Mixed HIV coreceptor use associated with lower CD4 count than CXCR4 use

Patients who have been heavily treated with antiretroviral drugs have a high proportion of viral strains that can use two types of chemokine receptors to infect cells, according to a study published in the February 15^th edition of Clinical Infectious Diseases.

The researchers, led by Timothy J Wilkin of Weill-Cornell Medical College, New York, also found that people with HIV that can use both receptors (known as dual-tropic virus) had lower CD4 cell counts than people with virus that uses the CXCR4 receptor (the viral type associated with a higher risk of disease progression). The findings lend further weight to the need to test for coreceptor usage in patients who may be eligible to take the new chemokine receptor inhibitor, maraviroc, now in development.

HIV infects cells by first binding to the CD4 receptor and then one of two coreceptors, the chemokine receptors CCR5 and CXCR4. Usually, these receptors are the targets for substances that activate white blood cells in response to inflammation. HIV that can use CCR5 tends to predominate early in infection while the presence of virus that can use CXCR4, known as syncitium-inducing virus, has been linked with an increased risk of progression to AIDS and death.

Currently, new potential antiretroviral treatments are in clinical trials to block chemokine receptors in the hope of preventing HIV entry into cells. The study reported here was part of a trial of the CCR5 inhibitor vicriviroc in heavily treatment-experienced patients.

The investigators write, “With their novel mechanism of action, CCR5 inhibitors should have antiretroviral activity for HIV-1–infected patients with uncontrolled viremia and few other treatment options (e.g. patients with multidrug-resistant virus)”. However, they note, these compounds are most likely to be effective if the individual is infected with CCR5-using virus alone. So the team tested the viral strains from all participants screened for a phase 2b study of vicriviroc (study ACTG A5211) to determine whether their strains used CCR5 alone, CXCR4 alone, or both receptors to infect cells.

Of 391 individuals who had available results, Wilkin and colleagues report that 50% of people had a strain of virus that used CCR5 alone, 46% had a mixed or 'dual-tropic' viral population, while only 4% had virus that used CXCR4 alone. An analysis of other factors found that people with dual-tropic viral strains had lower CD4 counts than those with CCR5-using or CXCR4-using virus alone (103 cells/mm³ vs 170 and 161 cells/mm³ respectively, p

Participants who had only CCR5-using viral strains were then eligible to participate in the drug trial. However, of 118 individuals who were eligible to enter the study, 10% had a dual-tropic strain by the time of study entry (a median interval of 37 days). The authors say they believe that this evidence of change in tropism is more likely to reflect the variability of the Trofile coreceptor assay used in the study rather than the speed at which tropism can switch in a treatment-experienced population.

Dual-tropic viral strains are found more commonly in treatment-experienced patients, and it has been suggested that CXCR4-using strains may develop due to antiretroviral treatment. Moreover, the authors suggest that the poorer prognosis associated with CXCR4-using viral strains might in fact be due to development of dual-tropic strains.

In an accompanying commentary, Thomas Melby of Trimeris, the company which developed the HIV entry inhibitor enfuvirtide (Fuzeon) concurs, noting a trend towards increasing frequency of dual-tropic virus with increasing treatment experience. He points to the high prevalence of dual-tropic virus in the TORO 1 and 2 studies of enfuvirtide, which also recruited highly treatment-experienced patients, and a similar association between dual-tropic virus and the lowest CD4 cell counts to the one found in ACTG A5211. He suggests that the poorer prognosis associated with syncitium-inducing virus might indeed be due to the presence of dual-tropic virus: 'a tangle of assaults from both CCR5-using and CXCR4-using viral envelopes'.

He goes on to suggest that dual-tropic virus may be more destructive of the CD4 cell population than CXCR4-tropic virus because of its ability to infect a wider range of target cells than either type of single-tropic virus.

However, the analyses of the TORO studies and ACTG A5211 did not find an association between dual-tropic virus and higher viral load, as would be expected if this hypothesis is correct. But Melby argues that this may be explained by the greater sensitivity of the Trofile coreceptor assay used in each study when compared to previous research, using older assays, that did suggest an association. The assay may be picking up the switch to dual-tropic virus earlier, at higher CD4 cell counts, he suggests.

The ACTG A5211 researchers point out that even at relatively high CD4 cell counts, a surprisingly large proportion of patients were found to have dual-tropic or CXCR4-using virus: 45% in the 200-350 cells/mm³ range and 29% in those with CD4 cell counts above 350 cells/mm³.

Thus, the researchers suggest that “assessment of coreceptor use may be a critical determinant of eligibility for treatment with the CCR5 and CXCR4 receptor inhibitors currently in clinical development”, noting that specialised tests may therefore be necessary before starting treatment with a chemokine-receptor blocking drug. “CD4 cell count alone cannot reliably predict coreceptor use”, they note.

The authors do not discuss the implications of dual-tropic virus for response to CCR5 antagonists. However a recent study of maraviroc in highly-treatment experienced patients with low CD4 cell counts who had dual-tropic or CXCR4-using virus has shown that while viral load suppression is not improved by adding maraviroc to a new regimen, CD4 cell responses were significantly better in the maraviroc-treated patients.