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CCL3L1-CCR5 genotype influences durability of immune recovery during antiretroviral therapy of HIV-1–infected individuals

Abstract

The basis for the extensive variability seen in the reconstitution of CD4+ T cell counts in HIV-infected individuals receiving highly active antiretroviral therapy (HAART) is not fully known. Here, we show that variations in CCL3L1 gene dose and CCR5 genotype, but not major histocompatibility complex HLA alleles, influence immune reconstitution, especially when HAART is initiated at <350 CD4+ T cells/mm3. The CCL3L1-CCR5 genotypes favoring CD4+ T cell recovery are similar to those that blunted CD4+ T cell depletion during the time before HAART became available (pre-HAART era), suggesting that a common CCL3L1-CCR5 genetic pathway regulates the balance between pathogenic and reparative processes from early in the disease course. Hence, 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. Furthermore, as reconstitution of CD4+ cells during HAART is more sensitive to CCL3L1 dose than to CCR5 genotypes, CCL3L1 analogs might be efficacious in supporting immunological reconstitution.

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Figure 1: Influence of CCL3L1-CCR5 genotypes on CD4+ T cell dynamics in the WHMC HIV+ cohort.
Figure 2: Influence of CCL3L1-CCR5 on CD4+ recovery in subjects initiating HAART during acute or early infection (AIEDRP cohorts, ac) and impact of the timing of HAART on effects of CCL3L1-CCR5 on CD4+ recovery in the WHMC cohort (d,e).
Figure 3: Influence of HLA alleles on early events and CD4+ T cell dynamics in subjects from the WHMC HIV+ cohort.

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Acknowledgements

The people and funding agencies that made this work possible are listed in the Acknowledgements section in the Supplementary information online.

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S.K.A., H.K. and M.J.D. conceptualized the research, conducted statistical analyses, analyzed the data and wrote the manuscript. G.C., B.K.A., J.F.C., W.H., R.J.O., V.C.M., J.D., J.E., R.A.C., S.F., J.M., S.S.A., S.G.D., S.L., D.R., and F.M.H. made substantial contributions to conceptual ideas, experimental data, analysis of data, preparation of the manuscript and/or cohort data and development. S.K.A. and M.J.D. directed the study and obtained the funding for the genetic work.

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Correspondence to Sunil K Ahuja or Matthew J Dolan.

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Ahuja, S., Kulkarni, H., Catano, G. et al. CCL3L1-CCR5 genotype influences durability of immune recovery during antiretroviral therapy of HIV-1–infected individuals. Nat Med 14, 413–420 (2008). https://doi.org/10.1038/nm1741

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