Evaluating risks of ZIKV co-infection in SIV-infected macaques

PROJECT SUMMARY Over 36 million people are living with HIV and there is large geographic overlap for areas endemic with flavivirus infection. Despite the occurrence of large flavivirus outbreaks, there is a severe lack of knowledge regarding the impact flavivirus infections may have on people living with HIV (PLWH). It is unclear what effect HIV co-infection has on the clinical consequences of flavivirus infection and current studies in humans are limited by low patient numbers and inconsistent incorporation of HIV disease status into interpretations of flavivirus disease. Non- human (NHP) models of Zika virus (ZIKV) infection recapitulate several aspects of human disease and are ideal for evaluating the impact of human flavivirus infection in people living with HIV. However, no established HIV- ZIKV co-infection animal model exists. In this proposal, we will study the natural history of HIV co-infection with flaviviruses to understand the risks, causes, and clinical outcomes in PLWH. Previously in NHPs, we showed that CD16+ monocytes are the major in vivo blood targets of ZIKV and similar results have been found in humans. Monocyte frequencies increase during HIV infection and although ART reduces total frequencies in HIV infected persons, CD16+ monocytes remain elevated. We will investigate the hypothesis that HIV infection promotes susceptibility to flavivirus infection by decreasing anti-viral innate and adaptive immune responses, increasing inflammation, and expanding cellular targets of infection, including monocytes. HIV invasion of the central nervous system (CNS) is mediated by CD16+ monocytes, therefore monocytes could also act to spread ZIKV to the CNS and promote neurological disease. Thus, HIV infection could promote ZIKV pathogenesis and neuroinvasion by expanding the cellular target pool and inducing inflammation. Additionally, we hypothesize that enhanced ZIKV pathogenesis occurs in PLWH, and we will experimentally test this using an NHP model of SIV infection. Specifically, in Aim 1 we will evaluate whether cells from SIV infected animals support greater ZIKV replication. In Aim 2 we will determine whether ZIKV pathogenesis is enhanced in SIV-infected macaques. We will determine whether SIV infection promotes invasion of ZIKV into the CNS and determine the innate and adaptive immune responses corresponding to enhanced infection. These studies will provide significant insights into the potential risk of enhanced ZIKV pathogenesis in the HIV population and determine if PLWH have a greater risk of ZIKV-associated pathologies. The goal of this K01 is to support the transition of developing my own independent research program focused on understanding the impact of viral co-infections in PLWH. In order to achieve this goal I will expand upon my previous training using NHP models of HIV and ZIKV human infection, will leverage the resources at the University of Washington and the Washington National Primate Research Center, and will work closely with my mentors, Dr. Deborah Fuller and Dr. Michael Gale.