More evidence of a link between the presence of HIV that uses the CXCR4 co-receptor and faster HIV disease progression has emerged in the findings of a study by researchers at the University of California–Los Angeles, reported in the September 1st issue of Clinical Infectious Diseases.
The findings suggest that a test which screens for HIV coreceptor usage may provide useful additional information about otherwise healthy patients who may be at high risk of HIV disease progression.
The link between faster disease progression and the CXCR4 co-receptor has long been suspected through a third piece of HIV biology. Well before the talk of co-receptors, HIV researchers noticed that when HIV was collected from an infected patient and then used to infect cell lines in vitro, it could develop one of two phenotypes: NSI (non-syncytium inducing) or SI (syncytium inducing). SI was associated with faster disease progression.
After the characterisation of co-receptors, transmembrane proteins on the surface of the CD4 cell that are used by HIV during cell entry, researchers linked the use of one co-receptor, CCR5, with the NSI phenotype and another, CXCR4, with the SI phenotype.
The development of a new group of anti-HIV drugs, the CCR5 antagonists, has sparked interest and work in co-receptor biology. The entry inhibitor maraviroc (Selzentry in the US, Celsentri in Europe) by Pfizer is the first to block HIV’s use of CCR5.
The drug has antiretroviral activity only in people carrying virus that uses CCR5, but not in those carrying virus that uses CXCR4. The drug recently received accelerated approval from US and European regulatory authorities and is expected on the US market this autumn.
There have been a series of small studies linking faster disease progression with CXCR4, but the study by Eric Daar and colleagues presents multi-year data from over 100 people with HIV who received minimal antiretroviral therapy.
To obtain their data, the research team used frozen blood samples collected during the Hemophilia Growth and Development study, a cohort that enrolled HIV-positive youth from several community-based sites in the US from 1989-1990. The 207 participants, aged 6 to 19 years gave blood samples every six months for a mean duration of follow-up of seven years. These initial samples were analysed for subsets of lymphocytes and the plasma was then preserved.
Daar and colleagues tested viral load in samples taken as close as possible to the participant’s enrolment in the study. Samples with a viral load above 500 copies/ml were analysed for co-receptor tropism using the new Trofile assay, which uses PCR and recombinant DNA techniques to assay the patient’s blood sample directly for the viral envelope proteins that determine tropism. Previous assays required extensive cell culture of sample HIV.
Using eligible longitudinal series of samples, CD4 cell counts were performed on samples taken every six months, while viral load was performed on annual samples. The researchers then linked these with data on disease progression for each participant.
From the total of 207 cohort members, 126 had samples suitable for tropism analysis. About half of participants with tropism data (62) were receiving antiretroviral therapy at the time samples were taken, with all but two receiving monotherapy with a nucleoside analogue. The other two patients received dual therapy of AZT (zidovudine, Retrovir) plus ddI (Videx).
At baseline co-receptor analysis, 75 of the 126 samples (60%) showed tropism for the CCR5 receptor (R5 virus). The remainder showed dual CCR5 and CXCR4 tropism, indicating dual or mixed (DM) virus. No sample showed only CXCR4 tropism (X4 virus).
The researchers then compared mean baseline CD4 cell counts between the tropism groups. Those with DM virus had a significantly lower count (200 cells) compared with the R5 group (449 cells). When stratified according to baseline CD4 count, DM virus was observed in over 80% of the participants with a baseline CD4 cell count below 100 cells/mm3. The proportion with DM virus dropped to between 15 and 25% among participants with a CD4 count 300 cells/mm3 or above.
A longitudinal analysis of the R5 and DM groups revealed that the presence of DM virus resulted in greater decreases in CD4 cell count over the study. Kaplan Meier curves for clinical progression to AIDS reveal that by year seven only about 15% of participants with DM virus had not developed AIDS, compared with over 70% of participants starting with R5 virus.
The researchers calculated that having detectable DM virus made a participant almost four times more likely to progress to AIDS (hazard ratio 3.8, P = 0.001). When adjustments for CD4 cell count and viral load were excluded, the hazard ratio rose to 6.3.
While confirming the results of the earlier, smaller studies, the authors highlight that the current work expands on it, “revealing that co-receptor tropism is a strong, independent predictor of disease progression in a considerably larger cohort and using a high-throughput assay that assesses viral tropism of uncultured, nonpassaged circulating plasma virus.”
What is still unclear is whether emergence of CXCR4 is a cause or an effect of disease progression.
Daar ES et al. Baseline HIV type 1 co-receptor tropism predicts disease progression. Clin Infect Dis 45 :643 – 649, 2007.