The goal of R01DA013324 renewal is to investigate the host genetic basis for hepatitis B virus (HBV) recovery in persons living with and without HIV. We propose to renew R01013324 to fill in the missing knowledge on host genetic basis for HBV recovery and to extend that work by detailed studies of host and virus. To this end, Aim 1 focuses on discovering novel genetic variants in a panel of African ancestry individuals by comparing single nucleotide polymorphisms (SNP) from existing genome wide association studies (GWAS) data in persons with HBV recovery (N=8667) and with chronic hepatitis B (CHB) (N=1594). The inclusion of persons living with HIV (PLWH) allows comparisons of mechanisms of recovery based on HIV. Aim 2 follows by performing a trans-ethnic GWAS analysis using the African ancestry panel from Aim 1 along with European ancestry individuals from North America and the UK Biobank and with Chinese ancestry individuals. These GWAS data are available through collaborators and will also include PLWH. Aim 3 focuses on integrating the host genomic data from Aims 1 and 2 with viral genomics to understand the influence of the host immune response on the viral genome. Using our developed expertise, we and our team of international collaborators will apply our methodological approaches to HBV recovery. Because CHB is the leading cause of liver disease and hepatocellular carcinoma and a leading cause of morbidity and mortality in PLWH, discovering a functional cure has important public health implications.