Peters PJ, Sullivan WM, Duenas-Decamp MJ, Bhattacharya J, Ankghuambom C, Brown R, Luzuriaga K, Bell J, Simmonds P, Ball J, Clapham PR

Peters PJ, Sullivan WM, Duenas-Decamp MJ, Bhattacharya J, Ankghuambom C, Brown R, Luzuriaga K, Bell J, Simmonds P, Ball J, Clapham PR. 2006. bridging sheet. These distinct specificities of CD4, b12, and VRC01 likely explain the observed differences in Env sensitivity HDACA to inhibition by these reagents and provide an insight into the Mirabegron envelope mechanisms that control macrophage tropism. We present a model where the efficiency of bridging-sheet recruitment by CD4 is a major determinant of HIV-1 R5 envelope sensitivity to soluble CD4 and macrophage tropism. INTRODUCTION Human immunodeficiency computer virus type 1 (HIV-1) entry into cells involves interactions with CD4 and coreceptor CCR5 or CXCR4 to trigger fusion of the computer virus and cell membranes. values of 0.0002. 0.0014, and 0.007, respectively, for correlations with VRC01 [Spearman analyses]). Open in a separate windows Fig 3 Macrophage-tropic R5 Env+ pseudovirions are not significantly more sensitive to neutralizing antibodies in HIV-1+ sera. Mann-Whitney analyses comparing macrophage-tropic and non-macrophage-tropic Env+ pseudovirions for sensitivity to HIV-1+ human sera are shown. There was no significant difference in the sensitivities of macrophage-tropic and non-macrophage-tropic Env+ pseudovirions to neutralization by 5 different HIV-1+ human sera. See also Table 3. Table 3 Sensitivities of HIV-1 Env+ pseudovirions to neutralization by heterologous neutralizing antibodies present in HIV-1+ sera Open in a separate windows = 0.002) but not quite for PG16 (= 0.05) (Fig. 4). In summary, our data with 447-52D, PG9, and PG16 have identified sets of Envs from 6 of 11 individuals where there is usually evidence consistent with a different arrangement of V1V2 and V3 loops at the trimer apex for macrophage-tropic and non-macrophage-tropic Envs. Open in a separate windows Fig 4 Macrophage-tropic R5 Env+ pseudovirions are significantly more resistant to PG9 neutralization but not to PG16. Mann-Whitney analyses comparing macrophage-tropic and non-macrophage-tropic Env+ pseudovirions for sensitivity to MAbs PG9 and PG16 (which recognize a quaternary epitope comprising determinants in V2 and V3), are shown. Limited changes in the sensitivity of macrophage-tropic R5 Env+ pseudovirions to MAbs and reagents that target other Env sites and downstream events in fusion. We next investigated the panel of Envs for their sensitivities to MAbs or reagents that target other Env sites or entry events subsequent to Env-CD4 binding. This approach was aimed at establishing whether Mirabegron Env changes that led to increased or decreased macrophage tropism were localized within or proximal to the CD4bs and at sites around the trimer apex or, alternatively, conferred more extensive effects on Env structure that would affect other functions, Mirabegron including coreceptor interactions and gp41 conformational changes that result in fusion. Non-macrophage-tropic Envs were significantly more sensitive to 2G12 than macrophage-tropic Envs (= 0.006), confirming our previous observations on a smaller panel of Envs (11). 2G12 binds to a glycan complex on the outer domain name of gp120. The decreased sensitivity to 2G12 for macrophage-tropic Envs is likely associated with the loss of a critical glycan or a change in the orientation of one or more glycans, as we previously reported (38). Such changes Mirabegron most likely influence exposure of CD4 contact residues around the outer domain name of gp120, although effects on coreceptor interactions are also possible. Physique 5 and Table 5 show that there were no significant differences between macrophage-tropic and non-macrophage-tropic Envs in sensitivity to maraviroc or to each of the gp41 reagents, including MAbs 2F5 and 4E10, or to the fusion inhibitor, T20. Together, these data indicate that major or global structural or functional alterations between trimers of macrophage-tropic Mirabegron and non-macrophage-tropic Envs were not apparent and emphasize that this differences described above are localized to sites within or proximal to CD4 contact residues and to the trimer apex. Open in a separate windows Fig 5 Macrophage-tropic R5 Env+ pseudovirions do not significantly differ from non-macrophage-tropic Envs in sensitivity to maraviroc, T20, 2F5, and 4E10. However, macrophage-tropic R5 Envs are significantly more resistant to neutralization by the glycan-specific MAb 2G12. Mann-Whitney analyses comparing macrophage-tropic and non-macrophage-tropic Env+ pseudovirions for sensitivity to the CCR5 antagonist maraviroc, the 6-helix bundle inhibitor T20, gp41 MAbs 4E10 and 2F5, and the gp120 glycan-specific MAb 2G12 are shown. Table 5 Sensitivities of HIV-1 Env+ pseudovirions to neutralization or inhibition by reagents that bind envelope sites distal from the CD4bs and/or block entry events.