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Two Genetic Variants Linked to HIV Treatment Response

NEW YORK (GenomeWeb News) – New research suggests that variants in two genes can help predict an individual’s response to an HIV treatment aimed at decreasing viral load and bolstering immune system function.
American researchers found that copy number variation and genotype, respectively, for genes called CCL3L1 and CCR5, influenced CD4+ T-cell immune system recovery in response to highly active antiretroviral therapy (HAART). The work, published in the advanced online version of Nature Medicine yesterday, may ultimately have applications for personalizing HIV treatments, particularly for deciding when they should be initiated.
“The new results suggest that we may be able to personalize the treatment of HIV as we might be able to predict, based on the presence of these gene variations, whether someone will have a better or worse immunological response when taking HAART,” lead author Sunil Ahuja, an infectious disease researcher with the University of Texas and the South Texas Veterans Health Care System, said in a statement.
HAART has been available since the mid-1990 and works by targeting and suppressing HIV replication. Ideally, this should result in better immune cell function, as measured, in part, by better CD4+ T-cell counts.
But not everyone responds equally to the treatment. Some see dramatic improvements in immune response while others exhibit only weak immune system recovery.
For this study, Ahuja and colleagues were interested in determining whether certain genes influence CD4+ depletion and recovery. In particular, they focused on CCR5, a gene coding for an HIV co-receptor that’s used by the virus to gain entry into human CD4+ cells, and CCL3L1, which codes for a molecule that binds the receptor and suppresses HIV. Both genes were previously shown to influence HIV and AIDS susceptibility, early immune damage upon HIV infection, and HIV progression.
Using a prospective, observational cohort, based at the Wilford Hall Medical Center in Texas, the researchers gathered data collected between the mid-1980s and 2005. Consequently, they had information about the influence of CCL3L1 and CCR5 variants on CD4+ counts and disease progression both before and after HAART became available in the mid-1990s.
The team found copy number variants in the CCL3L1 gene and CCR5 genotype both affected HAART response. For individuals of European and African descent, having more copies of CCL3L1 was associated with better CD4+ recovery. And CCL3L1 seemed to have a greater role in CD4+ recovery than CCR5.
“This suggests that drugs that mimic or amplify the activity of CCL3L1 may be very effective,” said senior author Matthew Dolan, an infectious disease researcher affiliated with the Uniformed Services University in Bethesda, Md., the Wilford Hall United States Air Force Medical Center, and the San Antonio Military Medical Center.
Even so, CCL3L1 and CCR5 seemed to have additive effects. In other words, it was more detrimental to have both low CCL3L1 dose and the CCR5 genotype than low CCL3L1 dose alone.
In the study, the researchers were able to classify subjects as having low, moderate, or high genetic risk. Those in the high genetic risk groups were not only more likely to have rapid CD4+ cell count depletion in the years before HAART was available, but also impaired CD4+ recovery during HAART, even if they did have viral load suppression. 
Subjects with low genetic risk factors generally had higher CD4+ cell counts going into HAART during acute or early infection and showed better CD4+ cell recovery in response to the treatment. The genetic effect was particularly influential when CD4+ counts before therapy had dropped below 350 cells per cubic millimeter.
On the other hand, HLA alleles, which code for the major histocompatibility complex, do not seem to influence how well the immune system bounces back in response to HAART, suggesting the genetic effects are specific and not simply a reflection of viral load.
“[A]lthough both CCL3L1-CCR5 genotype and HLA alleles affect the extent of early immune damage and HIV disease progression independently of viral load … only variations in the CCL3L1-CCR5 axis influence recovery of CD4+ counts,” the authors wrote.
In the future, the results may help determine how and when HAART should be used. “[T]he current debate about when to initiate antiretroviral therapy might need to be redirected toward first assessing for whom therapy should be considered, on the basis of host genotype,” the authors wrote.

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