Emergence, dominance, and possible decline of CXCR4 chemokine receptor usage during the course of HIV infection

Abstract

Binding to a chemokine receptor, either CCR5 or CXCR4, by the gp120 glycoprotein is an essential step in the pathway by which HIV enters host cells. Recently, CCR5 antagonists have been developed that obstruct binding of CCR5 by gp120, thus inhibiting host cell entry. Resistance to such CCR5 antagonists may emerge, however, through the selection of viral strains capable of utilizing CXCR4 receptors. This study explores the evolutionary context of emergence, and in many cases decline, of dominant CXCR4-usage (X4) during disease progression within a number of individuals. Of seven individuals exhibiting a switch to dominant CXCR4 usage, such dominance is transient in five of them with CCR5-usage (R5) re-emerging to dominate the viral population later in disease progression. Three individuals conform to documented X4 transience in that the re-emergence of R5 dominance is an outgrowth from the predominant R5 strain. However, in two individuals we observe a novel pathway for R5 re-emergence in that R5 strains emerge to dominate late in disease progression through continued evolution of the X4 population. This suggests that the molecular mechanism of such switches between R5 and X4-usage is strain specific and that no single mechanism is shared between individuals. These findings have implications for the understanding of the mechanisms of potential emergence of resistance to CCR5 antagonists through use of the CXCR4 receptor and support the importance to have an appropriately optimized background therapy for use with entry inhibitors and, as for all HAART, to monitor drug resistance in a comprehensive manner.

Coreceptor Usage, Diversity, and Divergence in Drug-Naive and Drug-Exposed Individuals from Malawi, Infected with HIV-1 Subtype C for More Than 20 Years

“…LTS10 was referred for ART in 2010 as the CD4 + cell count had dropped to 138 cells/mm 3 indicating progression, which was 6 years after viruses able to use CXCR4 are predicted (but only by two genotypic predictor tools). This may suggest that a switch to CXCR4 tropism within subtype C is not as strongly correlated with disease progression, consistent with the suggestion by Meehan et al 54 that CXCR4 usage can be transitory during disease progression. It may be that genotypic prediction by some but not all predictor tools indicates an intermediate phase or a dual phase for coreceptor usage or indeed that genotypic predictor tools are not yet sensitive enough to accurately predict coreceptor usage in subtype C. Of the six LTS who have been placed on ART, suggesting disease progression, four were CCR5 tropic, and of the two who had died one (LTS9) was at no time predicted to utilize CXCR4.…”

Protein structural disorder of the envelope V3 loop contributes to the switch in human immunodeficiency virus type 1 cell tropism

“…This indicates that X4 populations may commonly be present, but only transiently dominant, in the life time of an infection. Indeed, in the now classic longitudinal study of Shankarrapa et al [ 7 ], this is readily apparent (see Meehan et al for visualisations [ 8 ]), indicating that the true rates of X4 using virus are much higher than the commonly reported figure of 50% of patients observed to progress to X4 using virus, as confirmed by recent studies [ 3 , 9 ].…”

Protein Structural Disorder Of The Envelope V3 Loop Contributes To The Switch In Human Immunodeficiency Virus Type 1 Cell Tropism

“…This indicates that X4 populations may commonly be present, but only transiently dominant, in the life time of an infection. Indeed, in the now classic longitudinal study of Shankarrapa et al (7), this is readily apparent (see Meehan et al for visualisations (8)). This indicates that the true rates of X4 using virus are much higher than the commonly reported figure that 50% of patients are observed to progress to X4 using virus, as confirmed by recent studies (3, 9).…”