Role of the human immunodeficiency virus envelope glycoprotein in the infection and syncytia formation of microglia.

Format:

Book

Thesis/Dissertation

Author/Creator:

Shieh, Joseph Tay-Chang.

Contributor:

Gonzalez-Scarano, Francisco, advisor.

University of Pennsylvania.

Language:

English

Subjects (All):

Immunology.

Public health.

Microbiology.

0410.

0573.

0982.

Penn dissertations--Immunology.

Immunology--Penn dissertations.

Local Subjects:

Penn dissertations--Immunology.

Immunology--Penn dissertations.

0410.

0573.

0982.

Physical Description:

209 pages

Contained In:

Dissertation Abstracts International 60-11B.

System Details:

Mode of access: World Wide Web.

text file

Summary:

Individuals infected with Human Immunodeficiency Virus type 1 (HIV-1) can develop a severe neurologic disorder, HIV dementia (HIVD). Microglia likely play a key role in HIVD pathogenesis since they are the main cell type that habor HIV-1 in the brain. Furthermore, the neuropathologic hallmark of HIVD is the multinucleated giant cell (syncytia), formed by the fusion of infected microglia. To understand the interaction of HIV with microglia more completely, we identified the role of chemokine receptors, which act as coreceptors, in mediating HIV infection of microglia. We also examined viral determinants involved in inducing extensive syncytia formation.

To determine the role of chemokine receptors in infection, we used HIVD brain isolates and other strains that replicate well in cultured adult human microglia and cloned their envelope glycoprotein genes. We demonstrated that all of the envelopes utilized CCR5 in infection and fusion assays with coreceptor-transfected cells. There was less common and less efficient use of CCR3 and CXCR4. Furthermore, microglia expressed higher levels of CCR5 than CCR3 both immediately after isolation and after culture. Though virus strains could potentially use a number of chemokine receptors to infect microglia, we found that CCR5 was the predominant coreceptor used, since an anti-CCR5 antibody dramatically inhibited microglial infection while anti-CCR3 and anti-CXCR4 antibodies had little or no effect. Although the HIVD isolates could utilize other receptors, such as APJ, CCR8, and GPR15, to infect coreceptor-transfected cells, the in vivo significance of these coreceptors remains to be determined. We analyzed the ability of the microglia-passaged virus HIV-1BORI-15 to induce extensive syncytia formation in microglia and found that the phenotype was not due to a switch in coreceptor usage or CD4-independence, but that the HIV-1BORI-15 envelope, either alone or in a recombinant virus, mediated more efficient fusion of CD4+CCR5+ cells than its parental strain. Genetic analysis indicated that amino acid differences in the V1/V2 region of envelope were critical in the syncytia-forming phenotype and likely contribute to an altered interaction with CD4/CCR5. This thesis provides a framework for studying microglial infection and syncytia formation and explores the interaction of a highly fusogenic envelope with CD4/CCR5.

Notes:

Thesis (Ph.D. in Immunology) -- University of Pennsylvania, 1999.

Source: Dissertation Abstracts International, Volume: 60-11, Section: B, page: 5343.

Supervisor: Francisco Gonzalez-Scarano.

Local Notes:

School code: 0175.

ISBN:

9780599559219

Access Restriction:

Restricted for use by site license.