No full-text available
To read the full-text of this research,
you can request a copy directly from the author.
HIV-1 Cell-to-Cell Transmission and Antiviral Strategies: An Overview
Abstract
HIV-1 replicates by infecting new target cells either as cell-free viral particle or, much more efficiently, via cell-to-cell viral transmission. Cell-mediated viral spread, in which the infected cell directly transfers the viral particles to target cells via cell-cell contacts, in vitro is up to three orders of magnitude more efficient than transmission mediated by cell-free viral particles. Because of its potency, it has been suggested that current antiretroviral treatments could be less effective in blocking cell-to-cell viral transmission than cell-free. In this review, I will present an overview of the drugbased antiretroviral approaches as well as how the recently identified class of anti-HIV-1 broadly neutralizing antibodies could become part of an effective anti-viral strategy. I will discuss how both treatment strategies can be guided by our consideration that cell-to-cell HIV-1 spread is a major route of viral spread also in vivo.
... HIV-1 infects cells by multiple mechanisms, either as cell-free or cell-associated particles [2,3]. HIV-1 infection is more efficient when the virus is transmitted through direct cell contacts. ...
... All authors read and approved the final manuscript. 1 Virus and Immunity Unit, Department of Virology, Institut Pasteur, Paris, France. 2 CNRS-UMR3569, Paris, France. 3 Vaccine Research Institute, Créteil, France. ...
HIV-1 spreads through contacts between infected and target cells. Polarized viral budding at the contact site forms the virological synapse. Additional cellular processes, such as nanotubes, filopodia, virus accumulation in endocytic or phagocytic compartments promote efficient viral propagation. Cell-to-cell transmission allows immune evasion and likely contributes to HIV-1 spread in vivo. Anti-HIV-1 broadly neutralizing antibodies (bNAbs) defeat the major-ity of circulating viral strains by binding to the viral envelope glycoprotein (Env). Several bNAbs have entered clinical evaluation during the last years. It is thus important to understand their mechanism of action and to determine how they interact with infected cells. In experimental models, HIV-1 cell-to-cell transmission is sensitive to neutralization, but the effect of antibodies is often less marked than during cell-free infection. This may be due to differences in the conformation or accessibility of Env at the surface of virions and cells. In this review, we summarize the current knowl-edge on HIV-1 cell-to-cell transmission and discuss the role of bNAbs during this process.
... been a long-standing concern regarding the efficacy of ART, primarily however in terms of T cell-to-T cell infection (12,13,22,23). To our knowledge, there have not been comprehensive studies on the effects of ART on APC-to-T cell trans infection (15,21,24,25), although a recent report showed that two formulations of current ART drugs, i.e., tenofovir and raltegravir, administered in vitro fail to inhibit DC-to-T cell trans infection (16). Thus, our analysis is the first to assess both the effects of multiple types of ART on APC trans infection in vitro and ex vivo, and emphasizes the importance of this being a stealth mode to circumvent the antiviral effects of ART. ...
Background:
Antiretroviral therapy (ART) has dramatically improved the quality of life of people with HIV-1 infection (PWH). However, it is not curative, and interruption of ART results in rapid viral rebound. Cell-to-cell transfer of HIV-1, or trans infection, is a highly efficient mechanism of virus infection of CD4+ T cells by professional antigen-presenting cells (APCs), that is, dendritic cells (DCs), macrophages, and B lymphocytes.
Methods:
APC from HIV seronegative donors treated with ART in vitro (CCR5 agonist, NRTI, PI and NNRTI, alone or in combination), were loaded with HIV R5-tropic HIVBal and mixed with autologous or heterologous CD4+ T lymphocytes to assess trans infection. Ex vivo APC from chronic HIV-infected MACS participants before and after initiation of ART, were also loaded with HIV R5-tropic HIVBal and tested for trans infection against autologous or heterologous CD4+ T lymphocytes. Virus replication was measured by p24 ELISA.
Results:
Here we show in vitro that antiretroviral drugs did not block the ability of DCs and B cells to trans-infect CD4+ T cells, although they were effective in blocking direct cis infection of CD4+ T cells. Moreover, ex vivo DCs and B cells from ART-suppressed PWH mediated efficient HIV-1 trans infection of CD4+ T cells, which were resistant to direct cis infection.
Conclusions:
Our study supports a role for HIV-1 trans infection in maintenance of the HIV-1 reservoir during ART.
... Human OC Are Preferentially Infected by Transmission from Infected T Cells. HIV-1 spreads by infecting target cells either as cell-free particles or more efficiently via cell-to-cell transmission, both in vitro and in vivo (27)(28)(29)(30). We thus examined whether mature OC could be infected by contact with infected CD4 + T lymphocytes, first using Jurkat T cells infected with the HIV-1 R5-tropic NLAD8-VSVG strain (>50% of infected T cells, n = 8). ...
Significance
Bone deficits are frequent complications observed in HIV-1–infected patients. Our study demonstrates that HIV-1 infects osteoclasts, the cells specialized in bone degradation, using different models including HIV-1–infected humanized mice. We decipher the cellular mechanisms by which HIV-1 contributes to enhanced bone degradation in human osteoclasts, showing that the virus modifies the structure and function of the sealing zone, the bone resorption machinery of osteoclasts. We identify the viral protein Nef as the key factor responsible for such effects. As a proof-of-concept, we correlate bone deficit in transgenic Nef-expressing mice with enhanced osteoclast activity. Therefore, our findings provide formal evidence that osteoclasts constitute HIV-1 host target cells, contributing to bone deficits in vivo.
... In the last 25 years, a vast amount of evidence has accumulated and revealed cell-cell transfer of HIV to be more efficient than infection by cell-free virus in virtually every study which directly compared both, at least in vitro. This observation has gained further support from in silico [33,34], ex vivo [35,36], and in vivo studies [37][38][39][40][41][42], so that cell-cell transfer of HIV is now accepted by the field as a major mode of viral spread [42][43][44][45][46]. An integrated view is provided by Zhang et al., who combine patient data and mathematical modelling to conclude that both cell-cell and cell-free virus are required for HIV pathogenesis. ...
While significant progress has been made in terms of human immunodeficiency virus (HIV) therapy, treatment does not represent a cure and remains inaccessible to many people living with HIV. Continued mechanistic research into the viral life cycle and its intersection with many aspects of cellular biology are not only fundamental in the continued fight against HIV, but also provide many key observations of the workings of our immune system. Decades of HIV research have testified to the integral role of the actin cytoskeleton in both establishing and spreading the infection. Here, we review how the virus uses different strategies to manipulate cellular actin networks and increase the efficiency of various stages of its life cycle. While some HIV proteins seem able to bind to actin filaments directly, subversion of the cytoskeleton occurs indirectly by exploiting the power of actin regulatory proteins, which are corrupted at multiple levels. Furthermore, this manipulation is not restricted to a discrete class of proteins, but rather extends throughout all layers of the cytoskeleton. We discuss prominent examples of actin regulators that are exploited, neutralized or hijacked by the virus, and address how their coordinated deregulation can lead to changes in cellular behavior that promote viral spreading.
... Noteworthy, APCs have been described as "Trojan horses" that, in addition to their capacity to mount an efficient immune response, will also facilitate the spread of HIV by efficient HIV transmission and dissemination to the surrounding CD4 T lymphocytes. Indeed, spread of HIV-1 infection through direct cell-to-cell HIV-1 transmission has been shown to be 100-to 1,000-fold more efficient than infection by cell-free virus, making a large and efficient contribution to HIV propagation and dissemination through the body (10,(59)(60)(61). Therefore, preventing cell-to-cell transmission of HIV-1 by specific Abs is crucial for inhibiting HIV-1 propagation. ...
B cells produce a plethora of anti-HIV antibodies (Abs) but only few of them exhibit neutralizing activity. This was long considered a profound limitation for the enforcement of humoral immune responses against HIV-1 infection, especially since these neutralizing Abs (nAbs) are extremely difficult to induce. However, increasing evidence shows that additional non-neutralizing Abs play a significant role in decreasing the viral load, leading to partial and sometimes even total protection. Mechanisms suspected to participate in protection are numerous. They involve the Fc domain of Abs as well as their Fab part, and consequently the induced Ab isotype will be determinant for their functions, as well as the quantity and quality of the Fc-receptors (FcRs) expressed on immune cells. Fc-mediated inhibitory functions, such as Ab-dependent cellular cytotoxicity, antibody-dependent cellular phagocytosis, aggregation, and even immune activation have been proposed. However, as for nAbs, the non-neutralizing activities are limited to a subset of anti-HIV Abs. An improved in-depth characterization of the Abs displaying these functional responses is required for the development of new vaccination strategies, which aim to selectively trigger the B cells able to induce the right functional Ab combinations both at the right place and at the right time. This review summarizes our current knowledge on non-neutralizing functional inhibitory Abs and discusses the potential benefit of inducing them via vaccination. We also provide new insight into the roles of the FcγR-mediated Ab therapeutics in clinical trials for HIV diseases.
... Cell-to-cell HIV-1 infection was described as early as 1989, including one study that also established the relative levels of resistance of this transmission mode to neutralizing antibody (nAb) and the nucleoside reverse transcriptase inhibitor AZT (2,3). Cell-to-cell HIV-1 infection has also been estimated to be several orders of magnitude more efficient than cell-free infection (3)(4)(5)(6). Although it could represent a predominant mode of viral spread in vivo, cell-tocell transmission has not been studied to the same depth as cell-free infection, as almost all in vitro neutralization assays and in vivo broadly neutralizing antibody (bnAb) protection experiments have been performed using cell-free virus. ...
HIV-1 infection from cell to cell may provide an efficient mode of viral spread in vivo and could therefore present a significant challenge for preventative or therapeutic strategies based on broadly neutralizing antibodies. Indeed, Li et al show that the potency and magnitude of multiple HIV-1 broadly neutralizing antibody classes are decreased during cell to cell infection in a context dependent manner. A functional motif in gp41 appears to contribute to this differential susceptibility by modulating exposure of neutralization epitopes.
... All to all, there is still much to be understood in terms of the mechanisms behind cell-to-cell transmission, persistence and establishment of viral reservoirs in order to devise better therapies and aim to cure AIDS [9] . A very recent study suggests that maybe this cure is closer than expected. ...
We propose a mathematical model with memory for the dynamics of HIV epidemics, where two transmission modes, cell-to-cell and virus-to-cell, and drug resistance are considered. Systems with memory, or fractional order systems, have largely been applied to the modeling of several real life phenomena. Here, we consider a fractional model where the order of the non-integer derivative takes values in the interval [0.5, 1.0]. We prove the local and global stability of the disease-free equilibrium. We study the role of the cell-to-cell transmission probability on the dynamics of the model, and on the value of the reproduction number, R0, for distinct values of the fractional order derivative, α. Moreover, we show evidence of an improvement of HIV infected patients quality of life, due to the increase of the drug efficacy. In the end, important inferences are drawn.
Lors d’un rapport sexuel, le VIH-1, sous forme libre ou associé aux cellules, pénètre dans les tissus du tractus génital féminin. Les premières étapes de l’infection par le VIH-1 dans ces tissus sont très controversées. Afin d’analyser ces premiers évènements impliqués dans la transmission sexuelle, nous avons développé au cours de ma thèse, deux modèles d’infection de cellules isolées de tissu. Nous avons montré que les cellules dendritiques sont préférentiellement infectées et que les anticorps neutralisants inhibent ces premiers évènements de transmission du VIH-1. Dans le cadre de nouvelles stratégies vaccinales, l’inhibition de l’infection des cellules dendritiques sera à considérer afin de prévenir la transmission par voie sexuelle.
Objective:
In the semen, both free virus and infected cells are able to establish HIV infection during sexual intercourse. An efficient vaccine should, therefore, inhibit both infectious states. The aim of this study was to analyze the capacity of broadly neutralizing antibodies (bNAbs) to inhibit HIV transmission by the infected cells.
Design/methods:
We developed an in-vitro model aiming to mimic mucosal HIV transmission via infected cells. PHA-activated CD4 T cells stained with PKH26 from donor A were infected and co-cultured with CD4 T cells and dendritic cells from donor B in the presence of bNAbs.
Results:
We showed that dendritic cells were the preferential HIV target cells at early time points in this co-culture model. In the context of this co-culture model where infection and transmission occurred simultaneously, bNAbs efficiently inhibited HIV replication as well as HIV transmission from infected cells to allogenic dendritic cells and CD4 T cells.
Conclusion:
Overall, our results indicate that dendritic cells, in addition to CD4 T cells, are key cells that are efficiently infected by HIV and bNAbs are potent inhibitors of infection of both target cells. Future HIV prophylactic vaccine design should develop immune strategies able to prevent the infection of dendritic cells, in addition to the inhibition of CD4 T-cell infection.
ResearchGate has not been able to resolve any references for this publication.