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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 Effects of vpu start-codon mutations on human immunodeficiency virus type 1 replication in macrophages.
Academic Article Variation in HIV-1 R5 macrophage-tropism correlates with sensitivity to reagents that block envelope: CD4 interactions but not with sensitivity to other entry inhibitors.
Academic Article A conserved determinant in the V1 loop of HIV-1 modulates the V3 loop to prime low CD4 use and macrophage infection.
Academic Article Stromal down-regulation of macrophage CD4/CCR5 expression and NF-?B activation mediates HIV-1 non-permissiveness in intestinal macrophages.
Academic Article Independent evolution of macrophage-tropism and increased charge between HIV-1 R5 envelopes present in brain and immune tissue.
Academic Article Identification of a subset of human immunodeficiency virus type 1 (HIV-1), HIV-2, and simian immunodeficiency virus strains able to exploit an alternative coreceptor on untransformed human brain and lymphoid cells.
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 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 Non-macrophage-tropic human immunodeficiency virus type 1 R5 envelopes predominate in blood, lymph nodes, and semen: implications for transmission and pathogenesis.
Academic Article Variation of macrophage tropism among HIV-1 R5 envelopes in brain and other tissues.
Academic Article Determinants flanking the CD4 binding loop modulate macrophage tropism of human immunodeficiency virus type 1 R5 envelopes.
Academic Article Macrophages in vaginal but not intestinal mucosa are monocyte-like and permissive to human immunodeficiency virus type 1 infection.
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 Modulation of HIV-1 macrophage-tropism among R5 envelopes occurs before detection of neutralizing antibodies.
Academic Article Efficiency of bridging-sheet recruitment explains HIV-1 R5 envelope glycoprotein sensitivity to soluble CD4 and macrophage tropism.
Concept Macrophages
Concept Macrophage Inflammatory Proteins
Academic Article HIV-1 non-macrophage-tropic R5 envelope glycoproteins are not more tropic for entry into primary CD4+ T-cells than envelopes highly adapted for macrophages.
Academic Article Infection of ectocervical tissue and universal targeting of T-cells mediated by primary non-macrophage-tropic and highly macrophage-tropic HIV-1 R5 envelopes.
Academic Article Saturation Mutagenesis of the HIV-1 Envelope CD4 Binding Loop Reveals Residues Controlling Distinct Trimer Conformations.
Academic Article Targeted Delivery of Glucan Particle Encapsulated Gallium Nanoparticles Inhibits HIV Growth in Human Macrophages.
Academic Article Delineating CD4 dependency of HIV-1: Adaptation to infect low level CD4 expressing target cells widens cellular tropism but severely impacts on envelope functionality.
Academic Article Identification of Emerging Macrophage-Tropic HIV-1 R5 Variants in Brain Tissue of AIDS Patients without Severe Neurological Complications.
Academic Article HIV-1 R5 Macrophage-Tropic Envelope Glycoprotein Trimers Bind CD4 with High Affinity, while the CD4 Binding Site on Non-macrophage-tropic, T-Tropic R5 Envelopes Is Occluded.
Academic Article Ultradeep single-molecule real-time sequencing of HIV envelope reveals complete compartmentalization of highly macrophage-tropic R5 proviral variants in brain and CXCR4-using variants in immune and peripheral tissues.
Academic Article No detection of CD4-independent human immunodeficiency virus 1 envelope glycoproteins in brain tissue of patients with or without neurological complications.
Academic Article Implications of the 375W mutation for HIV-1 tropism and vaccine development.
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