HIV-1 Entry and Prospects for Protecting against Infection.

Jean-François Bruxelle,Ralph Pantophlet,Marianne W. Mureithi,Elise Landais,Nino Trattnig

doi:10.3390/microorganisms9020228

Abstract

Human Immunodeficiency Virus type-1 (HIV-1) establishes a latent viral reservoir soon after infection, which poses a major challenge for drug treatment and curative strategies. Many efforts are therefore focused on blocking infection. To this end, both viral and host factors relevant to the onset of infection need to be considered. Given that HIV-1 is most often transmitted mucosally, strategies designed to protect against infection need to be effective at mucosal portals of entry. These strategies need to contend also with cell-free and cell-associated transmitted/founder (T/F) virus forms; both can initiate and establish infection. This review will discuss how insight from the current model of HIV-1 mucosal transmission and cell entry has highlighted challenges in developing effective strategies to prevent infection. First, we examine key viral and host factors that play a role in transmission and infection. We then discuss preventive strategies based on antibody-mediated protection, with emphasis on targeting T/F viruses and mucosal immunity. Lastly, we review treatment strategies targeting viral entry, with focus on the most clinically advanced entry inhibitors.

Highlights

Human Immunodeficiency Virus type-1 (HIV-1) infection is commonly treated with highly active antiretroviral therapy (ART) (HAART); the drugs reduce the viral load to undetectable levels and prevent a progression to acquired immunodeficiency syndrome (AIDS) [218]
As shown in current HIV-1 infection models, the biological context of viral cell entry challenges the development of effective entry inhibitors and vaccine candidates
A better understanding of how the mucosal environments can increase or reduce mucosal barrier function against the virus is essential to the development of an efficient strategy preventing

Summary

Introduction

Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. The first lever of action to reduce HIV-1 mucosal transmission is based on social-behavioral variables that increase the risk, especially in women, of HIV exposure and acquisition. T/F virus and the molecular details of the interactions mediating viral cell entry could help to inform intervention strategies targeting the onset of the infection [21]. While systemic infection is currently irreversible after the onset of the acute infection, the most promising window of opportunity for viral clearance is in the earliest step of the infection during the eclipse phase It is at this step, normally lasting about one week [28], that mucosal transmission, viral entry into primary target cells, and T/F selection can be blocked to prevent irreversible infection. We discuss the mechanisms and the challenges of preventive and therapeutic strategies targeting mucosal transmission and HIV-1 cell entry

Viral Factors Modulating HIV-1 Mucosal Transmission and Infection

Phenotypes of Transmitted Founder Viruses

Identification of HIV-1 Target to Inhibit Viral Cell Binding and Entry

Early Cells Targeted by HIV-1 in the Mucosa

Factors Associated with Inflammation

Mucosal Correlates of Protection

Early Prevention of HIV-1 Infection

Neutralizing Antibodies

Targeting the Transmitted Founder Virus

Systemic and Mucosal Antibody-Mediated Protection agaisnt HIV-1

Mucosal Protection by Passive Immunization

Mucosal Protection Induced by Active Immunization