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A McKnight

Publications and source records attributed to A McKnight.

At least 19 recordsLinked to original sources
PubMed1999

HIV.

Explore the source record for details and available documents.

Acquired Immunodeficiency Syndrome↗
PubMed1999

Primary human immunodeficiency virus type 2 (HIV-2) isolates infect CD4-negative cells via CCR5 and CXCR4: comparison with HIV-1 and simian immunodeficiency virus and relevance to cell tropism in vivo.

Cell surface receptors exploited by human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) for infection are major determinants of tropism. HIV-1 usually requires two receptors to infect cells. Gp120 on HIV-1 virions binds CD4 on the cell surface, triggering conformational rearrangements that create or expose a binding site for a seven-transmembrane (7TM) coreceptor. Although HIV-2 and SIV strains also use CD4, several laboratory-adapted HIV-2 strains infect cells without CD4, via an interaction with the coreceptor CXCR4. Moreover, the envelope glycoproteins of SIV of macaques (SIV(MAC)) can bind to and initiate infection of CD4(-) cells via CCR5. Here, we show that most primary HIV-2 isolates can infect either CCR5(+) or CXCR4(+) cells without CD4. The efficiency of CD4-independent infection by HIV-2 was comparable to that of SIV, but markedly higher than that of HIV-1. CD4-independent HIV-2 strains that could use both CCR5 and CXCR4 to infect CD4(+) cells were only able to use one of these receptors in the absence of CD4. Our observations therefore indicate (i) that HIV-2 and SIV envelope glycoproteins form a distinct conformation that enables contact with a 7TM receptor without CD4, and (ii) the use of CD4 enables a wider range of 7TM receptors to be exploited for infection and may assist adaptation or switching to new coreceptors in vivo. Primary CD4(-) fetal astrocyte cultures expressed CXCR4 and supported replication by the T-cell-line-adapted ROD/B strain. Productive infection by primary X4 strains was only triggered upon treatment of virus with soluble CD4. Thus, many primary HIV-2 strains infect CCR5(+) or CXCR4(+) cell lines without CD4 in vitro. CD4(-) cells that express these coreceptors in vivo, however, may still resist HIV-2 entry due to insufficient coreceptor concentration on the cell surface to trigger fusion or their expression in a conformation nonfunctional as a coreceptor. Our study, however, emphasizes that primary HIV-2 strains carry the potential to infect CD4(-) cells expressing CCR5 or CXCR4 in vivo.

Animals↗
PubMed1998

CXCR4 as a functional coreceptor for human immunodeficiency virus type 1 infection of primary macrophages.

The coreceptors used by primary syncytium-inducing (SI) human immunodeficiency virus type 1 isolates for infection of primary macrophages were investigated. SI strains using only CXCR4 replicated equally well in macrophages with or without CCR5 and were inhibited by several different ligands for CXCR4 including SDF-1 and bicyclam derivative AMD3100. SI strains that used a broad range of coreceptors including CCR3, CCR5, CCR8, CXCR4, and BONZO infected CCR5-deficient macrophages about 10-fold less efficiently than CCR5(+) macrophages. Moreover, AMD3100 blocked infection of CCR5-negative macrophages by these strains. Our results therefore demonstrate that CXCR4, as well as CCR5, is used for infection of primary macrophages but provide no evidence for the use of alternative coreceptors.

HIV-1↗
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↗
PubMed1997

Role of the amino-terminal extracellular domain of CXCR-4 in human immunodeficiency virus type 1 entry.

We have studied the role of the N-terminal extracellular domain of the human immunodeficiency virus type 1 (HIV-1) coreceptor, CXCR-4, in the entry and fusion of syncytium-inducing strains of HIV-1. Progressive deletions were introduced in the N-terminal extracellular domain of CXCR-4 and the effect on infection by different isolates was tested. Infection of cells expressing the different CXCR-4 deletion mutants by HIV-1 LAI and 89.6 was reduced only about twofold. In contrast, the HIV-1 GUN-1 and RF isolates were substantially more impaired in their ability to mediate cell-free infection and cell-cell fusion. Since LAI and RF are T-cell line-tropic viruses while 89.6 and GUN-1 are dual tropic, no clear correlation between tropism and requirements for CXCR-4 N-terminal sequences emerged. We also introduced point mutations at the two N-linked glycosylation sites. The isolates tested (LAI, RF, GUN-1, and 89.6) were not affected by the removal of predicted N-linked glycosylation sites in CXCR-4. We conclude that distinct virus strains interact differently with the CXCR-4 coreceptor and that the N-terminal extracellular domain is not the sole functional domain important for HIV-1 entry.

Amino Acid Sequence↗
PubMed1997

CD4-independent infection by HIV-2 (ROD/B): use of the 7-transmembrane receptors CXCR-4, CCR-3, and V28 for entry.

We have assayed a variety of 7tm chemokine receptors (CCR-2b, CCR-3, CCR-4, CCR-5, CXCR-1, CXCR-4) and two orphan 7tm receptors (V28 and EBI.1) for their ability to allow infection of CD4-negative feline kidney CCC cells by the HIV-2 strains ROD/A and ROD/B. We found that ROD/B was able to use CXCR-4 transiently expressed in CCC cells, and infection by ROD/A was enhanced 15-fold in the presence of sCD4. Feline CCC cells also became permissive to ROD/B and ROD/A entry when transiently transfected with the chemokine receptor CCR-3 or the orphan 7tm receptor V2B, when cultured in the presence of sCD4. Entry of ROD/A into CCC cells expressing CCR-3 could be blocked by 800 ng/ml eotaxin, the natural ligand for CCR-3.

Animals↗
PubMed1997

Inhibition of human immunodeficiency virus fusion by a monoclonal antibody to a coreceptor (CXCR4) is both cell type and virus strain dependent.

CXCR4 (also termed fusin, LESTR, or HUMSTR) is a member of the G-protein-coupled chemokine receptor family with seven membrane-spanning domains. CXCR4 acts as a coreceptor for syncytium-inducing human immunodeficiency virus type 1 (HIV-1) strains, conferring entry into CD4+ cells. We show here that a novel mouse monoclonal antibody (12G5) that recognizes CXCR4 blocked cell-to-cell fusion and cell free-virus infection of CXCR4+ CD4+ RD rhabdomyosarcoma cells by seven HIV-1 and HIV-2 strains that had various cell tropisms for different CD4+ human cell types. Yet the majority of the members of the same virus panel resisted 12G5 inhibition on T-cell lines. When inhibition was observed on these cell types, it was both cell type and virus strain dependent. In at least one situation, 12G5 failed to block LAI infection of cells expressing CXCR4 as the only available coreceptor. Our observations suggest that CXCR4 could be processed or presented differently depending on the cell type, allowing some strains to evade 12G5 inhibition. Alternatively, since several of the viruses could infect certain CXCR4- CD4+ cell lines, it is conceivable that alternative coreceptors are active, enabling individual HIV strains to choose between compatible coreceptors during entry into cells. Moreover, the strain dependency of 12G5 inhibition implies that the interaction of different HIVs with CXCR4 varies.

Animals↗
PubMed1996

CD4-independent infection by HIV-2 is mediated by fusin/CXCR4.

Several members of the chemokine receptor family have been shown to function in association with CD4 to permit HIV-1 entry and infection. However, the mechanism by which these molecules serve as CD4-associated cofactors is unclear. In the present report, we show that one member of this family, termed Fusin/ CXCR4, is able to function as an alternative receptor for some isolates of HIV-2 in the absence of CD4. This conclusion is supported by the finding that (1) CD4-independent infection by these viruses is inhibited by an anti-Fusin monoclonal antibody, (2) Fusin expression renders human and nonhuman CD4-negative cell lines sensitive to HIV-2-induced syncytium induction and/or infection, and (3) Fusin is selectively down-regulated from the cell surface following HIV-2 infection. The finding that one chemokine receptor can function as a primary viral receptor strongly suggests that the HIV envelope glycoprotein contains a binding site for these proteins and that differences in the affinity and/or the availability of this site can extend the host range of these viruses to include a number of CD4-negative cell types.

Animals↗
PubMed1996

Location, exposure, and conservation of neutralizing and nonneutralizing epitopes on human immunodeficiency virus type 2 SU glycoprotein.

Eleven rat monoclonal antibodies (MAbs) that recognize the SU glycoprotein of human immunodeficiency virus type 2 (HIV-2) ROD were produced and characterized. Binding sites for eight of these MAbs were mapped to epitopes within the Cl, V1/V2, C2, and V3 envelope regions. The three other MAbs defined at least two conformation-dependent, strain-specific epitopes outside Vl/V2, V3, and the CD4-binding site. The MAbs were used to probe the tertiary structure of oligomeric envelope glycoprotein expressed on the surfaces of infected cells. Epitopes at the apices of V2 and V3 were exposed on the native molecule, whereas other epitopes on V1/V2, Cl, and C2 were hidden. The MAbs defined three neutralization targets on exposed domains: two linear epitopes in the V2 and the V3 loops and one conformational epitope outside V1, V2, and V3.

Amino Acid Sequence↗
PubMed1996

A comparison of three measures of perceived distress: results from a study of angina patients in general practice in Northern Ireland.

OBJECTIVE: To establish the effect of health education on the level of distress felt by patients with angina and to compare the results obtained using different measures. DESIGN: Randomised controlled trial of personal health education given every four months. SETTING: Eighteen general practices in the greater Belfast area. SUBJECTS: These comprised 688 patients aged less than 75 years and known to have had angina for at least six months: 342 were randomised to receive education and 346 no education. MAIN OUTCOME MEASURES: These were the Nottingham health profile (NHP), functional limitation profile (FLP), and a simple categorical scale (SCS). RESULTS: The intervention group showed a statistically significant improvement in health relative to the control group in terms of physical mobility and social isolation using the NHP. In terms of overall wellbeing, both the NHP and SCS results showed the intervention group had experienced statistically significant improvements in health relative to the control group. Results obtained using the NHP, FLP, and SCS were found to be correlated regardless of whether weighted or unweighted scores were used. CONCLUSION: The intervention produced a significant improvement in health status. Results from different survey instruments were correlated using both weighted and unweighted scores. An SCS was capable of detecting the improvement in health status.

Aged↗
PubMed1996

Cost effectiveness of personal health education in primary care for people with angina in the greater Belfast area of Northern Ireland.

STUDY OBJECTIVE: To investigate the cost effectiveness of personal health education for angina patients being treated in general practice. DESIGN: A randomised controlled trial in which people were randomised to intervention and control groups. All were assessed at the start and end of the study, with details recorded of disease status, coronary heart disease risk factors, and self assessed quality of life. A note was taken of their current use of drugs and over the course of the study their use of all health services. Those in the intervention group had three visits per year from a health visitor, whose brief was discuss ways of living more easily with their disease and in which risks of further events might be reduced. PATIENTS: Altogether 688 patents in the Greater Belfast area aged less than 75 years and known to have angina for at least six months. MAIN RESULTS: Significant improvements in survival and self assessed quality of life were found between the study and control groups. The intervention was associated with a reduction in drug usage and there was no significant difference between the intervention and control groups in terms of their use of other health services. CONCLUSION: Given the improvement in survival and self assessed quality of life and no significant differences in costs to the health service between the two groups, the intervention was deemed to be cost effective.

Angina Pectoris↗
PubMed1996

How do general practitioners qualify for their PGEA?

On average, general practitioners (GPs) achieved their five-day annual target for the postgraduate educational allowance (PGEA) mainly by attending short meetings in the disease management category. The pattern of uptake closely resembled that of provision, with relatively few meetings and attendances in the health promotion category. Sponsored meetings attracted more participants than non-sponsored ones, but mean attendances at all types of meetings were low. Implications and recommendations are discussed.

Accreditation↗