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

Maria Paz Gonzalez-Perez1, Olivia O'Connell1, Rongheng Lin2, W Matthew Sullivan1, Jeanne Bell3, Peter Simmonds4 and Paul R Clapham1*

Author Affiliations

1 Program in Molecular Medicine and Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Biotech 2, 373 Plantation Street, Worcester, Massachusetts 01605-2377

2 School of Public Health and Health Sciences, University of Massachusetts, 411 Arnold House, 715 North Pleasant Street, Amherst, MA 01003-9304

3 The MRC HIV brain and tissue bank in Edinburgh, Department of Pathology (Neuropathology), University of Edinburgh, Wilkie Building, Teviot Place, Edinburgh, UK EH8 9AG

4 Centre for Infectious Diseases, Summerhall, Edinburgh EH9 1QH, UK

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Retrovirology 2012, 9:20  doi:10.1186/1742-4690-9-20

Published: 15 March 2012

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.

Keywords:
HIV; Envelope; Macrophage-tropism; CD4; CCR5; Neurotropism; Immune tissue; Brain; Entry