Decreased plasticity of coreceptor use by CD4-independent SIV Envs that emerge in vivo

• Type of Material: Article
• Authors: Nicholas Francella, University of Pennsylvania; Sarah TC Elliott, University of Pennsylvania; Yanjie Yi, University of Pennsylvania; Sarah Gwyn, University of Pennsylvania; Alexandra M Ortiz, Emory University; Bing Li, Emory University; Guido Silvestri, Emory University; Mirko Paiardini, Emory University; Cynthia Derdeyn, Emory University; Ronald G Collman, University of Pennsylvania
• Language: English
• Date: 2013
• Publisher: BioMed Central
• Publication Version: Final Published Version
• Copyright Statement: © 2013 Francella et a
• License: Creative Commons Attribution 2.0 Generic
• Final Published Version (URL): http://www.retrovirology.com/content/10/1/133
• Title of Journal or Parent Work: Retrovirology
• ISSN: 1742-4690
• Volume: 10
• Issue: 133
• Grant/Funding Information: N.F. and S.T.E were supported by T32-AI007632.; We also acknowledge NIH support to the Yerkes National Primate Research Center (P51-RR000165 and P51-OD011132).; This work was supported by NIH grants AI091516 and MH61139 (R.G.C), AI58706 (C.A.D), and AI066998 (G.S.).
• Research Categories: Health Sciences, Immunology; Biology, Virology; Biology, Molecular

Abstract

Background HIV and SIV generally require CD4 binding prior to coreceptor engagement, but Env can acquire the ability to use CCR5 independently of CD4 under various circumstances. The ability to use CCR5 coupled with low-to-absent CD4 levels is associated with enhanced macrophage infection and increased neutralization sensitivity, but the additional features of these Envs that may affect cell targeting is not known. Results Here we report that CD4-independent SIV variants that emerged in vivo in a CD4+ T cell-depleted rhesus macaque model display markedly decreased plasticity of co-receptor use. While CD4-dependent Envs can use low levels of macaque CCR5 for efficient entry, CD4-independent variants required high levels of CCR5 even in the presence of CD4. CD4-independent Envs were also more sensitive to the CCR5 antagonist Maraviroc. CD4-dependent variants mediated efficient entry using human CCR5, whereas CD4-independent variants had impaired use of human CCR5. Similarly, CD4-independent Envs used the alternative coreceptors GPR15 and CXCR6 less efficiently than CD4-dependent variants. Env amino acids D470N and E84K that confer the CD4-independent phenotype also regulated entry through low CCR5 levels and GPR15, indicating a common structural basis. Treatment of CD4-dependent Envs with soluble CD4 enhanced entry through CCR5 but reduced entry through GPR15, suggesting that induction of CD4-induced conformational changes by non-cell surface-associated CD4 impairs use of this alternative co-receptor. Conclusions CD4 independence is associated with more restricted coreceptor interactions. While the ability to enter target cells through CCR5 independently of CD4 may enable infection of CD4 low-to-negative cells such as macrophages, this phenotype may conversely reduce the potential range of targets such as cells expressing low levels of CCR5, conformational variants of CCR5, or possibly even alternative coreceptors.