Abstract
BackgroundHIV 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.ResultsHere 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.ConclusionsCD4 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.
Highlights
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
CD4+ T cell-depleted animals failed to produce this CD4-inducible neutralization activity, enabling emergence of CD4-independent variants in these animals. These findings, along with other studies [5,6,7,8], suggest that antibodies shape the cellular tropism of the virus in vivo by preventing the emergence of CD4-independent variants during typical infection. Both CD4 independence and neutralization sensitivity were conferred by D470N/E84K mutations in Env that arose in these animals [9], indicating that these are linked phenotypes resulting from a common structural basis
CD4-independent SIV Envs have reduced capacity compared to CD4-dependent Env to use human CCR5 We previously described a model for in vivo emergence of CD4-independent SIV in which rhesus macaques were experimentally depleted of CD4+ T-cells before SIVmac251 infection [9,10]
Summary
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. We recently described a unique SIV model in which such CD4-independent Env variants emerged and dominated in the plasma of multiple rhesus macaques experimentally depleted of peripheral (but not mucosal) CD4+ T cells prior to infection [9,10] These animals displayed widespread infection of tissue macrophages, which express very low levels of CD4 compared to CD4+ T cells, indicating a mechanism by which virus could expand its target cell range in this setting of limited CD4+ T cell targets. These findings, along with other studies [5,6,7,8], suggest that antibodies shape the cellular tropism of the virus in vivo by preventing the emergence of CD4-independent variants during typical infection Both CD4 independence and neutralization sensitivity were conferred by D470N/E84K mutations in Env that arose in these animals [9], indicating that these are linked phenotypes resulting from a common structural basis
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