The Effects of Human Immunodeficiency Virus (HIV) Infection on Host DNA Methylation and Plasma Microbiome

The global dissemination of human immunodeficiency virus (HIV) has been a continuing health threat to mankind after 30 years since its discovery. At the same time, the next-generation sequencing has transformed today's research. In this study, we have made use of the next-generation high-throughput sequencing technology to study two aspects of HIV-1 induced biological changes. The HIV-associated DNA methylation was elucidated by comparing the DNA methylation pattern of T-lymphocytes between HIV-infected and uninfected identical twins. We found that genes regulating RNA splicing and cell cycle regulation were hypo-methylated whereas the genes regulating nerve functions and signal transduction were hypermethylated. The molecular study suggested that HIV-1 increases the transcription level of DNA methyltransferase (DNMT) 3A but not the DNMT1 or DNMT3B. The up-regulation of DNMT3A was not associated with the methylation of HIV-1 promoter LTR and latency in chronically infected cells with actively replicating viruses. In studying the more advanced HIV disease with AIDS and opportunistic infections, HIV/AIDS patients with very low CD4+ T-cell counts were recruited. We have profiled the plasma microbiome and virome of these AIDS patients in parallel with healthy adults. HIV/AIDS plasma microbiome was dominated by bacteria from the order Pseudomonadales while healthy control subjects carried few bacterial DNA in the blood. We have found that many of the microbes in HIV/AIDS plasma are similar to some of the microbes found in the human gut. The HIV/AIDS and normal plasma virome share some similarity in the presence of common ubiquitous eukaryotic viruses. The normal virome was mainly composed of viruses from Anelloviridae. The HIV/AIDS viromes was contrasted by the presence of a large proportion of bacteriophages, typical eukaryotic viruses and untypical non-human viruses. In addition, by means of sequencing, we have found several sequences which might belong to novel bacteria or endogenous retroviruses. The results described in this thesis manifest the use of the high-throughput technology in studying cellular genome and microbial metagenomics. The insights gained into the HIV-associated DNA methylation and the specific spectrum of microbes found in these patients may facilitate future research studies in combating HIV/AIDS.