Anti-SAMHD1 monoclonal antibody, clone 5C6.2

Background The use of the HIV antiretroviral drug stavudine (d4T), a thymidine analogue, is associated with the development of mitochondrial toxicities such as sensory neuropathy (SN). Genetic variation in genes relating to d4T transport and metabolism, as well as genetic variation in the thymidine synthesis pathway, could influence occurrence of d4T-related toxicity. Methods We examined this hypothesis in a cohort of HIV-positive South African adults exposed to d4T, including 143 cases with SN and 120 controls without SN. Ten SNPs in four genes associated with stavudine transport, and 16 SNPs in seven genes of the thymidine synthesis / phosphorylation pathway were genotyped using Agena mass spectrometry methods. Associations between sensory neuropathy and genetic variants were evaluated using PLINK by univariate and multivariable analyses. Result Age and height were significantly associated with SN occurrence. Using logistic regression with age and height as covariates, and uncorrected empirical p-values, genetic variation in SLC28A1, SAMHD1, MTHFR and RRM2B was associated with SN in South Africans using d4T. Conclusion Variation in genes relating to d4T transport and metabolism, as well as genetic variation in the thymidine synthesis pathway may influence occurrence of d4T-related SN. These data PLOS contribute to the characterisation of African pharmacogenetic variation and its role in adverse response to antiretroviral therapy.

Interferon (IFN) plays a central role in regulating host immune response to viral pathogens through the induction of IFN-Stimulated Genes (ISGs). IFN also enhances cellular SUMOylation and ISGylation, though the functional interplay between these modifications remains unclear. Here, we used a system-level approach to profile global changes in protein abundance in SUMO3-expressing cells stimulated by IFN alpha. These analyses revealed the stabilization of several ISG factors including SAMHD1, MxB, GBP1, GBP5, Tetherin/BST2 and members of IFITM, IFIT and IFI families. This process was correlated with enhanced IFN alpha-induced anti-HIV-1 and HSV-1 activities. Also IFN alpha upregulated protein ISGylation through increased abundance of E2 conjugating enzyme UBE2L6, and E3 ISG15 ligases TRIM25 and HERC5. Remarkably, TRIM25 depletion blocked SUMO3-dependent protein stabilization in response to IFN alpha. Our data identify a new mechanism by which SUMO3 regulates ISG product stability and reinforces the relevance of the SUMO pathway in controlling both the expression and functions of the restriction factors and IFN antiviral response.