Biology subjects

Hioe, C. E.

Publications and source records attributed to Hioe, C. E..

4 recordsLinked to original sources

bioRxiv2026

HIV-1 interactions with sialic acid-binding bacterial lectins promote virus infectivity in vitro and mucosal transmission in humanized mice

Most HIV-1 transmission occurs at mucosal surfaces, which are colonized by the host microbiota. However, interactions between HIV and bacteria or bacterial products derived from the human microbiome are poorly characterized, and their biological consequences are largely unexplored. Here, we evaluated the effects of sialic acid-binding lectins expressed by bacterial species ubiquitous in the human microbiota on HIV-1 infectivity using viruses produced in 293T cells and human primary cells. We demonstrated that these bacterial lectins enhanced HIV-1 infectivity in a sialoglycan-dependent manner. Specifically, Siglec-like binding region lectins (SLBR-N, SLBR-H, and SLBR-B) from Streptococcus gordonii and Staphylococcal superantigen-like lectins (SSL3, SSL4, and SSL11) from Staphylococcus aureus increased HIV-1 infectivity to varying extents, depending on lectin type and virus strain. Among these lectins, SLBR-N exhibited the greatest potency, corresponding with its superior ability to bind virions and promote virus-cell attachment. This enhancing activity was observed for direct infection of TZM-bl reporter cells and primary CD4+ T cells, as well as trans-infection in the presence or absence of the mannose-binding host lectin DC-SIGN. Importantly, these findings were corroborated in vivo using humanized mice, in which pre-exposure to SLBR-N promoted rectal HIV-1 transmission and increased viral burdens in plasma and splenic cells. Collectively, the data show sialoglycan-binding bacterial lectins as microbial factors that can enhance HIV-1 transmission at mucosal surfaces, highlighting a potential direct role for the microbiota in modulating HIV-1 acquisition risk. Author SummaryHIV is commonly transmitted from one person to another across mucosal surfaces, such as those lining the genital and rectal tracts, which are densely populated by bacteria that make up the human microbiota. Yet, surprisingly little is known about how these bacteria and the molecules they produce influence HIV infection. In this study, we investigated a group of bacterial proteins known as sialic acid-binding lectins that are expressed by common members of the human microbiome: Siglec-like binding region lectins from Streptococcus gordonii and superantigen-like lectins from Staphylococcus aureus. Using multiple HIV strains and several types of target cells, we demonstrate that lectin binding to HIV can increase virus attachment to target cells and thereby enhance infection, although the magnitude of this effect varies among lectins and virus strains. Lectin binding also facilitates HIV spread from cell to cell and promotes mucosal HIV infection in a humanized mouse model, resulting in a higher viral burden in the blood and tissues. These findings identify bacterial lectins as important factors that can influence HIV infection and implicate a potential role for the human microbiota in determining susceptibility to HIV infection.

microbiology↗

bioRxiv2021

Non-neutralizing antibodies targeting the immunogenic regions of HIV-1 envelope reduce mucosal infection and virus burden in humanized mice

Antibodies are principal immune components elicited by vaccines to induce protection from microbial pathogens. In the Thai RV144 HIV-1 vaccine trial, vaccine efficacy was 31% and the sole primary correlate of reduced risk was shown to be vigorous antibody response targeting the V1V2 region of HIV-1 envelope. Antibodies against V3 also were inversely correlated with infection risk in subsets of vaccinees. Antibodies recognizing these regions, however, do not exhibit potent neutralizing activity. Therefore, we examined the antiviral potential of poorly neutralizing monoclonal antibodies (mAbs) against immunodominant V1V2 and V3 sites by passive administration of human mAbs to humanized mice engrafted with CD34+ hematopoietic stem cells, followed by mucosal challenge with an HIV-1 infectious molecular clone (IMC) expressing the envelope of a tier 2 resistant HIV-1 strain. Treatment with anti-V1V2 mAb 2158 or anti-V3 mAb 2219 did not prevent infection, but both reduced the virus burden, and V3 mAb 2219 displayed a superior potency compared to V1V2 mAb 2158. While these mAbs had no or weak neutralizing activity and elicited undetectable levels of antibody-dependent cellular cytotoxicity (ADCC), V3 mAb 2219 displayed a greater capacity to bind virus- and cell-associated HIV-1 envelope and to mediate antibody-dependent cellular phagocytosis (ADCP) and C1q complement binding as compared to V1V2 mAb 2158. Mutations in the Fc region of 2219 abolished these effector activities and abrogated virus control in humanized mice. These results demonstrate the importance of Fc functions other than ADCC for antibodies without potent neutralizing activity.

immunology↗

bioRxiv2020

Signal Peptide of HIV-1 Envelope Functions to Modulate Glycosylation Impacting Exposure of V1V2 Epitopes

HIV-1 envelope (Env) is a trimer of gp120-gp41 heterodimers, synthesized from a precursor gp160 that contains an ER-targeting signal peptide (SP) at its amino-terminus. Each trimer is swathed by [~]90 N-linked glycans, comprising complex-type and oligomannose-type glycans, which play an important role in determining virus sensitivity to neutralizing antibodies. We previously examined the effects of single point SP mutations on Env properties and functions. Here, we aimed to understand the impact of the SP diversity on glycosylation of virus-derived Env and virus neutralization by swapping SPs. Analyses of site-specific glycans revealed that SP swapping altered Env glycan content and occupancy on multiple N-linked glycosites, including the conserved N156 and N160 glycans in the V1V2 region at the Env trimer apex. Virus neutralization was also affected, especially by antibodies against the V2i, V2p and V2q epitopes. Likewise, SP swaps affected the recognition of soluble and cell-associated Env by antibodies targeting distinct V1V2 configurations. These data highlight the contribution of SP sequence diversity in shaping the Env glycan content and its impact on the configuration and accessibility of V1V2 epitopes on Env. Author SummaryHIV-1 Env glycoprotein is produced by a precursor gp160 that has a signal peptide at its N-terminus. The SP is highly diverse among the HIV-1 isolates and no two SP are same. This study presents site-specific analyses of N-linked glycosylation on HIV-1 envelope glycoproteins from infectious viruses produced with different envelope signal peptides. We show that signal peptide swapping alters the envelope glycan shield, including the conserved N156 and N160 located in the V1V2 region on the trimer apex, to impact Env recognition and virus neutralization by antibodies, particularly those targeting the the V1V2 region. The data offer crucial insights into the role of signal peptide in the interplay between HIV-1 and antibodies and its potential utility to control Env glycosylation in the development of Env-based HIV-1 vaccine.

microbiology↗

bioRxiv2019

P2X1 selective antagonists block HIV-1 infection through inhibition of envelope conformation-dependent fusion

Purinergic receptors detect extracellular ATP and promote inflammatory processes. Emerging literature has demonstrated that inhibition of these proinflammatory receptors can block HIV-1 productive infection. The specificity of receptor type and mechanism of interaction has not yet been determined. Here we characterize the inhibitory activity of P2X1 receptor antagonists, NF279 and NF449 in cell lines, primary cells, and in a variety of envelope clades. NF279 and NF449 blocked productive infection at the level of viral membrane fusion with a range of inhibitory activities against different HIV-1 envelopes. A mutant virus carrying a truncation deletion of the C-terminal tail of HIV-1 envelope (Env) glycoprotein 41 (gp41) showed reduced sensitivity to P2X1 antagonists, indicating that the sensitivity of inhibition by these molecules is modulated by Env conformation. By contrast, a P2X7 antagonist, A438079, had limited effect on productive infection and fusion. Inhibition with NF449 interfered with the ability of the V1V2 targeted broadly neutralizing antibody PG9 to block productive infection, suggesting that these drugs may antagonize HIV-1 Env at gp120 V1V2 to block viral membrane fusion. Our observations indicate that P2X1 antagonism can inhibit HIV-1 replication at the level of viral membrane fusion through interaction with Env. Future studies will probe the nature of these compounds in inhibiting HIV-1 fusion and in development of a different class of small molecules to block HIV-1 entry.\n\nIMPORTANCEWhile effective treatment can lower the severe morbidity and mortality associated with HIV-1 infection, patients infected with HIV-1 suffer from significantly higher rates of non-communicable comorbidities associated with chronic inflammation. Emerging literature suggests a key role for P2X1 receptors in mediating this chronic inflammation but the mechanism is still unknown. Here, we demonstrate that HIV-1 infection is reduced by P2X1 receptor antagonism. This inhibition is mediated by interference with HIV-1 Env and can impact a variety of viral clades. These observations highlight the importance of P2X1 antagonists as potential novel therapeutics that could serve to block a variety of different viral clades with additional benefits for their anti-inflammatory properties.

microbiology↗