Changes of methylation at enhancers appear to be essential for HIV infection progression

We studied the influence of the European HIV-1 subtype B (most common in the Western and central Europe) and subtype A6 (prevalent in Eastern Europe including Ukraine and Russia) on host methylome during infection progression and in virus subtype specific manner. Our results show that regardless of virus subtype in the beginning of the infection HIV related methylation changes more frequently affect parts of the genome with low expression activity including heterochromatin and quiescent regions. However, the analysis of the methylomes of blood cells of PLWH at stage four of the infection showed that with the infection progression genomic regulatory elements that harbour infection related methylation changes are enhancers. We further showed that the effect of each of the virus subtype on host methylome is to a large extent similar and in general involve hypomethylation of loci associated with key pathways involved in viral infection. But our results also indicate that each of the virus subtype appears to at least to some extent affect host methylome in virus subtype specific manner. Most importantly we showed that progression related methylation changes that we identified are reversed with ART therapy. The study included 24 antiretroviral treatment naïve people with HIV, representing four equally sized (n = 6) groups stratified based on virus subtype (A6 and B) and WHO HIV disease stage (I/HIV and IV/AIDS).