Increases in CSF dopamine in HIV patients are due to the dopamine transporter 10/10-repeat allele which is more frequent in HIV-infected individuals

Abstract

Dysfunction of dopaminergic neurotransmission has been implicated in HIV infection. We showed previously increased dopamine (DA) levels in CSF of therapy-naïve HIV patients and an inverse correlation between CSF DA and CD4 counts in the periphery, suggesting adverse effects of high levels of DA on HIV infection. In the current study including a total of 167 HIV-positive and negative donors from Germany and South Africa (SA), we investigated the mechanistic background for the increase of CSF DA in HIV individuals. Interestingly, we found that the DAT 10/10-repeat allele is present more frequently within HIV individuals than in uninfected subjects. Logistic regression analysis adjusted for gender and ethnicity showed an odds ratio for HIV infection in DAT 10/10 allele carriers of 3.93 (95% CI 1.72-8.96; p = 0.001, Fishers exact test). 42.6% HIV-infected patients harbored the DAT 10/10 allele compared to only 10.5% uninfected DAT 10/10 carriers in SA (odds ratio 6.31), whereas 68.1 versus 40.9%, respectively, in Germany (odds ratio 3.08). Subjects homozygous for the 10-repeat allele had higher amounts of CSF DA and reduced DAT mRNA expression but similar disease severity compared with those carrying other DAT genotypes. These intriguing and novel findings show the mutual interaction between DA and HIV, suggesting caution in the interpretation of CNS DA alterations in HIV infection solely as a secondary phenomenon to the virus and open the door for larger studies investigating consequences of the DAT functional polymorphism on HIV epidemiology and progression of disease.

Fig. 1

Distribution of the DAT polymorphism in German (GER) and South African (SA) populations and its association with the HIV infection. a Distribution of different DAT polymorphisms in Germany with 94 individuals. b Distribution of different DAT polymorphisms in SA with 73 individuals. c DAT alleles in uninfected (n = 22) and HIV-infected (n = 72) study participants in Germany (p = 0.0266, Fisher’s exact test). d DAT alleles in uninfected (n = 19) and HIV-infected (n = 54) study participants in SA (p = 0.0121, Fisher’s exact test). e Risk of acquiring HIV infection associated with the different DAT genotypes. Odds ratios for HIV infection are shown in diamonds ±95 % confidence intervals. Polymorphisms associated with an increased infection risk are shown in red, polymorphisms associated with a reduced infection risk are shown in green. In addition to a separate analysis of the odds ratios for each study group, the 10/10 and 9/10-repeat alleles are also depicted as pooled data from the two study groups

Fig. 2

Participants carrying the DAT 10/10-repeat allele have higher levels of CSF DA compared with those with 9/10-repeat allele. DA concentration in CSF of German participants with 10/10-repeat allele (n = 55) and 9/10-repeat allele (n = 28). Box plots show the medians with upper and lower quartiles. *p = 0.03, significantly different from 9/10-repeat allele carriers (Mann–Whitney U test for non-parametric distributed values)

Fig. 3

Participants carrying the DAT 10/10-repeat allele have reduced levels of PBMC DAT mRNA expression compared with those with other DAT alleles. a DAT mRNA expression in PBMC of SA uninfected (n = 17) and HIV-infected subjects (n = 37); b DAT mRNA expression in PBMC of SA with DAT 10/10 (n = 17) and 9/10-repeat allele (n = 14); c DAT mRNA expression in PBMC of SA with DAT 10/10 (n = 17) compared with other DAT alleles (3/7, 3/9, 3/10, 7/9, 9/9, 7/10, 8/10, 9/10 and 10/11; n = 37). *p = 0.05, significantly different from DAT other allele carriers (Mann–Whitney U test for non-parametric distributed values)