Histidine-rich glycoprotein inhibits HIV-1 infection in a pH-dependent manner

DANTAS, EZEQUIEL; DÍAZ, FERNANDO ERRA; GERBER, PEHUÉN PEREYRA; VARESE, AUGUSTO; JERUSALINSKY, DIANA ALICIA; EPSTEIN, ALBERTO L.; RIVELLO, HERNÁN J. GARCÍA; DEL VALLE JAÉN, ANA; PANDOLFI, JULIETA B.; CEBALLOS, ANA; OSTROWSKI, MATIAS; SABATTÉ, JUAN; GEFFNER, JORGE

JOURNAL OF VIROLOGY

AMER SOC MICROBIOLOGY

Lugar: Washington, DC; Año: 2018

0022-538X

Histidine-rich glycoprotein (HRG) is an abundant plasma protein with a multidomain structure allowing its interaction with many ligands including phospholipids, plasminogen, fibrinogen, IgG antibodies, and heparan sulfate. HRG has shown to regulate different biological responses such as angiogenesis, coagulation and fibrinolysis. Here, we found that HRG almost completely abrogated the infection of GHOST, Jurkat, CD4+ T cells, and macrophages by HIV-1 at low pH (range 6.5 to 5.5) but not at neutral pH. HRG was shown to interact with heparan sulfate expressed by target cells inhibiting an early post-binding step associated to HIV-1 infection. More importantly, by acting on the viral particle itself, HRG induced a deleterious effect which reduces viral infectivity. Because cervicovaginal secretions in healthy women show low pH values, even after semen deposition, our observations suggest that HRG might represent a constitutive defence mechanism in the vaginal mucosa. Of note, low pH also enabled HRG to inhibit the infection of Hep-2 cells and Vero cells by respiratory syncytial virus (RSV) and herpes simplex virus-type 2 (HSV-2), respectively, suggesting that HRG might display a broad antiviral activity under acidic conditions.IMPORTANCE. Vaginal intercourse represents a high-risk route for HIV-1 transmission. The efficiency of male-to-female HIV-1 transmission has been estimated as 1 in every 1,000 episodes of sexual intercourse, reflecting a high degree of protection conferred by the genital mucosa. However, the contribution of different host factors to the protection against HIV-1 at mucosal surfaces remains poorly defined. Here, we report for the first time that acidic values of pH enable the plasma protein histidine-rich glycoprotein (HRG) to strongly inhibit HIV-1 infection. Because cervicovaginal secretions usually show low pH values, our observations suggest that HRG might represent a constitutive antiviral mechanism in the vaginal mucosa. Interestingly, infection by other viruses such as respiratory syncytial virus and herpes simplex virus-type 2 was also markedly inhibited by HRG at low pH values, suggesting that extracellular acidosis enables HRG to display a broad antiviral activity.