The chronic Epstein-Barr virus syndrome is a poorly defined symptom complex characterized primarily by chronic or recurrent debilitating fatigue and various combinations of other symptoms, including sore throat, lymph node pain and tenderness, headache, myalgia, and arthralgias. Although the syndrome has received recent attention, and has been diagnosed in many patients, the chronic Epstein-Barr virus syndrome has not been defined consistently. Despite the name of the syndrome, both the diagnostic value of Epstein-Barr virus serologic tests and the proposed causal relationship between Epstein-Barr virus infection and patients who have been diagnosed with the chronic Epstein-Barr virus syndrome remain doubtful. We propose a new name for the chronic Epstein-Barr virus syndrome--the chronic fatigue syndrome--that more accurately describes this symptom complex as a syndrome of unknown cause characterized primarily by chronic fatigue. We also present a working definition for the chronic fatigue syndrome designed to improve the comparability and reproducibility of clinical research and epidemiologic studies, and to provide a rational basis for evaluating patients who have chronic fatigue of undetermined cause.

Previous research has suggested that human herpesvirus-6 (HHV-6) may integrate into host cell chromosomes and be vertically transmitted in the germ line, but the evidence-primarily fluorescence in situ hybridization (FISH)-is indirect. We sought, first, to definitively test these two hypotheses. Peripheral blood mononuclear cells (PBMCs) were isolated from families in which several members, including at least one parent and child, had unusually high copy numbers of HHV-6 DNA per milliliter of blood. FISH confirmed that HHV-6 DNA colocalized with telomeric regions of one allele on chromosomes 17p13.3, 18q23, and 22q13.3, and that the integration site was identical among members of the same family. Integration of the HHV-6 genome into TTAGGG telomere repeats was confirmed by additional methods and sequencing of the integration site. Partial sequencing of the viral genome identified the same integrated HHV-6A strain within members of families, confirming vertical transmission of the viral genome. We next asked whether HHV-6A infection of naïve cell lines could lead to integration. Following infection of naïve Jjhan and HEK-293 cell lines by HHV-6, the virus integrated into telomeres. Reactivation of integrated HHV-6A virus from individuals' PBMCs as well as cell lines was successfully accomplished by compounds known to induce latent herpesvirus replication. Finally, no circular episomal forms were detected even by PCR. Taken together, the data suggest that HHV-6 is unique among human herpesviruses: it specifically and efficiently integrates into telomeres of chromosomes during latency rather than forming episomes, and the integrated viral genome is capable of producing virions.

Chronic fatigue syndrome (CFS) is a serious systemic illness of unknown cause. A recent study identified DNA from a xenotropic murine leukemia virus-related virus (XMRV) in peripheral blood mononuclear cells (PBMCs) from 68 of 101 patients (67%) by nested PCR, as compared with 8 of 218 (3.7%) healthy controls. However, four subsequent reports failed to detect any murine leukemia virus (MLV)-related virus gene sequences in blood of CFS patients. We examined 41 PBMC-derived DNA samples from 37 patients meeting accepted diagnostic criteria for CFS and found MLV-like virus gag gene sequences in 32 of 37 (86.5%) compared with only 3 of 44 (6.8%) healthy volunteer blood donors. No evidence of mouse DNA contamination was detected in the PCR assay system or the clinical samples. Seven of 8 gag -positive patients tested again positive in a sample obtained nearly 15 y later. In contrast to the reported findings of near-genetic identity of all XMRVs, we identified a genetically diverse group of MLV-related viruses. The gag and env sequences from CFS patients were more closely related to those of polytropic mouse endogenous retroviruses than to those of XMRVs and were even less closely related to those of ecotropic MLVs. Further studies are needed to determine whether the same strong association with MLV-related viruses is found in other groups of patients with CFS, whether these viruses play a causative role in the development of CFS, and whether they represent a threat to the blood supply.

Cytokine alterations are more strongly correlated with illness duration than with measures of illness severity.

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A sensitive and specific polymerase chain reaction method for the detection of human herpesvirus 6 (HHV-6) DNA in serum or plasma has been developed. In total, 157 human serum or plasma samples were studied. HHV-6 DNA was detected in 6 (85.7%) of 7 children with exanthem subitum, 3 (23.1%) of 13 bone marrow transplant (BMT) recipients, 4 (22.2%) of 18 human immunodeficiency virus (HIV)-infected patients, 1 (2.6%) of 39 patients with chronic fatigue syndrome, and none of 37 healthy adults. In the HHV-6-positive BMT recipients, HHV-6 plasma DNA was transiently detected during episodes of fever and respiratory infection. In children with exanthem subitum and in 1 HIV-infected patient, the HHV-6 strains were characterized as variant B, whereas variant A was detected in all other patients. Detection of viral DNA in serum or plasma is a marker of active infection that can be used to investigate the role of HHV-6 in human disease.

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An independent strain (JI) of human herpesvirus 7 (HV-7) was isolated from a patient with chronic fatigue syndrome (CFS). No s cant association could be established by seroepidemiology between HHV-7 and CFS. HHV-7 is a T-lymphotropic virus, infecting CD4+ and CD8+ primary lymphocytes. HHV-7 can also infect SUP-T1, an immature T-cell line, with variable success. Southern blot analysis with DNA probes scanning 58.8% of the human herpesvirus 6 (HHV-6) genome and hybridizing to all HHV-6 strains tested so far revealed homology to HHV-7 with only 37.4% of the total probe length. HHV-7 contains the GGGTTA repetitive sequence, as do HHV-6 and Marek's disease chicken herpesvirus. DNA sequencing of a 186-base-pair fragment of HHV-7(JI) revealed an identity with HHV-6 and human cytomegalovirus of 57.5% and 36%, respectively. Oligonudeotide primers derived from this sequence (HV7/HV8, HV10/HV11) amplified HHV-7 DNA only and did not amplfy DNA from other human herpesviruses, incuding 12 different HHV-6 strains. Southern blot analysis with the p43L3 probe containing the 186-base-pair HHV-7 DNA fragment hybridized to HHV-7 DNA only. The molecular divergence between human cytomegalovirus, on the one hand, and HHV-6 and HHV-7, on the other, is greater than between HHV-6 and HHV-7, which, in turn, is greater than the difference between HHV-6 strains. This study supports the classification ofHHV-7 as an additional member of the human f3-herpesviruses.An additional lymphotropic herpesvirus, human herpesvirus 6 (HHV-6), was reported a few years ago by several laboratories (1-4). HHV-6 productively infects T lymphocytes in vitro (5) and in vivo (6). Recently, another T-lymphotropic herpesvirus, human herpesvirus 7 (HHV-7), was described by Frenkel et al. (7). Independently, we have isolated HHV-7 (strain JI) from peripheral blood mononuclear cells (PBMC) of a patient with chronic fatigue syndrome (CFS) (8). We describe here the serological, immunological, and molecular characteristics of HHV-7(JI). We also show that HHV-7 has a tropism for primary human T lymphocytes and for the SUP-T1 T-cell line. A sequence was obtained of HHV-7 DNA, which shows a homology with HHV-6 and with human cytomegalovirus (HCMV).tt This HHV-7 sequence enabled us to establish molecular reagents for identification of the virus.#