The speed and duration of immune system recovery after starting highly active antiretroviral therapy (HAART) appear to be governed by human genetic differences, raising the prospect that genetic testing may soon help to determine when to start treatment and drugs given specifically to influence the expression of genes that promote immune reconstitution.
The findings, published online on March 30th by Nature Medicine, are derived from a study of participants in a number of large US cohorts.
Two genes appear to be critical - CCR5, an HIV-1 co-receptor or portal of entry for the virus into CD4+ T cells, and CCL3L1, an HIV-suppressing molecule that binds to CCR5. Both are strongly implicated in HIV disease progression in untreated people.
The new study, led by Dr Sunil Ahuja, Professor of Medicine at the University of Texas in San Antonio, found a strong correlation between a genetic pattern associated with slower CD4 cell loss in untreated people and stronger CD4 cell gains after starting treatment, suggesting that these genes regulate the pathway determining the extent to which HIV damages the immune system.
Dr Mike McCune, chief of the Division of Experimental Medicine at the University of California, San Francisco, said the study has potentially important practical applications. “By showing that the same genetic makeup increases susceptibility to immune depletion and impaired immune recovery, the authors provide novel tools that may allow us to predict both those who will progress faster after HIV infection as well as those who might benefit from earlier initiation of HAART,” he said.
The researchers categorised the copy number of the CCL3L1 gene and variations in the CCR5 gene into three groups designated as high, moderate and low genetic risk groups. Those with a higher level of the CCL3L1 gene and a CCR5 genotype not associated with fast disease progression were classified as low risk. This corresponds to a higher level of circulating CCL3L1 and less expression of the CCR5 receptor on CD4+ T-cells.
“Those HIV-positive persons categorised into the low genetic risk group did the best on HAART. In contrast, those categorised into the high genetic risk group initially did fine during the first two years of therapy, but then their immune reconstitution failed and their CD4 cell counts began to decline,” Dr. Matthew Dolan of the Uniformed Services University, Bethesda, said.
The researchers also looked at the interaction between genetic profile and CD4 cell count at the time treatment started. In those who started treatment with a CD4 cell count below 350, even a genetic profile classified as `moderate` risk resulted in a diminished CD4 cell recovery rate.
Every 50-cell decrease in the CD4 level at which treatment was initiated resulted in a correspondingly poorer recovery rate in the `moderate` and `high risk` groups. The same was not true in those who started treatment at a CD4 count above 350.
“The current debate about when to initiate antiretroviral therapy might need to be redirected toward first assessing who should be considered for therapy, on the basis of the host genetic endowment,” Dr. Ahuja commented.
Capt. Gregory Martin, programme director for the Infectious Diseases Clinical Research Program at the Uniformed Services University, said, “The finding that CCL3L1-CCR5 genetic makeup has its greatest impact on immune recovery when persons were started on therapy with CD4 counts of less than 350 cells/mm3 highlights the importance of starting persons on therapy earlier rather than later.”
The CD4 cell restoration was more closely associated with number of copies of CCL3L1 than with CCR5 status. “This suggests that drugs that mimic or amplify the activity of CCL3L1 could be effective for HIV treatment,” Dr. Dolan said.
Ahuja SK et al. CCL3L1-CCR5 genotype influences durability of immune recovery during antiretroviral therapy of HIV-1-infected individuals. Nature Medicine, advance online publication, March 30 2008.