According to the WHO, HIV/AIDS is the leading cause of death among women of reproductive age, worldwide and adolescent girls and young women are twice as likely to be at risk of HIV infection compared to boys and young men. Thus, there is an urgency to find new, effective ways to fight HIV transmission in women. Knowledge of how transmission occurs and of the early viral-host dynamics that determine susceptibility to vaginal HIV infection is critical for the development of novel strategies to fight HIV transmission and/or halt disease progression. During the past 4 years, we determined that ?4?7+ cells play an important role in HIV infection, that their availability is an important susceptibility factor and that ?4?7 activation may have a previously unrecognized role in viral spread, especially early after transmission. Indeed, Act-1, a primatized mAb that inhibits ?4?7 activation and blocks ?4?7? s interactions with its ligands, is able to protect from SIV vaginal infection 50% of challenged macaques and protects from disease progression all the animals that become infected. The primary goal of this proposal is to understand the mechanisms of protection of Act-1. We will address the questions of how Act-1 protects from SIV acquisition and how it changes the early viral-host dynamics so that the animals that become infected remain healthy. In answering these questions, we will also learn more of the process of vaginal SIV infection and the factors that may impact susceptibility. We will address Act-1?s mechanism of action (MOA) both in vitro and in vivo. Specifically, in vitro we will study how Act-1 can interfere with the ?4?7-driven formation of virological synapses and viral transfer from stromal cells to CD4+ T cells and the importance of ?4?7 as co-stimulatory molecule. In vivo, we will explore Act-1?s ability to interfere with cell trafficking and cell activation in tissues in presence and absence of SIV challenge. Finally, we will address if Act-1?s effect is modified by increased ?4?7 availability due to HSV-2 infection. Indeed, we have previously demonstrated that HSV-2 increases the frequency of CD4+ T cells expressing high levels of ?4?7 and this is associated with increased susceptibility to SHIV. Our studies will shed light on a novel and promising anti-HIV strategy, while increasing our understanding of mucosal biology, response to HIV within mucosal and lymphoid tissues and early events that influence the fate of the virus after mucosal exposure.
The rates of vaginal HIV transmission are extremely high, while we are still missing an effective prevention strategy that could help curb the HIV epidemic especially in young women. This proposal seeks a better understanding of a promising HIV prevention strategy through studies that have the potential to reveal new insights into the mechanisms of vaginal HIV transmission and disease progression.