HIV interacts with a CD4+ cell by first binding to the CD4 receptor. After a conformational change, it then binds to either the CCR5 (abbreviated R5) or CXCR4 (abbreviated X4) co-receptor. After these 2 steps, viral-cell fusion may occur. As several investigational drugs are in development that selectively block the R5 or X4 co-receptors, it is important to understand the prevalence of R5 versus X4 viruses among patients. Graeme Moyle from Chelsea and Westminster Hospital in London described the epidemiological and predictive factors for co-receptor usage among a cohort from this London treatment site.

Blood samples were obtained from a specimen repository and tested for co-receptor usage using the modified PhenoSense assay from ViroLogic. These specimens were matched with the subject's genotype, virus clade, CD4+ cell count, HIV RNA and treatment history. Multivariate models were constructed to establish independent predictors of R5 versus X4 tropism.

The study included 865 samples, out of which 65% were from treatment-naive subjects. Overall, 80% of the viruses tested exclusively utilized the R5 receptor; only 4 samples exclusively used X4, while the remainder were dual tropic (R5/X4). The prevalence of R5 virus was not influenced by age, gender, virus clade, ethnicity or antiretroviral exposure.

As noted in prior studies, however, having a more advanced stage of HIV disease as measured by CD4+ cell count and HIV RNA increased the likelihood of having X4-utilizing virus. Specifically, for patients with a CD4+ cell count less than 100, around 40% were R5/X4, while for those whose CD4+ cell counts were greater than 100, only 15% of viruses were dual tropic.

Similarly, an HIV RNA greater than 100,000 conferred a 28% likelihood of R5/X4, versus only a 12% likelihood of dual tropism for viral loads less than 5,000. Similar correlations between co-receptor tropism and disease stage were described in a different presentation during this slide session.¹

Despite the rise in prevalence of X4 usage with advancing HIV disease, an important observation in both these studies is the continued high rate of exclusive R5 tropism even among patients with low CD4+ cell counts and high viral loads. As a result, it is likely that the CCR5 inhibitors now in clinical trials will be potential options for therapy in the majority of patients at all stages of HIV disease.

In addition, while use of a CCR5 inhibitor in a patient with dual-tropic virus would select for X4 viruses -- which are potentially more virulent -- it is conversely possible that using CCR5 inhibitors in this context will provide a benefit so long as these drugs are used in combination with other antivirals, as is the current standard of care for all HIV therapy. This last hypothesis is being tested in a prospective clinical trial of the Pfizer CCR5 antagonist UK-427,857; this study has just gotten underway.

Footnote

1. Demarest J, Bonny T, Vavro C, et al. HIV-1 co-receptor tropism in treatment naive and experienced subjects. In: Program and abstracts of the 44th Interscience Conference on Antimicrobial Agents and Chemotherapy; October 30 - November 2, 2004; Washington, D.C. Abstract H-1136.