Complement-Opsonized HIV Modulates Pathways Involved in Infection of Cervical Mucosal Tissues: A Transcriptomic and Proteomic Study

Abstract

Genital mucosal transmission is the most common route of HIV spread. The initial responses triggered at the site of viral entry are reportedly affected by host factors, especially complement components present at the site, and this will have profound consequences on the outcome and pathogenesis of HIV infection. We studied the initial events associated with host-pathogen interactions by exposing cervical biopsies to free or complement-opsonized HIV. Opsonization resulted in higher rates of HIV acquisition/infection in mucosal tissues and emigrating dendritic cells. Transcriptomic and proteomic data showed a significantly more pathways and higher expression of genes and proteins associated with viral replication and pathways involved in different aspects of viral infection including interferon signaling, cytokine profile and dendritic cell maturation for the opsonized HIV. Moreover, the proteomics data indicate a general suppression by the HIV exposure. This clearly suggests that HIV opsonization alters the initial signaling pathways in the cervical mucosa in a manner that promotes viral establishment and infection. Our findings provide a foundation for further studies of the role these early HIV induced events play in HIV pathogenesis.

Complement contributes to antibody-mediated protection against repeated SHIV challenge

“…Because studies in NHP have shown that the importance of effector functions vary among bNAbs, and because the sole NHP experiment probing the contribution complement activation alone was conducted in the context of a bNAb without potent complement activity ( 30 , 39 , 40 ), we sought to revisit the contribution of antibody-mediated complement activation on bNAb efficacy using a bNAb with high activity ( 39 , 40 ). While the role of complement in HIV protection and pathogenesis has been rigorously studied and debated for decades, data present a complicated picture ( 27 , 33 , 38 , 63 – 78 ). Importance is both illustrated and equivocated based on the complement evasion mechanisms that have been developed by the virus ( 39 , 79 ).…”

The initial interplay between HIV and mucosal innate immunity

“…However, activation of the complement system from host-HIV interaction is mainly investigated as it makes HIV more accessible to host cells ( 246 ). In fact, complement opsonization of HIV results in higher infectivity and viral transfer from DCs to T cells in a CR3 and DC-SIGN-dependent matter ( 247 ), but also transfer from Langerhans cells ( 248 ) and causes a higher expression of genes and proteins involved in viral replication and other aspects of the infection ( 249 ). Moreover, opsonization reduces antiviral and inflammatory responses compared to free HIV ( 250 , 251 ).…”