Investigators
looked at variations in the CCR5 gene, which controls expression of the CCR5 co-receptor
on surfaces of CD4 cells, in a large cohort of HIV positive patients. HIV uses
CCR5 or another co-receptor, CXCR4, to enter cells. CCR5 antagonists such as maraviroc (Selzentry) work
by blocking this process. The researchers also assessed the number of copies of
the CCL3L1 gene, which encode a protein that binds to CCR5 and suppresses HIV.
Prior
research has shown that variations in the CCR5 and CCL3L1 genes predicted more
rapid immune system decline in the pre-HAART era. In the current study, the investigators
assessed whether the same genes also influenced immunological response to therapy.
Based on their genetic profiles, participants were classified as high, moderate,
or low risk.
Results
•
Both variations in expression of the
CCL3L1 gene and CCR5 genotype influenced the speed and extent of CD4 cell reconstitution.
•
This was especially apparent when
HAART was initiated with a CD4 count below 350 cells/mm3.
•
By contrast, major histocompatibility
complex HLA (human leukocyte antigen)
variations did not have an effect on CD4 cell recovery.
•
The CCL3L1 and CCR5 genotypes favoring
CD4 cell recovery were similar to those associated with less severe CD4 cell depletion
in the pre-HAART era.
•
High-risk participants tended to do
well after starting anti-HIV treatment, but immune recovery faltered after 2 years
on therapy.
Conclusion
“CCL3L1-CCR5
variations influence HIV pathogenesis even in the presence of HAART and, therefore,
may prospectively identify subjects in whom earlier initiation of therapy is more
likely to mitigate immunologic failure despite viral suppression by HAART,” the
researchers concluded.
They
noted that since similar genetic variations are associated with both CD4 cell
decline in the absence of HAART and recovery after starting therapy, this suggests
that “a common CCL3L1-CCR5 genetic
pathway regulates the balance between pathogenic and reparative processes from
early in the disease course.”
Based
on their findings, the study authors suggested that since CD4 cell recovery during
HAART is more sensitive to CCL3L1 dose than to CCR5 genotypes, CCL3L1 analogs
“might be efficacious in supporting immunological reconstitution.”
The
poor immunological response observed in high-risk and even moderate-risk individuals
starting treatment with fewer than 350 CD4 cells/mm3
adds to the growing
body of evidence that earlier initiation of therapy, with a higher
CD4 count, might lead to improved long-term outcomes.
The
results also suggest that in the future, a genetic test might be developed to
predict treatment response and possibly to further tailor antiretroviral regimens
to individual patients.
4/04/08
Reference
SK Ahuja, H Kulkarni, G Catano, and others. CCL3L1-CCR5 genotype influences durability of immune recovery during antiretroviral
therapy of HIV-1-infected individuals. Nature Medicine. March 30, 2008
[Epub ahead of print].
