Neutralizing antibody responses during natural control of acute hepatitis B with and without HIV-1 coinfection

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.

Grant Number: 5R01AI162094-04
NIH Institute/Center: NIH
Principal Investigator: Justin Bailey