Abstract
Tenascin-C (TNC) is a newly identified innate HIV-1-neutralizing protein present in breast milk, yet its presence and potential HIV-inhibitory function in other mucosal fluids is unknown. In this study, we identified TNC as a component of semen and cervical fluid of HIV-1-infected and uninfected individuals, although it is present at a significantly lower concentration and frequency compared to that of colostrum and mature breast milk, potentially due to genital fluid protease degradation. However, TNC was able to neutralize HIV-1 after exposure to low pH, suggesting that TNC could be active at low pH in the vaginal compartment. As mucosal fluids are complex and contain a number of proteins known to interact with the HIV-1 envelope, we further studied the relationship between the concentration of TNC and neutralizing activity in breast milk. The amount of TNC correlated only weakly with the overall innate HIV-1-neutralizing activity of breast milk of uninfected women and negatively correlated with neutralizing activity in milk of HIV-1 infected women, indicating that the amount of TNC in mucosal fluids is not adequate to impede HIV-1 transmission. Moreover, the presence of polyclonal IgG from milk of HIV-1 infected women, but not other HIV-1 envelope-binding milk proteins or monoclonal antibodies, blocked the neutralizing activity of TNC. Finally, as exogenous administration of TNC would be necessary for it to mediate measurable HIV-1 neutralizing activity in mucosal compartments, we established that recombinantly produced TNC has neutralizing activity against transmitted/founder HIV-1 strains that mimic that of purified TNC. Thus, we conclude that endogenous TNC concentration in mucosal fluids is likely inadequate to block HIV-1 transmission to uninfected individuals.
Highlights
According to the 2014 UNAIDS report, about 2.1 million new HIV infections occurred with over 200,000 being new pediatric infections, approximately half of which are due to transmission via breastfeeding [1]
As mucosal fluids are complex and contain a number of proteins known to interact with the HIV-1 envelope, we further studied the relationship between the concentration of TNC and neutralizing activity in breast milk
To explore the presence of TNC at mucosal compartments other than breast milk, we first screened for the presence of TNC in various mucosal fluids by TNC ELISA
Summary
According to the 2014 UNAIDS report, about 2.1 million new HIV infections occurred with over 200,000 being new pediatric infections, approximately half of which are due to transmission via breastfeeding [1]. Establishing the anti-HIV-1 activities of natural host HIV-1 inhibitors in the setting of the complex mucosal environment is a primary step in achieving the goal of safe and effective nonvaccine prevention methods. Studies have shown that secretory leukocyte protease inhibitor (SLPI) is another mucosal factor that can inhibit HIV-1 replication [9], but unlike lactoferrin and MUC-1, the anti-viral mechanism of SLPI does not involve direct binding to HIV-1 virions but interaction with the target cells [10]. Studying the kinetics and function of TNC both alone and in concert with other mucosal factors that interact with the HIV-1 Env would contribute to understanding the role of TNC in HIV-1 transmission and its potential to be developed as a safe, novel prophylaxis agent to prevent HIV-1 transmission
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