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. 2012 Mar 15:9:20.
doi: 10.1186/1742-4690-9-20.

Independent evolution of macrophage-tropism and increased charge between HIV-1 R5 envelopes present in brain and immune tissue

Maria Paz Gonzalez-Perez  1 , Olivia O'Connell, Rongheng Lin, W Matthew Sullivan, Jeanne Bell, Peter Simmonds, Paul R Clapham
Affiliations

Independent evolution of macrophage-tropism and increased charge between HIV-1 R5 envelopes present in brain and immune tissue

Maria Paz Gonzalez-Perez et al. Retrovirology. .

Abstract

Background: Transmitted HIV-1 clade B or C R5 viruses have been reported to infect macrophages inefficiently, while other studies have described R5 viruses in late disease with either an enhanced macrophage-tropism or carrying envelopes with an increased positive charge and fitness. In contrast, our previous data suggested that viruses carrying non-macrophage-tropic R5 envelopes were still predominant in immune tissue of AIDS patients. To further investigate the tropism and charge of HIV-1 viruses in late disease, we evaluated the properties of HIV-1 envelopes amplified from immune and brain tissues of AIDS patients with neurological complications.

Results: Almost all envelopes amplified were R5. There was clear compartmentalization of envelope sequences for four of the five subjects. However, strong compartmentalization of macrophage-tropism in brain was observed even when brain and immune tissue envelope sequences were not segregated. R5 envelopes from immune tissue of four subjects carried a higher positive charge compared to brain envelopes. We also confirm a significant correlation between macrophage tropism and sensitivity to soluble CD4, a weak association with sensitivity to the CD4 binding site antibody, b12, but no clear relationship with maraviroc sensitivity.

Conclusions: Our study shows that non-macrophage-tropic R5 envelopes carrying gp120s with an increased positive charge were predominant in immune tissue in late disease. However, highly macrophage-tropic variants with lower charged gp120s were nearly universal in the brain. These results are consistent with HIV-1 R5 envelopes evolving gp120s with an increased positive charge in immune tissue or sites outside the brain that likely reflect an adaptation for increased replication or fitness for CD4+ T-cells. Our data are consistent with the presence of powerful pressures in brain and in immune tissues selecting for R5 envelopes with very different properties; high macrophage-tropism, sCD4 sensitivity and low positive charge in brain and non-macrophage-tropism, sCD4 resistance and high positive charge in immune tissue.

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Figures

Figure 1
Figure 1
Phylogenetic analysis (MEGA 5) of HIV-1 envelope nucleotide sequences amplified from brain and immune tissue. Tight compartmentalization of brain and immune tissue envelope sequences was observed for subjects CA110, 6568, 7766 and NA20. Envelope compartmentalization was less clear for subject 10017. Numbers at branch points represent bootstrap values.
Figure 2
Figure 2
Compartmentalized macrophage infectivity for brain and immune tissue envelopes. Nearly all envelopes amplified from brain tissue efficiently infected primary macrophage cultures. In contrast, envelopes from immune tissue varied in the capacity to infect macrophages with infection ranging from background levels to highly efficient infection for a small minority. Infectivity is presented as FFU/ml and was derived from titers averaged from at least two assays using macrophage prepared from different donors.
Figure 3
Figure 3
Overall positive charge of HIV-1 V1-V2 and V1-V5 regions of envelopes amplified from brain and immune tissue. Immune tissue envelopes from four of five subjects carry a significantly higher positive charge compared to corresponding envelopes from brain. A-B: Overall positive charge of V1-V5 (A) and V1-V2 (B) amino acid sequences. All amplified envelopes shown in Figure 1 were included in this analysis.
Figure 4
Figure 4
Brain and immune tissue V1-V5 gp120 do not significantly differ in length (A) and or extent of N-linked glycosylation sites (B). All amplified envelopes shown in Figure 1 were included in this analysis.
Figure 5
Figure 5
Sensitivity of brain and immune tissue envelopes to inhibition by soluble CD4, the CD4bs mab, b12 and the CCR5 antagonist maraviroc: The impact of macrophage tropism. A panel of 32 envelopes that represented the full range of macrophage-tropism observed for LN/spleen envelopes and included highly macrophage-tropic envelopes from the brain was tested for their sensitivity to sCD4, b12 and maraviroc using env+ pseudovirions. A. Brain envelopes were significantly more sensitive to sCD4 compared to those from immune tissues, but are not significantly more sensitive to maraviroc or the CD4bs mab, b12. B. Soluble CD4 sensitivity correlates with macrophage infectivity and is highly significant. There is a weaker correlation between b12 sensitivity and macrophage infection. Control envelopes JR-FL (mac-tropic) and JR-CSF (non-mac-tropic) are depicted as green and red spots respectively. C. Even when just LN/spleen envelopes are analyzed, there is a strong correlation between macrophage infection and sCD4 sensitivity as well as a weaker association with b12. This latter observation rules out the possibility that brain or LN/spleen founder effects affect the correlations shown.
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