Histidine-Rich Glycoprotein Inhibits HIV-1 Infection in a pH-Dependent Manner

Abstract

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 been shown to regulate different biological responses, such as angiogenesis, coagulation, and fibrinolysis. Here, we found that HRG almost completely abrogated the infection of Ghost cells, Jurkat cells, CD4+ T cells, and macrophages by HIV-1 at a low pH (range, 6.5 to 5.5) but not at a neutral pH. HRG was shown to interact with the heparan sulfate expressed by target cells, inhibiting an early postbinding step associated with 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 defense 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 2 (HSV-2), respectively, suggesting that HRG might display 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 to be 1 in every 1,000 episodes of sexual intercourse, reflecting the 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 2, was also markedly inhibited by HRG at low pH values, suggesting that extracellular acidosis enables HRG to display broad antiviral activity.

Extracellular acidosis enhances Zika virus infection both in human cells and ex-vivo tissue cultures from female reproductive tract

“…Then, Vero cells were cultured for three days in a sulphate-free medium supplemented with sodium chlorate, an inhibitor of sulphation. As we previously shown [ 40 ], this treatment resulted in a marked reduction (> 90%) in the expression cell surface HS (data not shown). These cells were incubated with ZIKV at pH 7.3 or 6.2 for 1 h, washed, and incubated for 48 h at 37°C.…”

“…In fact, low pH values (range 6.0 to 7.0) have shown to increase the binding of a variety of proteins, such as the prion protein, gp64 of baculovirus, GM-CSF, selenoprotein P, vascular endothelial growth factor, and the nonfibrillar form of beta-amyloid peptide to HS via protonation of histidine residues [53][54][55][56][57][58] The ability of low pH to increase the binding of viruses to target cells is not exclusive of ZIKV. We have previously reported that low pH enhances the binding of HIV-1 to spermatozoa and epithelial cells, but not to CD4+ T cells or dendritic cells 40,44 .…”

“…To evaluate the specific role of HS and to distinguish it from other glycosaminoglycans, such as dermatan sulphate, Vero cells were first treated with a mixture of heparinases I and III [ 40 , 44 ], and then infected at pH 7.3 or 6.2. Enzymatic removal of HS with heparinases significantly prevented the infection when cells were infected at low pH ( Figure 4 (E)).…”

“…The ability of low pH to increase the binding of viruses to target cells is not exclusive of ZIKV. We have previously reported that low pH enhances the binding of HIV-1 to spermatozoa and epithelial cells, but not to CD4+ T cells or dendritic cells [ 40 , 44 ].…”

pH-dependent and dynamic interactions of cystatin C with heparan sulfate

“…It is important to note that Cst-3 is not the only HS-binding protein that displayed acidic pH-dependence. In fact, histidine-rich glycoprotein protein, which contains two cystatin-like domains, has been shown to bind HS in an acidic pH-dependent manner 21 , 22 . Other examples include selenoprotein P 23 , serum amyloid A 24 , diphtheria toxin 25 , and gp64 26 .…”