The role of neutralizing antibodies in natural and treatment-induced control of hepatitis B with and without HIV-1 co-infection

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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 (NAbs), B cell repertoires, and monoclonal antibodies that develop after acute hepatitis B infection or after treatment-induced control of infection. This proposal will study 185 persons (74 HIV+) in the MACS-WIHS Combined Cohort Study who had acute hepatitis B while in follow- up and whose outcome of either spontaneous control (n=163) or chronic infection (n=22) was previously determined. We will also study an additional 21 participants with functional cure while on HBV treatment (treatment-induced control). The first Aim focuses on plasma NAb responses during and 30 months after spontaneous control of acute HBV infection in persons with and without HIV infection. We hypothesize that in persons with HIV (PWH), 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. We will also assess plasma NAbs in participants with treatment-induced control of infection. We hypothesize that these participants will demonstrate high NAb titers similar to those with spontaneous control of acute infection. In the second Aim, we will isolate HBV surface antigen (HBsAg)-specific B cells from specimens obtained during acute infection or before and after treatment-induced control. We will compare the molecular features of HBsAg-specific B cell receptors between those with spontaneous control of acute infection, those who develop chronic hepatitis B, and those with treatment-induced control of infection. We will also determine the effects of HIV on these molecular features. In the third Aim, we will clone monoclonal antibodies (mAbs) from these HBsAg-specific B cells and determine the mAbs’ functional characteristics. We expect that the mAbs from persons with spontaneous control of acute infection will bind with higher affinity and neutralize more potently than those who develop chronic infection, and that post-control mAbs from treatment- induced controllers will be more potent than pre-control mAbs. We also expect that HIV will decrease the affinity and potency of anti-HBs mAbs. Innovative aspects of this project include: 1) The unique cohort with a large number of incident HBV infections with either spontaneous control or viral persistence in people living with and without HIV infection, as well as rare individuals with treatment-induced control of HBV, 2) The ability to detect NAb responses in plasma from human subjects, and 3) The ability to isolate HBsAg-specific B cells for ex vivo study. To date, such studies have not been possible, explaining why there is little information on NAb responses in HBV-infected humans. Results from this proposal will contribute to our understanding of the effects of HIV on the immune response to hepatitis B and could facilitate development of a functional cure for hepatitis B, the leading cause of cirrhosis and hepatocellular carcinoma worldwide.