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Search Results to Paul R Clapham PhD

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The HIV envelope: Biology, Receptors and Cellular Tropisms

HIV uses cell surface receptors to attach to and enter cells. Interactions with CD4 and a coreceptor are usually required for HIV to efficiently enter cells. Coreceptors are seven-transmembrane receptors that belong to the chemokine receptor family. Viruses transmitted and present in the asymptomatic stages of infection use the chemokine receptor CCR5 as a coreceptor, while variants that use CXCR4 emerge later in disease in up to 50% of AIDS patients. More than a dozen other coreceptors have been identified that confer infection in vitro for various HIV and SIV strains. However, these are not currently believed to be significant for HIV replication in vivo.Dr. Paul Clapham

Our group is investigating how HIV-1 adapts for replication in different environments and cell types in vivo. We use PCR to amplify envelopes from patient tissue. This avoids viral culture that may introduce mutations into envelope genes. We have shown that CCR5-using envelopes vary substantially in tropism and capacity to exploit low levels of CD4 and/or CCR5 for infection. Thus, envelopes from brain tissue are predominantly highly macrophage-tropic and can exploit low levels of CD4 for infection. In contrast, the majority of envelopes from immune tissue required high levels of CD4 for infection and were non-macrophage-tropic. Current research aims to evaluate whether highly macrophage-tropic variants evolve at different sites in vivo. For example, if highly macrophage-tropic variants are present in semen, they may confer more efficient transmission. We are also investigating the selective pressures that confer macrophage-tropic and non-macrophage-tropic phenotypes for CCR5-using HIV-1. Do these phenotypes simply reflect adaptation for replication in T-cells in immune tissue and for macrophages in the brain? Or do the phenotypes result from different immune pressures conferred by neutralizing antibodies in immune tissue, contrasting with brain tissue where neutralizing antibodies are usually excluded by the blood brain barrier.

Projects that examine other aspects of the biology of the HIV-1 envelope are also ongoing to investigate (1) the trafficking of newly synthesized envelope glycoproteins to the sites of virus budding and (2) vpu regulation of envelope expression and maturation in vitro and in vivo.

Paul Clapham, PhD

One or more keywords matched the following items that are connected to Clapham, Paul

Item TypeName
Academic Article T-cell line adaptation of human immunodeficiency virus type 1 strain SF162: effects on envelope, vpu and macrophage-tropism.
Academic Article Changes in the V3 region of gp120 contribute to unusually broad coreceptor usage of an HIV-1 isolate from a CCR5 Delta32 heterozygote.
Academic Article Plugging gp120s cavity.
Academic Article Stromal down-regulation of macrophage CD4/CCR5 expression and NF-?B activation mediates HIV-1 non-permissiveness in intestinal macrophages.
Academic Article CD4-independent infection of HIV and SIV: implications for envelope conformation and cell tropism in vivo.
Academic Article Biological analysis of human immunodeficiency virus type 1 R5 envelopes amplified from brain and lymph node tissues of AIDS patients with neuropathology reveals two distinct tropism phenotypes and identifies envelopes in the brain that confer an enhanced tropism and fusigenicity for macrophages.
Academic Article Evolutionary genetics: Ambiguous role of CCR5 in Y. pestis infection.
Academic Article The promiscuous CC chemokine receptor D6 is a functional coreceptor for primary isolates of human immunodeficiency virus type 1 (HIV-1) and HIV-2 on astrocytes.
Academic Article Inhibition of CCR5-mediated infection by diverse R5 and R5X4 HIV and SIV isolates using novel small molecule inhibitors of CCR5: effects of viral diversity, target cell and receptor density.
Academic Article The promise of CCR5 antagonists as new therapies for HIV-1.
Academic Article Variation of macrophage tropism among HIV-1 R5 envelopes in brain and other tissues.
Academic Article Complexity in human immunodeficiency virus type 1 (HIV-1) co-receptor usage: roles of CCR3 and CCR5 in HIV-1 infection of monocyte-derived macrophages and brain microglia.
Academic Article Genotypic and functional properties of early infant HIV-1 envelopes.
Concept Receptors, CCR5

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  • Receptors CCR5