Abstract
HIV-1 R5 viruses vary widely in their capacity to infect primary macrophages. R5 macrophage-tropism is associated with an increased envelope:CD4 affinity that partly results from an increased exposure of CD4 contact residues on gp120 and allows the use of low levels of CD4 for infection. The selective pressures in vivo that modulate R5 macrophage-tropism are not understood. It is possible that different R5 variants adapt for replication in either T-cells (high CD4) or in macrophages (low CD4). However, other selective pressures in vivo (e.g. neutralizing antibodies) may also impact R5 tropism. Here, we measured macrophage infectivity conferred by gp120 sequences amplified sequentially from subjects in London followed from the acute stage of infection. We report wide variation in the capacity of these envelopes to confer macrophage infection in the complete absence of both autologous and heterologous neutralizing antibodies. Our data show that the variation in macrophage tropism observed at early times cannot have been influenced by neutralizing antibodies.
Highlights
HIV-1 R5 viruses vary widely in their capacity to infect primary macrophages
HIV-1 R5 viruses that use CCR5 (R5) as a coreceptor are preferentially transmitted. Such viruses are often termed macrophage-tropic or M-tropic [1], we and others have described a wide variation in their capacity to infect primary macrophages [2,3,4,5,6,7]
We showed that R5 envelopes amplified from brain tissue of subjects with neurological complications were frequently highly macrophage-tropic, while many of those from immune tissue, blood, and semen infected macrophages inefficiently [3]
Summary
HIV-1 R5 viruses vary widely in their capacity to infect primary macrophages. R5 macrophage-tropism is associated with an increased envelope:CD4 affinity that partly results from an increased exposure of CD4 contact residues on gp120 and allows the use of low levels of CD4 for infection. In agreement with these observations, we and others have identified gp120 determinants within or proximal to the CD4 binding site (CD4bs) that modulate R5 mac-tropism [11,12,13,14,15,16]. Brain macrophages and microglia are the predominant targets for HIV-1 in the brain, and the presence of highly mac-tropic variants there may reflect an adaptation for infection of these low CD4 cell types.
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