Endogenous receptors for HIV in CNS - role in the neuropathogenesis of HIV-1 infection

Endogenous receptors for HIV in CNS - role in the neuropathogenesis of HIV-1 infection

Field: Neurotransmitters and receptors

Authors: Karlsson, Ulf
Kidd-Ljunggren, Karin
Ljungberg, Bengt
Svennerholm, Bo
Owman, Christer

Address of presenting
author: Dr Ulf Karlsson
Avdelningen för Molekylär Neurobiologi
Wallenberg Neurocentrum
Universitetssjukhuset
221 85 Lund

E-mail: ulf.karlsson@mphy.lu.se

Phone: 046 222 0581

Fax: 046 222 0568

Text of abstract: Human immunodeficiency virus type 1 (HIV-1) infects the brain and frequently causes dementia and other neurologic disorders in patients with AIDS. Common neuropathologic findings include the formation of giant cells, widespread reactive gliosis and white-matter pallor. Recent discoveries have revealed that certain G-protein-coupled receptors (GPCR) act as necessary HIV-1-coreceptors allowing the virus to enter CD4+ human immune cells. These receptors have now become important targets for HIV-1-blocking pharmaceutical agents. Outside the central nervous system (CNS) the chemokine receptors CCR5 and CXCR4 function as the principal coreceptors for HIV-1. However, coreceptor function has also been demonstrated for a variety of related GPCRs, many of which are widely expressed by different celltypes in the CNS.The role of different coreceptors in HIV-1 infection of the brain and the development of AIDS-related neuropathologic conditions is studied.
Viral isolates have been recovered from cerebrospinal fluid and plasma of HIV-1 infected patients with and without AIDS dementia. The isolates are used in infectivity assays performed on CD4- and CD4+ NP-2 cells (a glial cell line lacking endogenous coreceptor expression) that have been transfected with one of the CNS-coreceptors to be studied. P24gag-ELISA, RT-PCR and microscopic evaluation of syncytiaformation are used to detect successful infections. Sequence analysis of the envelope genes enable us to correlate viral surface structures with coreceptor utilisation.
Understanding the role of strain variability and coreceptor usage in HIV-1 neurotropism and neurovirulence may advance the development of new theurapeutic strategies to inhibit HIV-1 replication in the CNS and prevent neurologic injury in AIDS patients.

Keywords: HIV-1, coreceptors, CNS, neuropathogenesis

	Endogenous receptors for HIV in CNS - role in the neuropathogenesis of HIV-1 infection
Field:	Neurotransmitters and receptors
Authors:	Karlsson, Ulf Kidd-Ljunggren, Karin Ljungberg, Bengt Svennerholm, Bo Owman, Christer
Address of presenting author:	Dr Ulf Karlsson Avdelningen för Molekylär Neurobiologi Wallenberg Neurocentrum Universitetssjukhuset 221 85 Lund
E-mail:	ulf.karlsson@mphy.lu.se
Phone:	046 222 0581
Fax:	046 222 0568
Text of abstract:	Human immunodeficiency virus type 1 (HIV-1) infects the brain and frequently causes dementia and other neurologic disorders in patients with AIDS. Common neuropathologic findings include the formation of giant cells, widespread reactive gliosis and white-matter pallor. Recent discoveries have revealed that certain G-protein-coupled receptors (GPCR) act as necessary HIV-1-coreceptors allowing the virus to enter CD4+ human immune cells. These receptors have now become important targets for HIV-1-blocking pharmaceutical agents. Outside the central nervous system (CNS) the chemokine receptors CCR5 and CXCR4 function as the principal coreceptors for HIV-1. However, coreceptor function has also been demonstrated for a variety of related GPCRs, many of which are widely expressed by different celltypes in the CNS.The role of different coreceptors in HIV-1 infection of the brain and the development of AIDS-related neuropathologic conditions is studied. Viral isolates have been recovered from cerebrospinal fluid and plasma of HIV-1 infected patients with and without AIDS dementia. The isolates are used in infectivity assays performed on CD4- and CD4+ NP-2 cells (a glial cell line lacking endogenous coreceptor expression) that have been transfected with one of the CNS-coreceptors to be studied. P24gag-ELISA, RT-PCR and microscopic evaluation of syncytiaformation are used to detect successful infections. Sequence analysis of the envelope genes enable us to correlate viral surface structures with coreceptor utilisation. Understanding the role of strain variability and coreceptor usage in HIV-1 neurotropism and neurovirulence may advance the development of new theurapeutic strategies to inhibit HIV-1 replication in the CNS and prevent neurologic injury in AIDS patients.

Keywords:	HIV-1, coreceptors, CNS, neuropathogenesis

Index

Created 2000-03-27

Department of Physiological Sciences, Lund University

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