Abstract

Background: HBV and HIV are both major global health concerns as HBV infects 296 million people while HIV infects 38 million individuals worldwide. HIV/HBV co-infection is common due to similar routes of transmission, with an estimated 10% of HIV-infected individuals also infected with HBV. HIV/HBV co-infected individuals progress to chronic HBV infection more frequently and exhibit reduced HBV-specific T cell responses, with a higher probability of extensive liver fibrosis and hepatocellular carcinomas. Thus, a greater understanding of the interplay between HIV and HBV infections is urgently needed to design strategies to prevent accelerated liver disease. Rhesus macaques (RM) are a well-established non-human primate model for HIV research, and we discovered recently that antibody-mediated CD4⁺ T cell depletion in RM leads to long-term, high-titer HBV replication. In this study, we investigated the potential of inducing natural CD4⁺ T cell depletion via SHIV_{DH12 Clone 7} infection and using it to establish HIV/HBV co-infection in RM.

Methods: Animals were intravenously infected with SHIV_{DH12 Clone 7} (5x10³ TCID₅₀) and then three weeks later challenged with HBV (genotype D, 1x10⁹ virions, i.v). Weekly blood draws were taken to monitor HBV and SHIV infection, and track CD4⁺ T cells and HBV surface antigens (HBsAg). Liver biopsies were obtained every four weeks to quantify HBV replication in the liver by quantitative PCR. Serum chemistries were run weekly to monitor metabolic changes in the liver associated with co-infection.

Results: Preliminary studies showed successful CD4⁺ T cell depletion in two RM following SHIV infection. However, one RM controlled SHIV infection (Mamu-B*08⁺) and CD4⁺ T cells returned concurrent with clearance of HBV. The second RM exhibited SHIV (>10⁵ copies/ml) and HBV (>10⁴ copies/ml) chronic co-infection (>24 weeks). HBV infection was validated by the presence of HBsAg and HBV DNA in the serum and HBV RNA in the liver. Based on the preliminary results, we repeated the study with nine additional animals and found that four exhibited a similar trend of co-infection.

Conclusion: These results indicate that SHIV-mediated CD4⁺ T cell depletion helps sustain HBV infection. Thus, we show for the first time an HIV/HBV co-infection model in RM that can be beneficial for studies investigating pathogenesis associated with co-infection; which will be critical for the further development of this model.