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

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.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.Human immunodeficiency virus type 1 requires interactions with CD4 and either CCR5 or CXCR4 coreceptors to trigger fusion of viral and cellular membranes and entry into cells. CCR5-using (R5) viruses are mainly transmitted and individuals homozygous for a defective CCR5 gene (Δ32 CCR5) are substantially protected from infection [1]. Recent studies of clade B and clade C transmission events have shown that the transmitted R5 viruses are unable to efficiently infect macrophages, whether transmission is sexual [2,3] or via mother-to-child [4]. In late disease