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Genetic variations in the host dependency factors ALCAM and TPST2 impact HIV-1 disease progression.

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 analyzed whether naturally occurring genetic variations were associated with the clinical course of infection.


DESIGN/METHODS
Single nucleotide polymorphisms (SNP) in ALCAM and TPST2 were analyzed in a cohort of 304 HIV-1 infected MSM 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 analyze 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.


CONCLUSIONS
Our data demonstrates 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.