Sex differences in modulating HIV/SIV reservoirs in the context of opioids

Abstract Due to the widespread use of antiretroviral therapy, HIV replication is effectively controlled in infected individuals. However, viral reservoirs form early post-infection, posing a persistent challenge to complete virus eradication. It has been suggested that sex differences may influence the establishment of HIV reservoirs, with variations between women and men attributed to socio-economic and biological factors, a phenomenon further compounded by opioid use. Established knowledge indicates that women are more susceptible to HIV acquisition than men due to robust estrogen receptor signaling. Despite this, women tend to exhibit lower viral loads and more robust antiviral responses than men, potentially contributing to differences in the size of viral reservoirs. Moreover, opioid abuse remains a significant problem among HIV-infected individuals, with common opioids like morphine implicated in differentially augmenting SIV/HIV persistence within the Central Nervous System (CNS) and periphery. The overarching goal of this proposal is to explore the role of sex differences in the establishment and maintenance of HIV/SIV reservoirs in the context of substance use. Preliminary studies using SIV-infected rhesus macaques as a model of HIV infection demonstrate that chronic use of morphine modulates SIV reservoirs differentially. Higher reservoir sizes are observed in CNS-derived microglial cells compared to peripheral PBMC and lymph nodes in animals exposed to morphine, as opposed to control animals. However, systematic studies are needed to document these differences comprehensively. To address this question, we plan to utilize age/sex-matched rhesus macaques and unique reagents prepared in our laboratory. This involves employing a well-established model of the SIVmac251 virus, which has been previously used to generate preliminary data, demonstrating efficient replication in both the CNS and periphery. The proposed research aims to delineate the role of sex factors in seeding and establishing viral reservoirs (Aim 1). Subsequently, we will determine the location, abundance, and persistence of viral reservoirs in the context of opioid dependence. Modeling simulations will be performed to understand the differences between establishing reservoirs in males and females (Aim 2). These studies are expected to reveal whether sex differences play a significant role in establishing reservoirs in people living with HIV infection (PLWH) in the setting of opioid usage. This information will be valuable for designing effective HIV cure strategies.