates from HD were predominately Variant B (67%). Moreover, one isolate from OND was also Variant B. Persistent HHV-6 infection was found in two CFS patients over a period of 2.5 years and HHV-6 specific cellular immune responses were detected in PBMCs from ten CFS patients. CONCLUSION: In both MS and CFS patients, we found increased levels of HHV-6 antibody and HHV-6 DNA. A decrease in cellular immune responses was also detected in CFS patients. These data suggest that HHV-6 reactivation plays a role in the pathogenesis of these disorders.

Characterization of the human herpesvirus 8 (Kaposi's sarcoma-associated herpesvirus) oncogene, kaposin (ORF K12).

BACKGROUND: Human herpesvirus 8 (HHV-8) has been implicated in the etiology of Kaposi's sarcoma (KS), a highly angiogenic tumor of complex histology, and two lymphoproliferative diseases, primary effusion lymphoma (PEL) and multicentric Castleman's disease (MCD). A number of HHV-8 encoded genes have been proposed to be involved in the pathogenesis of KS and PEL and a few have been shown to be oncogenic in heterologous systems (Reyes GR, LaFemina R, Hayward SD, Hayward GS. Morphological transformation by DNA fragments of human herpesviruses: evidence for two distinct transforming regions in herpes simplex virus types 1 and 2 and lack of correlation with biochemical transfer of the thymidine kinase gene. Cold Spring Harbor Symp Quant Biol 1980;44:629-641; Moore PS, Boshoff C, Weiss RA, Chang Y. Molecular mimicry of human cytokine and cytokine response pathway genes by KSHV. Science 1996;274:1739-1744; Cheng EH, Nicholas J, Bellows DS, Hayward GS, Guo HG, Reitz MS, Hardwick JM. A Bcl-2 homolog encoded by Kaposi sarcoma-associated virus, human herpesvirus 8, inhibits apoptosis but does not heterodimerize with Bax or Bak. Proc Natl Acad Sci USA 1997;94:690-694; Li M, Lee H, Yoon DW, Albrecht JC, Fleckenstein B, Neipel F, Jung JU. Kaposi's sarcoma-associated herpesvirus encodes a functional cyclin. J Virol 1997;71:1984-1991; Neipel F, Albrecht J-C, Fleckenstein B. Cell-homologous genes In the Kaposi's sarcoma-associated rhadinovirus human herpesvirus 8: determinants of its pathogenicity? J Virol 1997;71:4187-4192; Nicholas J, Ruvolo VR, Burns WH, Sandford G, Wan X, Ciufo D, Hendrickson SB, Guo HG, Hayward GS, Reitz MS. Kaposi's sarcoma-associated human herpesvirus-8 encodes homologues of macrophage inflammatory protein-1 and interleukin-6. Nat Med 1997;3:287-292; Nicholas J, Zong J, Alcendor DJ, Ciufu DM, Poole LJ, Sarisky RT, Chiuo C, Zhang X, Wan X, Guo H, Reitz MS, Hayward GS. Novel organizational features, captured cellular genes, and strain variability within the genome of KSHV/HHV-8. JNCI Monographs 1998;23:79-88; Muralidhar S, Pumfery AM, Hassani M, Sadaie MR, Azumi N, Kishishita M, Brady JN, Doniger J, Medveczky P, Rosenthal LJ. Identification of kaposin (ORF K12) as a human herpesvirus 8 (Kaposi's sarcoma associated herpesvirus) transforming gene. J Virol 1998;72:4980-4988). The kaposin gene (ORF K12) encoded by the abundant latency-associated HHV-8 transcript, T0.7, has been previously shown to induce tumorigenic transformation of Rat-3 cells (Muralidhar S, Pumfery AM, Hassani M, Sadaie MR, Azumi N, Kishishita M, Brady JN, Doniger J, Medveczky P, Rosenthal LJ. Identification of kaposin (ORF K12) as a human herpesvirus 8 (Kaposi's sarcoma associated herpesvirus) transforming gene. J Virol 1998;72:4980-4988). The current study is a further characterization of kaposin protein. OBJECTIVES: Characterization of kaposin expression in transformed and tumor-derived Rat-3 cells as well as PEL cell lines, BCBL-1, BC-3 and KS-1 and analysis of mechanism(s) of transformation. DESIGN: The presence of kaposin DNA in transformed cells was determined by fluorescent in situ hybridization (FISH). Expression of kaposin protein was analyzed by Western blot analysis and indirect immunofluorescence assay (IFA). (ABSTRACT TRUNCATED)

Human herpesvirus type 8 in salivary gland tumors.

BACKGROUND: The new human herpesvirus type 8 (HHV-8) has been detected in all types of Kaposi's sarcomas, as well as in body-cavity lymphomas and Castleman's disease, furthermore molecular biologic studies have identified a number of potential viral oncogenes. There is evidence for sexual transmission of HHV-8 in HIV-seropositive patients, but the route of infection among the HIV-seronegative population is uncertain. Findings of HHV-8 DNA in saliva in some cases are suggestive of nonsexual transmission associated with latent infection of the salivary gland (as it is known for EBV, CMV, HHV-6 and HHV-7). OBJECTIVE: As little is known about the etiological factors of salivary gland tumors and to give more insights into HHV-8 cell tropism normal salivary gland tissue (n=12) and different salivary glands neoplasm (n=58) were tested for HHV-8 sequences and antigens in HIV-seronegative patients. STUDY DESIGN: Biopsies of both normal salivary gland and tumors were investigated for HHV-8 sequences. A nested-PCR method was used for amplification of HHV-8 DNA fragments and the nature of the amplification products was confirmed by Southern blot hybridization. In addition, we used an in situ hybridization technique and immunohistochemical staining for detection of HHV-8 infected cells. The sera of the respective patients were tested for anti-HHV-8 antibodies using commercial IFA and an ELISA-assay. RESULTS: HHV-8 DNA sequences could be detected in one bilateral MALT-lymphoma of the parotid gland of a HHV-8 seropositive female patient suffering from Sjögren's syndrome (SS). The remaining parotid samples did neither show HHV-8 sequences nor HHV-8 antigens. Using above assays only one additional patient was seropositive for HHV-8. CONCLUSION: Our data suggest that HHV-8 does not usually infect the salivary gland in HIV-seronegative patients and does not seem to play a pathogenic role in vascular and epithelial salivary gland neoplasm. Pathogenic role of HHV-8 in Sjögren's syndrome associated MALT-lymphoma remains unclear and should be subject of further studies.

Seroprevalence of human herpesvirus-8 (HHV-8) in countries of Southeast Asia compared to the USA, the Caribbean and Africa.

Seroprevalence of HHV-8 has been studied in Malaysia, India, Sri Lanka, Thailand, Trinidad, Jamaica and the USA, in both healthy individuals and those infected with HIV. Seroprevalence was found to be low in these countries in both the healthy and the HIV-infected populations. This correlates with the fact that hardly any AIDS-related Kaposi's sarcoma has been reported in these countries. In contrast, the African countries of Ghana, Uganda and Zambia showed high seroprevalences in both healthy and HIV-infected populations. This suggests that human herpes virus-8 (HHV-8) may be either a recently introduced virus or one that has extremely low infectivity. Nasopharyngeal and oral carcinoma patients from Malaysia, Hong Kong and Sri Lanka who have very high EBV titres show that only 3/82 (3.7%) have antibody to HHV-8, demonstrating that there is little, if any, cross-reactivity between antibodies to these two gamma viruses.

Seroprevalence of human herpesvirus-8 (HHV-8) in countries of Southeast Asia compared to the USA, the Caribbean and Africa

Seroprevalence of HHV-8 has been studied in Malaysia, India, Sri Lanka, Thailand, Trinidad, Jamaica and the USA, in both healthy individuals and those infected with HIV. Seroprevalence was found to be low in these countries. In contrast, the African countries of Ghana, Uganda and Zambia showed high seroprevalences in both healthy and HIV-infected populations. This suggests that human herpes virus-8 (HHV-8) may be either a recently introduced virus or one that has extremely low infectivity. Nasopharyngeal and oral carcinoma patients from Malaysia, Hong Kong and Sri Lanka who have very high EBV titres to show that only 3/82 (3.7 percent) have antibody to HHV-8, demonstrating that there is little, if any, cross-relativity between antibodies to these two gamma viruses. (AU)

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.

Seroepidemiology of Kaposi's sarcoma-associated herpesvirus (KSHV).

Since the Kaposi's sarcoma-associated herpesvirus (KSHV also referred to as HHV-8, human herpesvirus-8) was discovered it has been shown that the virus is associated with all cases of Kaposi's sarcoma (KS) classical, endemic, or AIDS associated. In the numerous countries where the seroprevalence of this virus has been studied, data demonstrate that the virus is not ubiquitous in general healthy human populations as is the case with other human herpesviruses. Many seroprevalence studies to detect antibodies to HHV-8 have now been conducted using a variety of immunologic techniques. While these assays are not in total agreement and may overstate or understate the positivity of sera in the general population, they all show similar general antibody trends. For general populations the seroprevalence in sub-Saharan Africa is the highest, approximately 40% positive; in Mediterranean countries the seroprevalence is approximately 10%; whereas northern European, southeast Asian, and Caribbean countries have seroprevalence rates in the 2-4% range. In the United States, a 'mixing bowl' country the seroprevalence is in the range of 5-20%. In people with KS whether AIDS associated, classical, or endemic and other HHV-8 associated diseases such as multicentric Castleman's disease and certain body cavity lymphomas (BCL), also called primary effusion lymphoma (PEL) the seroprevalency rates are >90%. In populations with HIV-1 infection but no diagnosis of KS, the seroprevalency rates are elevated (20-50%) above those in the general population except in southeast Asia and the Caribbean where no AIDS associated KS has been reported. No correlation has been found between the presence of KSHV antibodies and other malignancies.