Abstract
HIV-associated sensory neuropathy (HIV-SN) is a debilitating neurological complication of HIV infection potentiated by the antiretroviral drug stavudine. While stavudine is no longer used, HIV-SN now affects around 15% of HIV+ Indonesians. Here, we investigate whether polymorphisms within the P2X-block (P2X4R, P2X7R, CAMKK2) and/or ANAPC5 mark susceptibility to HIV-SN in this setting. As polymorphisms in these genes associated with HIV-SN in African HIV patients receiving stavudine, the comparison can identify mechanisms independent of stavudine. HIV patients who had never used stavudine (n = 202) attending clinics in Jakarta were screened for neuropathy using the AIDS Clinical Trials Group Brief Peripheral Neuropathy Screen. Open-array technology was used to type 48 polymorphisms spanning the four genes. Haplotypes were derived for each gene using fastPHASE. Haplogroups were constructed with median-joining methods. Multivariable models optimally predicting HIV-SN were based on factors achieving p < 0.2 in bivariate analyses. Minor alleles of three co-inherited polymorphisms in CAMKK2 (rs7975295*C, rs1560568*A, rs1132780*T) associated with a reduced prevalence of HIV-SN individually and after adjusting for lower CD4 T cell count and viremia (p = 0.0002, pseudo R2 = 0.11). The optimal model for haplotypes linked HIV-SN with viremia and lower current CD4 T cell count, plus CAMKK2 haplotypes 6 and 11 and P2X7R haplotypes 2 and 12 (p = 0.0002; pseudo R2 = 0.11). CAMKK2 haplogroup A (includes 16 haplotypes and all instances of rs7975295*C, rs1560568*A, rs1132780*T) associated with reduced rates of HIV-SN (p = 0.02, OR = 0.43 CI = 0.21–0.88). These findings support a protective role for these three alleles, suggesting a role in the pathogenesis of HIV-SN that is independent of stavudine.
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Acknowledgements
The authors thank the staff and patients of the POKDISUS HIV Care Clinic, Cipto Mangunkusumo Hospital Jakarta Indonesia, Denise D Setiawan and Ahmad Yanuar Safri of Universitas Indonesia for collection and compilation of clinical records and assistance in the laboratory, and Lidija Milicic and Tenielle Porter of Edith Cowan University for their assistance with genotyping.
The authors acknowledge the support of the Australian Government Research Training Program Scholarship, Curtin University and Curtin Health Innovation Research Institute, and the Victorian Operational Infrastructure Support Program received by the Burnet Institute (CLC).
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Gaff, J., Octaviana, F., Ariyanto, I. et al. Polymorphisms in CAMKK2 associate with susceptibility to sensory neuropathy in HIV patients treated without stavudine. J. Neurovirol. 25, 814–824 (2019). https://doi.org/10.1007/s13365-019-00771-w
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DOI: https://doi.org/10.1007/s13365-019-00771-w