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Biomedical subjects

D Whitby

Publications and source records attributed to D Whitby.

At least 37 records · Page 2Linked to original sources
PubMed1998

Kaposi's sarcoma herpesvirus as a new paradigm for virus-induced oncogenesis.

Seroepidemiologic studies show that Kaposi's sarcoma herpesvirus (KSHV) is more prevalent in those populations at higher risk to develop Kaposi's sarcoma (KS). Anti-KSHV antibody titer is also higher in those who develop KS. KSHV is a sexually transmitted disease among homosexual men, but other routes of transmission appear to be more important in Africa and Mediterranean Europe. KSHV encodes numerous cellular homologues that might be involved in KS and lymphoma pathogenesis. The characterization of these homologues provides insight into the functions of their cellular counterparts. KSHV is also unique among human herpesviruses by encoding chemokine homologues. Unlike cellular MIP1 alpha and RANTES, KSHV-chemokines are promiscuous in their receptor usage and do induce angiogenesis. They may also play a role in preventing central nervous system diseases in HIV-positive individuals.

Herpesviridae Infections↗
PubMed1998

A broad range of chemokine receptors are used by primary isolates of human immunodeficiency virus type 2 as coreceptors with CD4.

Like human immunodeficiency virus type 1 (HIV-1) and simian immunodeficiency virus (SIV), HIV-2 requires a coreceptor in addition to CD4 for entry into cells. HIV and SIV coreceptor molecules belong to a family of seven-transmembrane-domain G-protein-coupled receptors. Here we show that primary HIV-2 isolates can use a broad range of coreceptor molecules, including CCR1, CCR2b, CCR3, CCR4, CCR5, and CXCR4. Despite broad coreceptor use, the chemokine ligand SDF-1 substantially blocked HIV-2 infectivity of peripheral blood mononuclear cells, indicating that its receptor, CXCR4, was the predominant coreceptor for infection of these cells. However, expression of CXCR4 together with CD4 on some cell types did not confer susceptibility to infection by all CXCR4-using virus isolates. These data therefore indicate that another factor(s) influences the ability of HIV-2 to replicate in human cell types that express the appropriate receptors for virus entry.

Adaptation, Biological↗
PubMed1998

Limited transmission of Kaposi's sarcoma-associated herpesvirus in cultured cells.

Kaposi's sarcoma-associated herpesvirus (KSHV) (also called human herpesvirus 8) is a novel gammaherpesvirus strongly implicated in the pathogenesis of Kaposi's sarcoma. Although virions can be produced in high yield from latently infected B-cell lines treated with phorbol esters, little is known about the infectivity of such virus, and efficient serial propagation of KSHV has been problematic. Here we report on the infectivity of KSHV produced from phorbol-induced BCBL-1 cells, employing an assay based on the detection of a spliced late mRNA by a sensitive reverse transcriptase PCR (RT-PCR) method. The results of this study confirm previous observations that 293 cells are susceptible to viral infection; however, infection with BCBL-1-derived virus is inefficient and the pattern of viral gene expression in infected cells may not fully reproduce that of authentic lytic infection. In keeping with this finding, serial propagation of BCBL-1-derived virus could not be demonstrated on 293 cells. Eleven of 38 other cell lines tested also supported KSHV infection, as judged by this RT-PCR assay, including cells of B-cell, endothelial, epithelial, and fibroblastic origin; however, in all cases, infection proceeded at or below the levels observed in 293 cells.

Gene Expression Regulation, Viral↗
PubMed1998

Association of Kaposi's sarcoma associated herpesvirus (KSHV) DNA in bronchoalveolar lavage fluid of HIV infected individuals with bronchoscopically diagnosed tracheobronchial Kaposi's sarcoma.

OBJECTIVES: To determine the frequency of detection of Kaposi's sarcoma associated herpesvirus (KSHV), also known as human herpesvirus (HHV) type 8, DNA in bronchoalveolar lavage (BAL) fluid from HIV infected individuals with and without KS and to compare this with the detection rate in peripheral blood. Also to identify whether KSHV was associated with specific cell types in lavage fluid. METHODS: Nested PCR was used to detect KSHV DNA in BAL fluid from 41 consecutive individuals with Kaposi's sarcoma (KS) and in 41 controls with similar CD4 lymphocyte counts. Semiquantification of viral DNA was by end point titration. A positive cell sorting selection procedure was used to isolate specific BAL fluid cell types. RESULTS: KSHV DNA was detected in BAL fluid from 24 of 29 (83%) individuals with a bronchoscopic diagnosis of tracheobronchial KS. None was detected in 12 individuals with only cutaneous KS, or in 41 matched controls without KS. In five, KSHV DNA was detected in the cell depleted and cellular fractions of BAL fluid and in 1/5 in the CD14 (macrophage) fractions. None was detected in the CD19 (B lymphocyte) or CD4/CD8 (T lymphocyte) fractions. CONCLUSIONS: There was a clear association between the diagnosis of tracheobronchial KS and detection of KSHV DNA in BAL fluid. The cell type supporting KSHV in the respiratory tract is not CD 19 positive and has yet to be conclusively identified.

Bronchial Neoplasms↗
PubMed1997

The evaluation of velopharyngeal function using flexible nasendoscopy.

Nasendoscopy is an essential tool in assessing the dynamic function and structure of the velopharyngeal sphincter during speech and swallowing. Flexible fibre-optic nasendoscopy has been used by the cleft palate team at Withington Hospital, Manchester since 1989. Seventy-six patients were referred between 1989 and 1994 for evaluation of velopharyngeal function during speech. Flexible nasendoscopic evaluation was attempted in 50 patients, and successfully carried out in 43 patients. The age range was four years to 77 years (mean 21 years). The patients were divided into two groups: Group 1 consisting of patients with cleft palate and Group 2 comprised of patients with non-overt cleft palate-related velopharyngeal dysfunction of various aetiologies; such as, submucous cleft, post-tonsillectomy, post-adenoidectomy, neurological and post-traumatic. Based on the findings on nasendoscopy, videofluoroscopy and clinical speech/voice analysis the following treatment options were recommended: 17 (40 per cent) for pharyngoplasty, five (11 per cent) for revision pharyngoplasty, 15 (35 per cent) for speech therapy, four for an obturator and one for tonsillectomy. Two previously undetected submucous clefts were diagnosed.

Adolescent↗
PubMed1997

Detection of human herpesvirus 8 DNA in semen from HIV-infected individuals but not healthy semen donors.

OBJECTIVE: To ascertain the prevalence of Kaposi's sarcoma-associated herpesvirus (KSHV), also known as human herpesvirus (HHV) type 8, and cytomegalovirus (CMV) DNA in semen was investigated. METHODS: Amplification by nested polymerase chain reaction was used to detect viral DNA sequences in samples from 24 HIV-infected gay men, 15 of them with Kaposi's sarcoma (KS), and 115 healthy donors. RESULTS: Six of the 24 HIV-infected patients had detectable HHV-8 DNA in their semen: three of the 15 patients with KS and three of the nine patients without KS. CMV DNA was detected in 20 semen samples from HIV-infected patients. None of the semen samples from healthy donors had detectable HHV-8 DNA and rates of CMV DNA detection were low (3%). CONCLUSIONS: The study demonstrates the presence of HHV-8 in semen from HIV-infected individuals with, or at risk, of developing KS and the potential for sexual transmission of the virus. We found no evidence of HHV-8 in the semen of HIV-uninfected donors.

Cytomegalovirus↗
PubMed1997

Etiology of AIDS-related Kaposi's sarcoma and lymphoma.

Kaposi's sarcoma (KS) and non-Hodgkin's lymphomas (NHL) are common consequences of HIV infection. These tumours appear to be precipitated by herpesviruses. Epstein-Barr virus (EBV) is implicated as a cause of up to 50% of systemic NHLs and up to 100% of central nervous system lymphomas in patients with AIDS. KS may be a consequence of the newly identified gamma-herpesvirus KSHV (KS-associated herpesvirus or HHV-8). This herpesvirus is found in all KS biopsies from different epidemiologic forms of this disease. KSHV is also implicated in the pathogenesis of a rare form of B cell lymphoma called body-cavity based lymphoma or primary effusion lymphoma (PEL).

AIDS-Related Opportunistic Infections↗
PubMed1996

Prevalence of Kaposi's sarcoma associated herpesvirus infection measured by antibodies to recombinant capsid protein and latent immunofluorescence antigen.

BACKGROUND: Kaposi's sarcoma-associated herpesvirus (KSHV), also known as human herpesvirus 8, may be the infectious cause of KS. Its prevalence in the general population, on the basis of detection of the virus genome, is controversial. To investigate the seroprevalence, we measured antibodies to a recombinant capsid-related (lytic cycle) KSHV antigen and a latent antigen complex. METHODS: We selected potentially immunoreactive capsid-related proteins of KSHV by expressing them as recombinant proteins and testing them in western blot assays. We used a truncated recombinant protein encoded by KSHV open reading frame 65 (orf 65) to develop a diagnostic enzyme-linked immunosorbent assay (ELISA) and tested sera from HIV-infected individuals with KS, HIV-uninfected patients with "classic" KS, other HIV risk groups, and blood donors. We also compared the antibody response to this capsid-related protein to the response to latent antigen(s) in an immunofluorescence assay. FINDINGS: 77/92 (84%) sera from KS patients reacted with the KSHV orf 65 protein and 84/103 (81.5%) reacted with KSHV latent antigen(s). The dominant immunogenic region of orf 65 is within the carboxyterminal 80 aminoacids, a region with little sequence similarity to the related Epstein-Barr virus, suggesting that orf 65 is a KSHV specific antigen. Only three sera from patients with haemophilia (1/84) or from intravenous drug users (2/63) had KSHV specific antibodies in the orf 65 assay whereas none of these sera reacted with latent antigen. Antibodies to KSHV were also infrequently found in UK and US blood donors by either assay (UK, 3/174 with orf 65 and 4/150 with latent antigen; US, 6/117 with orf 65 and 0/117 with latent antigen). They were more common among HIV-infected gay men without KS (5/16 by orf 65 ELISA, 10/33 by IFA), HIV-uninfected STD clinic attenders (14/166 by IFA), and Ugandan HIV-uninfected controls (6/17 by orf 65 ELISA, 9/17 by IFA). Antibody reactivity to the orf 65 protein (ELISA) and to latent antigen(s) (IFA) was concordant in 89% of 462 sera tested but reactive blood donor sera were discordant in both assays. Four AIDS-KS sera were unreactive in both assays. INTERPRETATION: The distribution of antibodies to both a capsid-related recombinant protein and latent antigen(s) of KSHV strongly supports the view that infection with this virus is largely confined to individuals with, or at increased risk for, KS. However, infection with KSHV does occur, rarely, in the general UK and US population and is more common in Uganda. Antibodies to latent antigen(s) or to orf 65 encoded capsid protein will not detect all cases of KSHV infection, and a combination of several antigens will probably be required for accurate screening and confirmatory assays.

Adult↗
PubMed1996

Kaposi's sarcoma-associated herpesvirus and Kaposi's sarcoma in Africa. Uganda Kaposi's Sarcoma Study Group.

BACKGROUND: Endemic Kaposi's sarcoma (KS) is a clinically and epidemiologically distinct human immunodeficiency virus negative form of KS occurring in Africa. Kaposi's sarcoma is now the most frequently reported cancer in some areas of Africa. OBJECTIVE: To determine if a KS-associated herpesvirus (KSHV) is present in both endemic HIV-seronegative and HIV-seropositive KS lesions from African patients. METHODS: Paraffin-embedded tissue specimens from Ugandan patients with KS and non-KS tumor control patients attending a university-based oncology clinic were examined in a blinded case-control study. Tissue DNA specimens were examined for detectable KSHV genome by nested polymerase chain reaction performed at two independent laboratories. RESULTS: We identified KSHV in 17 (85%) of 20 KS tissue specimens from HIV-seronegative patients and 22 (92%) of 24 KS tissue specimens from HIV-infected persons. Kaposi's sarcoma lesions from four HIV-infected persons and four HIV-seronegative persons were positive for KSHV. Unlike previous studies in North America and Europe, three (14%) of 22 non-KS cancer control patients' tissue specimens were also positive for KSHV that resulted in an overall odds ratio of 49.2 (95% confidence interval, 9.1 to 335) for detecting KSHV in KS lesions from patients in Uganda. CONCLUSION: As in North America and Europe, KSHV infection is strongly associated with both HIV-seropositive and HIV-seronegative KS in Africa. However, it is likely that infection with this virus is more highly prevalent in Uganda.

Case-Control Studies↗
PubMed1995

Detection of Kaposi sarcoma associated herpesvirus in peripheral blood of HIV-infected individuals and progression to Kaposi's sarcoma.

Kaposi sarcoma-associated herpesvirus (KSHV) is consistently found in biopsy samples from patients with AIDS-related and "classical" Kaposi's sarcoma (KS). Although highly suggestive of a causal role of KSHV in the pathogenesis of KS, this observation does not exclude the possibility that KSHV, like other herpesviruses, is widely distributed and is a mere "passenger" in these lesions. Here we report that KSHV was detectable in peripheral blood mononuclear cells of 24/46 (52%) of KS patients, but in none of 134 blood donors or 26 HIV-uninfected hospital controls. KSHV detection increased with immunosuppression, as shown by a correlation with a reduced number of CD4-positive T-cells. Moreover, KSHV detection in peripheral blood cells of HIV-infected individuals without KS predicted the subsequent appearance of KS lesions. 143 patients who did not have KS at the time of their first (or only) blood sample were followed up for a median of 30 months. Of the 11 who had been KSHV positive 6 developed KS compared with only 12 out of 132 who were KSHV negative. These findings are compatible with a causative role of KSHV in KS. KSHV was rarely detected in sputum and throat swabs of HIV-infected patients, providing a potential explanation for the apparently limited spread of this virus.

AIDS-Related Opportunistic Infections↗
PubMed1995

HIV-specific cytotoxic T-cells in HIV-exposed but uninfected Gambian women.

A crucial requirement in the rational design of a prophylactic vaccine against the human immunodeficiency virus (HIV) is to establish whether or not protective immunity can occur following natural infection. The immune response to HIV infection is characterized by very vigorous HIV-specific cytotoxic T-lymphocyte (CTL) activity. We have identified four HIV-1 and HIV-2 cross-reactive peptide epitopes, presented to CTL from HIV-infected Gambians by HLA-B35 (the most common Gambian class I HLA molecule). These peptides were used to elicit HIV-specific CTLs from three out of six repeatedly exposed but HIV-seronegative female prostitutes with HLA-B35. These women remain seronegative with no evidence of HIV infection by polymerase chain reaction or viral culture. Their CTL activity may represent protective immunity against HIV infection.

Acquired Immunodeficiency Syndrome↗
PubMed1992

A measles virus isolate from a child with Kawasaki disease: sequence comparison with contemporaneous isolates from 'classical' cases.

We examined the relationship between a measles virus isolate from a child with Kawasaki disease and two contemporaneous wild-type isolates from children with 'classical' measles and the Schwarz vaccine strain. Sequence analysis of 3118 bp from the nucleoprotein, matrix, fusion and haemagglutinin genes of each virus revealed that the isolate from the child with Kawasaki disease was not related to measles vaccine strains and did not contain any of the marked abnormalities previously found in subacute sclerosing panencephalitis isolates, but was more akin to wild-type isolates currently circulating in the U.K. A comparison of our sequences with those obtained from earlier wild-type U.K. isolates suggests significant evolution of measles virus in the U.K. over the last decade.

Amino Acid Sequence↗
PubMed1990

Biological and molecular variability of human immunodeficiency virus type 2 isolates from The Gambia.

Seven new human immunodeficiency virus type 2 (HIV-2) isolates (CBL-20 to CBL-26) from The Gambia were characterized. Their cytopathogenicity and growth in vitro correlated with the severity of clinical disease. CBL-22 was highly sensitive to neutralization by HIV-2 sera and was cross-neutralized by some HIV-1 sera. These findings, the differing sizes of envelope glycoproteins of individual isolates, and the sequence analysis of amplified regions of the viral DNAs show that these HIV-2 isolates from one geographical region in West Africa exhibit biological and genome variability comparable to that observed for HIV-1.

Adult↗
PubMed1989

The anti-conformation of 2',3'-dideoxy nucleosides may be essential for anti-HIV activity: evidence from the crystal structure of 2',3'-dideoxy formycin A.

The crystal structure of the nucleoside 2',3'-dideoxyformycin A has been determined. The structure shows a syn conformation about the glycosidic bond, stabilised by an intramolecular hydrogen bond between the 05' and N3 atoms. HIV activity was examined in a syncytium inhibition assay. In contrast to the marked decrease in viral titre observed with 2',3'-dideoxycytidine, the formycin analogue produced no effect. It may be concluded that the syn conformation for a dideoxy nucleoside is probably deleterious to HIV inhibition of HIV replication.

Antiviral Agents↗
PubMed1989

Soluble CD4 blocks the infectivity of diverse strains of HIV and SIV for T cells and monocytes but not for brain and muscle cells.

The CD4 antigen has been subverted as a receptor by the human and simian immunodeficiency viruses (HIV-1, HIV-2 and SIV). Several groups have reported that recombinant, soluble forms of the CD4 molecule (sCD4) block the infection of T lymphocytes by HIV-1, as CD4 binds the HIV envelope glycoprotein, gp120, with high affinity. We now report that sCD4 blocks diverse strains of HIV-1, HIV-2 and SIV, but is less effective for HIV-2. The blocking effect is apparent even after adsorption of virions to CD4 cells. Soluble CD4 prevents HIV infection of T-lymphocytic and myelomonocytic cell lines, but neither sCD4 nor anti-CD4 antibodies inhibit infection of glioma and rhabdomyosarcoma cell lines.

Antigens, Surface↗