TY - JOUR
T1 - Genetic variations in the host dependency factors ALCAM and TPST2 impact HIV-1 disease progression
AU - Kruize, Zita
AU - Maurer, Irma
AU - Boeser-Nunnink, Brigitte D. M.
AU - Booiman, Thijs
AU - Kootstra, Neeltje A.
PY - 2020/7/15
Y1 - 2020/7/15
N2 - OBJECTIVES: Recently, the activated leukocyte cell adhesion molecule (ALCAM) and tyrosylprotein sulfotransferase 2 (TPST2) have been identified as important host dependency factors (HDFs) for in-vitro HIV-1 replication. To determine whether these genes play a role in HIV-1 pathogenesis, we analysed whether naturally occurring genetic variations were associated with the clinical course of infection. DESIGN/METHODS: Single nucleotide polymorphisms (SNPs) in ALCAM and TPST2 were analysed in a cohort of 304 HIV-1-infected men who have sex with men and survival analysis was used to determine their effect on the outcome of untreated HIV-1 infection. Flowcytometry was used to determine the effect of SNPs on CD4 T-cell activation prior to HIV-1 infection and 1 and 5 years after infection. In-vitro HIV-1 infections were performed to analyse the effect of the SNPs on HIV-1 replication. RESULTS: We observed that the minor allele of rs1344861 in ALCAM was associated with accelerated disease progression, whereas the minor allele of rs9613199 in TPST2 was associated with delayed disease progression. In-vitro infection assays did not demonstrate any differences in HIV-1 replication associated with rs9613199. However, the increase in CD4 T-cell immune activation levels during HIV-1 infection was less pronounced in infected individuals homozygous for rs9613199, which is in agreement with delayed disease progression. CONCLUSION: Our data demonstrate that ALCAM and TPST2 play a role in HIV-1 pathogenesis. SNPs in these genes, without known functional implications, had a major effect on disease progression, and therefore, these HDFs may be attractive and effective targets for new treatment strategies.
AB - OBJECTIVES: Recently, the activated leukocyte cell adhesion molecule (ALCAM) and tyrosylprotein sulfotransferase 2 (TPST2) have been identified as important host dependency factors (HDFs) for in-vitro HIV-1 replication. To determine whether these genes play a role in HIV-1 pathogenesis, we analysed whether naturally occurring genetic variations were associated with the clinical course of infection. DESIGN/METHODS: Single nucleotide polymorphisms (SNPs) in ALCAM and TPST2 were analysed in a cohort of 304 HIV-1-infected men who have sex with men and survival analysis was used to determine their effect on the outcome of untreated HIV-1 infection. Flowcytometry was used to determine the effect of SNPs on CD4 T-cell activation prior to HIV-1 infection and 1 and 5 years after infection. In-vitro HIV-1 infections were performed to analyse the effect of the SNPs on HIV-1 replication. RESULTS: We observed that the minor allele of rs1344861 in ALCAM was associated with accelerated disease progression, whereas the minor allele of rs9613199 in TPST2 was associated with delayed disease progression. In-vitro infection assays did not demonstrate any differences in HIV-1 replication associated with rs9613199. However, the increase in CD4 T-cell immune activation levels during HIV-1 infection was less pronounced in infected individuals homozygous for rs9613199, which is in agreement with delayed disease progression. CONCLUSION: Our data demonstrate that ALCAM and TPST2 play a role in HIV-1 pathogenesis. SNPs in these genes, without known functional implications, had a major effect on disease progression, and therefore, these HDFs may be attractive and effective targets for new treatment strategies.
UR - http://www.scopus.com/inward/record.url?scp=85087320665&partnerID=8YFLogxK
U2 - https://doi.org/10.1097/QAD.0000000000002540
DO - https://doi.org/10.1097/QAD.0000000000002540
M3 - Article
C2 - 32287057
SN - 0269-9370
VL - 34
SP - 1303
EP - 1312
JO - AIDS (London, England)
JF - AIDS (London, England)
IS - 9
ER -