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Differential CD4/CCR5 utilization, gp120 conformation, and neutralization sensitivity between envelopes from a
J Martín1, C C LaBranche, F González-Scarano
1Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
Journal of Virology
|March 27, 2001
Summary
Human immunodeficiency virus type 1 (HIV-1) adapted to grow in microglia shows altered envelope glycoproteins. These changes enhance its ability to infect cells with low CD4 and CCR5 levels, impacting immune responses.
Area of Science:
- Virology
- Immunology
- Neuroscience
Background:
- Human immunodeficiency virus type 1 (HIV-1) infects central nervous system (CNS) microglial cells, inducing syncytium formation.
- Sequential passaging of HIV-1(BORI) in microglia yielded HIV-1(BORI-15), exhibiting enhanced fusion and replication in these cells.
- The parent and adapted viruses utilized CCR5 as a coreceptor, with syncytium-inducing phenotype linked to four amino acid changes in the V1/V2 region of gp120.
Purpose of the Study:
- To investigate the impact of microglial adaptation on HIV-1 envelope glycoproteins (gp120) and their interaction with cell surface receptors (CD4 and CCR5).
- To characterize the infectivity and neutralization sensitivity of recombinant HIV-1 viruses with specific gp120 modifications.
- To understand how adaptation to CNS microglial cells influences HIV-1's interaction with host cell receptors and immune responses.
Main Methods:
- Production of luciferase-reporter, env-pseudotyped viruses (rBORI, rB15, rV1V2) using plasmids encoding specific HIV-1 env sequences.
- Infection of cells expressing varying levels of CD4 and CCR5 with pseudotyped viruses.
- Assessment of infectivity with chimeric or deleted coreceptors and neutralization sensitivity using HIV-positive sera and the 17b monoclonal antibody.
Main Results:
- Adapted viruses (rB15, rV1V2) maintained infectivity in cells with low CD4 levels, independent of CCR5 levels, and utilized modified coreceptors.
- The CD4-induced 17b epitope on gp120 was more accessible in adapted viruses, increasing sensitivity to 17b antibody neutralization.
- Adapted viruses showed increased sensitivity to neutralization by a panel of HIV-positive sera compared to the parent virus.
Conclusions:
- Adaptation of HIV-1 to microglia involves gp120 changes that enhance utilization of CD4 and CCR5, particularly under low receptor expression conditions.
- Conformational changes in gp120, evidenced by altered 17b epitope accessibility, are associated with microglial adaptation.
- HIV-1 adaptation to specific tissue types like the CNS directly modulates envelope glycoprotein interactions with cell surface molecules and humoral immune responses.