Summary This proposal aims to understand the effects of HIV on the humoral immune response to hepatitis B by focusing on HBV-specific neutralizing antibodies (NAb), B cell repertoire, and monoclonal antibodies that develop after an acute hepatitis B infection. This proposal will study 185 men (74 HIV+) in the MACS-WIHS Combined Cohort Study who had acute hepatitis B while in follow-up and whose outcome of either natural recovery (n=163) or viral persistence (n=22) was previously determined. The first Aim focuses on comparing the prevalence and magnitude of the anti-HBs NAb responses over 30 months after natural control of an acute HBV infection in people living with and without HIV. We hypothesize that in persons living with HIV (PLWH), the NAb responses will be weaker and less durable than in persons without HIV infection. Decreased durability of NAb responses could contribute to the increased risk of HBV reactivation with HIV infection. In the second Aim, we will tag HBV specific B cells isolated from participants’ specimens obtained during their acute infection period. We will then determine and compare the molecular features of HBV-specific B cell receptors during the acute infection period between those with natural recovery and those who develop chronic hepatitis B. We will also determine the effects of HIV on these molecular features and on frequency of B cells specific for HBV. In the third Aim, we will clone monoclonal antibodies (mAbs) from these HBV-specific B cells and determine the mAbs’ functional characteristics and binding affinities. We expect that the mAbs from persons with natural recovery will bind with higher affinity and neutralize more potently than those who develop chronic infection. We also expect that HIV will decrease the affinity and potency of the mAbs. Innovative aspects of this project include: 1) The unique cohort of a large number of incident HBV infections where both natural recovery and viral persistence occur in prospectively-followed people living with and without HIV infection, 2) The ability to detect NAb responses in plasma from human subjects using the HepG2-NTCP infection model system, and 3) The ability to isolate HBV-specific B cells for ex vivo study. To date, such studies have not been possible explaining why there is little information on NAb responses to HBV obtained directly from infected humans. The results from this proposal will contribute to our understanding of the effects of HIV on the immune response to hepatitis B and could facilitate future research to develop a functional cure for hepatitis B, which is the leading cause of cirrhosis and hepatocellular carcinoma worldwide.