Abstract
A change in coreceptor preference from CCR5 to CXCR4 towards the end stage disease in some HIV-1 infected individuals has been well documented, but the reasons and mechanisms for this tropism switch remain elusive. It has been suggested that envelope structural constraints in accommodating amino acid changes required for CXCR4 usage is an obstacle to tropism switch, limiting the rate and pathways available for HIV-1 coreceptor switching. The present study was initiated in two R5 SHIVSF162P3N-infected rapid progressor macaques with coreceptor switch to test the hypothesis that an early step in the evolution of tropism switch is the adoption of a less constrained and more “open” envelope conformation for better CD4 usage, allowing greater structural flexibility to accommodate further mutational changes that confer CXCR4 utilization. We show that, prior to the time of coreceptor switch, R5 viruses in both macaques evolved to become increasingly sCD4-sensitive, suggestive of enhanced exposure of the CD4 binding site and an “open” envelope conformation, and this correlated with better gp120 binding to CD4 and with more efficient infection of CD4low cells such as primary macrophages. Moreover, significant changes in neutralization sensitivity to agents and antibodies directed against functional domains of gp120 and gp41 were seen for R5 viruses close to the time of X4 emergence, consistent with global changes in envelope configuration and structural plasticity. These observations in a simian model of R5-to-X4 evolution provide a mechanistic basis for the HIV-1 coreceptor switch.
Highlights
The human immunodeficiency virus (HIV) enters target cells via interaction of the viral glycoprotein with the cellular receptor CD4 and chemokine coreceptors, either CCR5 (R5 viruses) or CXCR4 (X4 viruses) [1]
We found no significant difference in the entry efficiency of R5 viruses bearing envelope gp160s (Envs) amplified from macaque BR24 at 2–16 wpi, when measured in CD4hi CCR5hi TZM-bl cells, but R5 viruses present during and following the time of X4 emergence at 20 wpi infected TZM-bl cells less efficiently (2–3 fold reduction in RLU; Figure 1A)
Because X4 emergence is strongly associated with rapid CD4+ T– cell loss and disease progression, and concerns that the introduction of CCR5 entry inhibitors as anti-HIV therapeutics could facilitate X4 emergence and exacerbate disease, there is an increasing need to improve our understanding of the selection pressures which favor CCR5-to-CXCR4 switch
Summary
The human immunodeficiency virus (HIV) enters target cells via interaction of the viral glycoprotein with the cellular receptor CD4 and chemokine coreceptors, either CCR5 (R5 viruses) or CXCR4 (X4 viruses) [1]. Given the minimal requirement for V3 sequence change to confer the ability to use CXCR4, the high levels of virus replication and associated error rate [11,12,13], and the selective advantage of expanded target cell population in vivo [14,15], it is surprising that the switch from R5 to X4 virus does not occur more rapidly and frequently in HIV-1 infected individuals. The mechanistic basis and blockade(s) for virus coreceptor switch remain ill-defined, several selective factors such as high viral load and evolutionary rate, CD4+CCR5+ target T cell limitation, and weakening of immune-driven pressures have been proposed as playing important roles [16,17,18]
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