Human Immunodeficiency Virus Type 1 Infection Research Articles

The Role of Extracellular Traps in HIV Infection.

Human immunodeficiency virus (HIV) infection is still an important public health problem, which justifies the research of new therapies to combat it. Recent studies show that Extracellular Traps (ETs) are cellular mechanisms useful in the capture and destruction of some viruses, such as the HIV. Here, we show that neutrophils from peripheral blood, genital tissues, and placenta are activated when exposed to human immunodeficiency virus type 1 (HIV-1) and release Neutrophil Extracellular Traps (NETs). The NETs can capture, neutralize, and inactivate the virus and, also, protect other target cells from HIV infection, as long as the DNA and other constituents of the NETs remain intact. Further, the review indicates that the immunoprotective role of NETs in the context of HIV-1 infection is a promising finding for the development of new antiviral therapies. It is necessary, however, the development of studies that evaluate the tissue injury that NETs can cause and the biological relationships with other cells to improve them as therapeutic targets.

Association of TREX1 polymorphism with disease progression in human immunodeficiency virus type-1 (HIV-1) infected patients.

The time interval between HIV-1 infection and AIDS development is not the same in all patients and depends largely on the genetic background of the individual. Polymorphisms in the TREX1 gene, the main enzyme in the clearance of cytosolic DNA, affect type 1 interferon-mediated inflammatory response in HIV-1 infection. We aimed to study the role of a single nucleotide polymorphism (rs3135941) of the TREX1 gene and the rate of disease progression in patients infected with HIV-1. A total of 190 HIV-1 infected patients were recruited. Patients' demographic and laboratory data including CD4 counts, viral load, and antiretroviral therapy (ART) were collected. The genotype of rs3135941 was determined by a PCR-SSP method. The rate of progression to AIDS was calculated with Kaplan-Meier survival analysis using Stata software. The patients were divided into rapid and slow progressors based on time interval of CD4 drop below 350/µl. Kaplan-Meier analysis revealed an accelerated disease progression in patients with TC and CC genotypes (HR = 1.49, 95% CI = 1.01-2.17). The mean values of the first 5-year CD4 counts were significantly different in patients who had CC and TC genotypes compared to the TT group (p = 0.036). The result of this study emphasizes the importance of TREX1 polymorphism in HIV-1 progression. These data warrant further investigation into the role of other polymorphisms of TREX1.

Global Properties of HIV-1 Dynamics Models with CTL Immune Impairment and Latent Cell-to-Cell Spread

This paper presents and analyzes two mathematical models for the human immunodeficiency virus type-1 (HIV-1) infection with Cytotoxic T Lymphocyte cell (CTL) immune impairment. These models describe the interactions between healthy CD4+T cells, latently and actively infected cells, HIV-1 particles, and CTLs. The healthy CD4+T cells might be infected when they make contact with: (i) HIV-1 particles due to virus-to-cell (VTC) contact; (ii) latently infected cells due to latent cell-to-cell (CTC) contact; and (iii) actively infected cells due to active CTC contact. Distributed time delays are considered in the second model. We show the nonnegativity and boundedness of the solutions of the systems. Further, we derive basic reproduction numbers ℜ0 and ℜ˜0, that determine the existence and stability of equilibria of our proposed systems. We establish the global asymptotic stability of all equilibria by using the Lyapunov method together with LaSalle’s invariance principle. We confirm the theoretical results by numerical simulations. The effect of immune impairment, time delay and CTC transmission on the HIV-1 dynamics are discussed. It is found that weak immunity contributes significantly to the development of the disease. Further, we have established that the presence of time delay can significantly decrease the basic reproduction number and then suppress the HIV-1 replication. On the other hand, the presence of latent CTC spread increases the basic reproduction number and then enhances the viral progression. Thus, neglecting the latent CTC spread in the HIV-1 infection model will lead to an underestimation of the basic reproduction number. Consequently, the designed drug therapies will not be accurate or sufficient to eradicate the viruses from the body. These findings may help to improve the understanding of the dynamics of HIV-1 within a host.

The Use of CBD and Its Synthetic Analog HU308 in HIV-1-Infected Myeloid Cells.

Currently, there is no cure for human immunodeficiency virus type 1 (HIV-1) infection. However, combined antiretroviral therapy (cART) aids in viral latency and prevents the progression of HIV-1 infection into acquired immunodeficiency syndrome (AIDS). cART has extended many lives, but people living with HIV-1 (PLWH) face lifelong ailments such as HIV-associated neurocognitive disorders (HAND) that range from asymptomatic HAND to HIV-1-associated dementia. HAND has been attributed to chronic inflammation and low-level infection within the central nervous system (CNS) caused by proinflammatory cytokines and viral products. These molecules are shuttled into the CNS within extracellular vesicles (EVs), lipid bound nanoparticles, and are released from cells as a form of intercellular communication. This study investigates the impact of cannabidiol (CBD), as a promising and potential therapeutic for HAND patients, and a similar synthetic molecule, HU308, on the EVs released from HIV-1-infected myeloid cells as well as HIV-1-infected 3D neurospheres. The data shows that both CBD and HU308 decrease non-coding and coding viral RNA (TAR and env) as well as proinflammatory cytokines as IL-1β and TNF-α mRNA. This decrease in viral RNA occurs in in vitro differentiated primary macrophages, in EVs released from HIV-1-infected cells monocytes, and infected neurospheres. Furthermore, a 3D neurosphere model shows an overall decrease in proinflammatory mRNA with HU308. Finally, using a humanized mouse model of HIV-1 infection, plasma viral RNA was shown to significantly decrease with HU308 alone and was most effective in combination with cART, even when compared to the typical cART treatment. Overall, CBD or HU308 may be a viable option to decrease EV release and associated cytokines which would dampen the virus spread and may be used in effective treatment of HAND in combination with cART.

Inhibition of salt inducible kinases reduces rhythmic HIV-1 replication and reactivation from latency.

Human immunodeficiency virus type 1 (HIV-1) causes a major burden on global health, and eradication of latent virus infection is one of the biggest challenges in the field. The circadian clock is an endogenous timing system that oscillates with a ~24 h period regulating multiple physiological processes and cellular functions, and we recently reported that the cell intrinsic clock regulates rhythmic HIV-1 replication. Salt inducible kinases (SIK) contribute to circadian regulatory networks, however, there is limited evidence for SIKs regulating HIV-1 infection. Here, we show that pharmacological inhibition of SIKs perturbed the cellular clock and reduced rhythmic HIV-1 replication in circadian synchronised cells. Further, SIK inhibitors or genetic silencing of Sik expression inhibited viral replication in primary cells and in a latency model, respectively. Overall, this study demonstrates a role for salt inducible kinases in regulating HIV-1 replication and latency reactivation, which can provide innovative routes to better understand and target latent HIV-1 infection.

Molecular mechanisms by which the HIV-1 latent reservoir is established and therapeutic strategies for its elimination.

The human immunodeficiency virus type 1 (HIV-1) reservoir, composed of cells harboring the latent, integrated virus, is not eliminated by antiretroviral therapy. It therefore represents a significant barrier to curing the infection. The biology of HIV-1 reservoirs, the mechanisms of their persistence, and effective strategies for their eradication are not entirely understood. Here, we review the molecular mechanisms by which HIV-1 reservoirs develop, the cells and compartments where the latent virus resides, and advancements in curative therapeutic strategies. We first introduce statistics and relevant data on HIV-1 infection, aspects of pathogenesis, the role of antiretroviral therapy, and the general features of the latent HIV reservoir. Then, the article is built on three main pillars: The molecular mechanisms related to latency, the different strategies for targeting the reservoir to obtain a cure, and the current progress in immunotherapy to counteract said reservoirs.

Triple Inhibitor Mechanism of Antiretroviral from Sambucus nigra Phytochemical through Screening Docking

Human immunodeficiency virus type 1 (HIV-1) has a higher infectious nature than HIV-2 because of the genetic drift mechanism. Several HIV-1 strains such as A, B, C, D, E, F, G, H, & J were obtained from Africa, Asia, Europe, Australia, and America. Endemic cases of HIV-1 are often found and HIV-2 is very rare, therefore the development of antiretroviral drugs is currently focused on treating HIV-1 infection5. Research on HIV-1 vaccines is still in the research phase and some patients are only taking antiretrovirals to survive. Sambucus nigra L. is used by the community for traditional medicine such as influenza A, B, C and SARS-CoV-2 infectious diseases. There are no research reports related to the potential of Sambucus nigra L. as an antiretroviral in the treatment of HIV-1 infection and the specific molecular mechanisms that explain it, therefore this research is important for the discovery of alternative antiretroviral drugs from natural materials. The in silico method used in this study consists of Sambucus nigra L. compounds retrieval, HIV-1 protein preparation, molecular docking, and 3D visualization. Sambucus nigra L. can have inhibitory activity on three enzymes of HIV-1 such as protease (PR), reverse transcriptase (RT), integrase (INT) through naringenin and Cyanidin-3,5-diglucoside compounds. Both compounds have more negative binding energy, form stable binding interactions in the target domain, and trigger inhibitory activity.

Stability of HIV-1 Dynamics Models with Viral and Cellular Infections in the Presence of Macrophages

In this research work, we suggest two mathematical models that take into account (i) two categories of target cells, CD4+T cells and macrophages, and (ii) two modes of infection transmissions, the direct virus-to-cell (VTC) method and cell-to-cell (CTC) infection transmission, where CTC is an effective method of spreading human immunodeficiency virus type-1 (HIV-1), as with the VTC method. The second model incorporates four time delays. In both models, the presence of a bounded and positive solution of the biological model is investigated. The existence conditions of all equilibria are established. The basic reproduction number R0 that identifies a disease index is obtained. Lyapunov functions are utilized to verify the global stability of all equilibria. The theoretical findings are verified through numerical simulations. According to the outcomes, the trajectories of the solutions approach the infection-free equilibrium and infection-present equilibrium when R0≤1 and R0>1, respectively. Further, we study the sensitivity analysis to investigate how the values of all the parameters of the suggested model affect R0 for given data. We discuss the impact of the time delay on HIV-1 progression. We find that a longer time delay results in suppression of the HIV-1 infection and vice versa.

SAMHD1 impairs type I interferon induction through the MAVS, IKKε, and IRF7 signaling axis during viral infection

Sterile alpha motif and HD domain-containing protein 1 (SAMHD1) restricts human immunodeficiency virus type 1 (HIV-1) infection by reducing the intracellular dNTP pool. We have shown that SAMHD1 suppresses nuclear factor kappa-B activation and type I interferon (IFN-I) induction by viral infection and inflammatory stimuli. However, the mechanism by which SAMHD1 inhibits IFN-I remains unclear. Here, we show that SAMHD1 inhibits IFN-I activation induced by the mitochondrial antiviral-signaling protein (MAVS). SAMHD1 interacted with MAVS and suppressed MAVS aggregation in response to Sendai virus infection in human monocytic THP-1cells. This resulted in increased phosphorylation of TANK binding kinase 1 (TBK1), inhibitor of nuclear factor kappa-B kinase epsilon (IKKε), and IFN regulatory factor 3 (IRF3). SAMHD1 suppressed IFN-I activation induced by IKKε and prevented IRF7 binding to the kinase domain of IKKε. We found that SAMHD1 interaction with the inhibitory domain (ID) of IRF7 (IRF7-ID) was necessary and sufficient for SAMHD1 suppression of IRF7-mediated IFN-I activation in HEK293T cells. Computational docking and molecular dynamics simulations revealed possible binding sites between IRF7-ID and full-length SAMHD1. Individual substitution of F411, E416, or V460 in IRF7-ID significantly reduced IRF7 transactivation activity and SAMHD1 binding. Furthermore, we investigated the role of SAMHD1 inhibition of IRF7-mediated IFN-I induction during HIV-1 infection. We found that THP-1cells lacking IRF7 expression had reduced HIV-1 infection and viral transcription compared to control cells, indicating a positive role of IRF7 in HIV-1 infection. Our findings suggest that SAMHD1 suppresses IFN-I induction through the MAVS, IKKε, and IRF7 signaling axis.

Toll-like Receptor Response to Human Immunodeficiency Virus Type 1 or Co-Infection with Hepatitis B or C Virus: An Overview.

Toll-like receptors (TLRs) are evolutionarily conserved pattern recognition receptors that play important roles in the early detection of pathogen-associated molecular patterns and shaping innate and adaptive immune responses, which may influence the consequences of infection. Similarly to other viral infections, human immunodeficiency virus type 1 (HIV-1) also modulates the host TLR response; therefore, a proper understanding of the response induced by human HIV-1 or co-infection with hepatitis B virus (HBV) or hepatitis C virus (HCV), due to the common mode of transmission of these viruses, is essential for understanding HIV-1 pathogenesis during mono- or co-infection with HBV or HCV, as well as for HIV-1 cure strategies. In this review, we discuss the host TLR response during HIV-1 infection and the innate immune evasion mechanisms adopted by HIV-1 for infection establishment. We also examine changes in the host TLR response during HIV-1 co-infection with HBV or HCV; however, this type of study is extremely scarce. Moreover, we discuss studies investigating TLR agonists as latency-reverting agents and immune stimulators towards new strategies for curing HIV. This understanding will help develop a new strategy for curing HIV-1 mono-infection or co-infection with HBV or HCV.

HIV-1 activates oxidative phosphorylation in infected CD4 T cells in a human tonsil explant model.

Human immunodeficiency virus type 1 (HIV-1) causes a chronic, incurable infection leading to immune activation and chronic inflammation in people with HIV-1 (PWH), even with virologic suppression on antiretroviral therapy (ART). The role of lymphoid structures as reservoirs for viral latency and immune activation has been implicated in chronic inflammation mechanisms. Still, the specific transcriptomic changes induced by HIV-1 infection in different cell types within lymphoid tissue remain unexplored. In this study, we utilized human tonsil explants from healthy human donors and infected them with HIV-1 ex vivo. We performed single-cell RNA sequencing (scRNA-seq) to analyze the cell types represented in the tissue and to investigate the impact of infection on gene expression profiles and inflammatory signaling pathways. Our analysis revealed that infected CD4+ T cells exhibited upregulation of genes associated with oxidative phosphorylation. Furthermore, macrophages exposed to the virus but uninfected showed increased expression of genes associated with the NLRP3 inflammasome pathway. These findings provide valuable insights into the specific transcriptomic changes induced by HIV-1 infection in different cell types within lymphoid tissue. The activation of oxidative phosphorylation in infected CD4+ T cells and the proinflammatory response in macrophages may contribute to the chronic inflammation observed in PWH despite ART. Understanding these mechanisms is crucial for developing targeted therapeutic strategies to eradicate HIV-1 infection in PWH.

Fostemsavir (Rukobia)


 CADTH recommends that Rukobia be reimbursed by public drug plans for the treatment of HIV type 1 (HIV-1) infection in heavily treatment-experienced adults with multidrug-resistant (MDR) HIV-1 infection for whom it is otherwise not possible to construct a suppressive antiviral regimen due to resistance, intolerance, or safety considerations if certain conditions are met.
 Rukobia should be covered for patients living with HIV-1 whose disease does not respond to the majority of antiretroviral therapies (ARVs) available (ARVs in at least 3 classes) because the available ARVs no longer work, for those who cannot tolerate side effects, or for those who have other safety concerns. In addition, patients should have 1 fully active available drug left in no more than 2 ARV classes based on current and/or documented historical resistant testing. Lastly, Rukobia should be covered for patients who have a viral load that suggests poor control of their infection (≥ 400 copies/mL of HIV-1 ribonucleic acid [RNA]).
 Rukobia should only be reimbursed if it is initially prescribed by, or in conjunction with, a physician who specializes in the management of HIV-1 infection and if the cost of Rukobia is reduced. Reimbursement of Rukobia should be discontinued if the patient’s viral load is not improving, as this suggests that treatment is not working.

TRPV1 activation in human Langerhans cells and T cells inhibits mucosal HIV-1 infection via CGRP-dependent and independent mechanisms

Upon its mucosal transmission, HIV type 1 (HIV-1) rapidly targets genital antigen-presenting Langerhans cells (LCs), which subsequently transfer infectious virus to CD4+ Tcells. We previously described an inhibitory neuroimmune cross talk, whereby calcitonin gene-related peptide (CGRP), a neuropeptide secreted by peripheral pain-sensing nociceptor neurons innervating all mucosal epithelia and associating with LCs, strongly inhibits HIV-1 transfer. As nociceptors secret CGRP following the activation of their Ca2+ ion channel transient receptor potential vanilloid 1 (TRPV1), and as we reported that LCs secret low levels of CGRP, we investigated whether LCs express functional TRPV1. We found that human LCs expressed mRNA and protein of TRPV1, which was functional and induced Ca2+ influx following activation with TRPV1 agonists, including capsaicin (CP). The treatment of LCs with TRPV1 agonists also increased CGRP secretion, reaching its anti-HIV-1 inhibitory concentrations. Accordingly, CP pretreatment significantly inhibited LCs-mediated HIV-1 transfer to CD4+ Tcells, which was abrogated by both TRPV1 and CGRP receptor antagonists. Like CGRP, CP-induced inhibition of HIV-1 transfer was mediated via increased CCL3 secretion and HIV-1 degradation. CP also inhibited direct CD4+ Tcells HIV-1 infection, but in CGRP-independent manners. Finally, pretreatment of inner foreskin tissue explants with CP markedly increased CGRP and CCL3 secretion, and upon subsequent polarized exposure to HIV-1, inhibited an increase in LC-Tcell conjugate formation and consequently Tcell infection. Our results reveal that TRPV1 activation in human LCs and CD4+ Tcells inhibits mucosal HIV-1 infection, via CGRP-dependent/independent mechanisms. Formulations containing TRPV1 agonists, already approved for pain relief, could hence be useful against HIV-1.

Glutamylation of an HIV-1 protein inhibits the immune response by hijacking STING

Cyclic GMP-AMP synthase (cGAS) recognizes Y-form cDNA of human immunodeficiency virus type 1 (HIV-1) and initiates antiviral immune response through cGAS-stimulator of interferon genes (STING)-TBK1-IRF3-type I interferon (IFN-I) signalingcascade. Here, we report that the HIV-1 p6 protein suppresses HIV-1-stimulated expression of IFN-I and promotes immune evasion. Mechanistically, the glutamylated p6 at residue Glu6 inhibits the interaction between STING and tripartite motif protein 32 (TRIM32) or autocrine motility factor receptor (AMFR). This subsequently suppresses the K27- and K63-linked polyubiquitination of STING at K337, therefore inhibiting STING activation, whereas mutation of the Glu6 residue partially reverses the inhibitory effect. However, CoCl2, an agonist of cytosolic carboxypeptidases (CCPs), counteracts the glutamylation of p6 at the Glu6 residue and inhibits HIV-1 immune evasion. These findings reveal a mechanism through which an HIV-1 protein mediates immune evasion and provides a therapeutic drug candidate to treat HIV-1 infection.

HIV-1 Infection Promotes Cholesterol Aggregation by Inducing miR-33b-5p to Suppress ABCA1 Expression.

MicroRNAs play an important role in the interaction between viruses and hosts. In this study, we found that the expression level of miR-33b-5p was markedly increased in human immunodeficiency virus type 1 (HIV-1)-infected cell lines and the serum of person with HIV-1. Further investigation revealed that the level of ATP-binding cassette transporter (ABCA1), which transports cholesterol between intracellular and extracellular compartments to maintain cholesterol homeostasis, was reduced in HIV-1-infected target cells, as the target gene of miR-33b-5p. Furthermore, HIV-1 infection stimulated abnormal lipid transport in macrophages, resulting in lipid accumulation in cells. These changes can be reversed by an miR-33b-5p inhibitor. We discovered a mechanism through which HIV-1 infection caused miR-33b-5p to target ABCA1 and caused aberrant lipid transport, providing a novel method for diagnosing and treating poor lipid metabolism in person with HIV-1.

A Novel Vpu Adaptive Mutation of HIV-1 Degrades Tetherin in Northern Pig-Tailed Macaques (Macaca leonina) Mainly via the Ubiquitin-Proteasome Pathway and Increases Viral Release.

Tetherin prevents viral cross-species transmission by inhibiting the release of multiple enveloped viruses from infected cells. With the evolution of simian immunodeficiency virus of chimpanzees (SIVcpz), a pandemic human immunodeficiency virus type 1 (HIV-1) precursor, its Vpu protein can antagonize human tetherin (hTetherin). Macaca leonina (northern pig-tailed macaque [NPM]) is susceptible to HIV-1, but host-specific restriction factors limit virus replication in vivo. In this study, we isolated the virus from NPMs infected with strain stHIV-1sv (with a macaque-adapted HIV-1 env gene from simian-human immunodeficiency virus SHIV-KB9, a vif gene replaced by SIVmac239, and other genes originating from HIV-1NL4.3) and found that a single acidic amino acid substitution (G53D) in Vpu could increase its ability to degrade the tetherin of macaques (mTetherin) mainly through the proteasome pathway, resulting in an enhanced release and resistance to interferon inhibition of the mutant stHIV-1sv strain, with no influence on the other functions of Vpu. IMPORTANCE HIV-1 has obvious host specificity, which has greatly hindered the construction of animal models and severely restricted the development of HIV-1 vaccines and drugs. To overcome this barrier, we attempted to isolate the virus from NPMs infected with stHIV-1sv, search for a strain with an adaptive mutation in NPMs, and develop a more appropriate nonhuman primate model of HIV-1. This is the first report identifying HIV-1 adaptations in NPMs. It suggests that while tetherin may limit HIV-1 cross-species transmission, the Vpu protein in HIV-1 can overcome this species barrier through adaptive mutation, increasing viral replication in the new host. This finding will be beneficial to building an appropriate animal model for HIV-1 infection and promoting the development of HIV-1 vaccines and drugs.

The impact of cannabinoids on inflammasome signaling in HIV-1 infection.

Human immunodeficiency virus type 1 (HIV-1) is a chronic disease that afflicts over 38 million people worldwide without a known cure. The advent of effective antiretroviral therapies (ART) has significantly decreased the morbidity and mortality associated with HIV-1 infection in people living with HIV-1 (PWH), thanks to durable virologic suppression. Despite this, people with HIV-1 experience chronic inflammation associated with co-morbidities. While no single known mechanism accounts for chronic inflammation, there is significant evidence to support the role of the NLRP3 inflammasome as a key driver. Numerous studies have demonstrated therapeutic impact of cannabinoids, including exerting modulatory effects on the NLRP3 inflammasome. Given the high rates of cannabinoid use in PWH, it is of great interest to understand the intersecting biology of the role of cannabinoids in HIV-1-associated inflammasome signaling. Here we describe the literature of chronic inflammation in people with HIV, the therapeutic impact of cannabinoids in PWH, endocannabinoids in inflammation, and HIV-1-associated inflammation. We describe a key interaction between cannabinoids, the NLRP3 inflammasome, and HIV-1 viral infection, which supports further investigation of the critical role of cannabinoids in HIV-1 infection and inflammasome signaling.

Inhibition of matrix metalloproteinases by HIV-1 integrase strand transfer inhibitors.

More than fifteen million women with the human immunodeficiency virus type-1 (HIV-1) infection are of childbearing age world-wide. Due to improved and affordable access to antiretroviral therapy (ART), the number of in utero antiretroviral drug (ARV)-exposed children has exceeded a million and continues to grow. While most recommended ART taken during pregnancy suppresses mother to child viral transmission, the knowledge of drug safety linked to fetal neurodevelopment remains an area of active investigation. For example, few studies have suggested that ARV use can be associated with neural tube defects (NTDs) and most notably with the integrase strand transfer inhibitor (INSTI) dolutegravir (DTG). After risk benefit assessments, the World Health Organization (WHO) made recommendations for DTG usage as a first and second-line preferred treatment for infected populations including pregnant women and those of childbearing age. Nonetheless, long-term safety concerns remain for fetal health. This has led to a number of recent studies underscoring the need for biomarkers to elucidate potential mechanisms underlying long-term neurodevelopmental adverse events. With this goal in mind, we now report the inhibition of matrix metalloproteinases (MMPs) activities by INSTIs as an ARV class effect. Balanced MMPs activities play a crucial role in fetal neurodevelopment. Inhibition of MMPs activities by INSTIs during neurodevelopment could be a potential mechanism for adverse events. Thus, comprehensive molecular docking testing of the INSTIs, DTG, bictegravir (BIC), and cabotegravir (CAB), against twenty-three human MMPs showed broad-spectrum inhibition. With a metal chelating chemical property, each of the INSTI were shown to bind Zn++ at the MMP's catalytic domain leading to MMP inhibition but to variable binding energies. These results were validated in myeloid cell culture experiments demonstrating MMP-2 and 9 inhibitions by DTG, BIC and CAB and even at higher degree than doxycycline (DOX). Altogether, these data provide a potential mechanism for how INSTIs could affect fetal neurodevelopment.

Get in and get out: Remodeling of the cellular actin cytoskeleton upon HIV-1 infection.

The human immunodeficiency virus type 1 (HIV-1) is an intracellular pathogen whose replication cycle strictly depends on the host cell molecular machinery. HIV-1 crosses twice the plasma membrane, to get in and to get out of the cell. Therefore, the first and the last line of intracellular component encountered by the virus is the cortical actin network. Here, we review the role of actin and actin-related proteins in HIV-1 entry, assembly, budding, and release. We first highlight the mechanisms controlling actin polymerization at the entry site that promote the clustering of HIV-1 receptors, a crucial step for the virus to fuse with the plasma membrane. Then, we describe how actin is transiently depolymerized locally to allow the capsid to cross the actin cortex, before migrating towards the nucleus. Finally, we review the role of several actin-binding proteins in actin remodeling events required for membrane deformation and curvature at the viral assembly site as well as for virus release. Strikingly, it appears that common actin-regulating pathways are involved in viral entry and exit. However, while the role of actin remodeling during entry is well understood, this is not the case during exit. We discuss remaining challenges regarding the actin-dependent mechanisms involved in HIV-1 entry and exit, and how they could be overcome.

HIV-1 transmission: modelling and direct visualization in the third dimension.

Identifying initial events of mucosal entry of human immunodeficiency virus type-1 (HIV-1) in laboratory-based, physiologically relevant and high-throughput contexts may aid in designing effective strategies to block local transmission and spread of HIV-1. Several paradigms have been posited for how HIV-1 crosses mucosal barriers to establish infection based on two dimensional (2D) culture-based or animal-based models. Nevertheless, despite these models stemming from 2D culture and animal studies, monolayers of cells poorly replicate the complex niche that influences viral entry at mucosal surfaces, whereas animal models often inadequately reproduce human disease pathophysiology and are prohibitively expensive. Organoids, having never been directly utilized in HIV-1 transmission investigations, may offer a compromise between 2D culture and animal models as they provide a platform that mimics the biophysical and biochemical niche of mucosal tissues. Importantly, observation of events downstream of viral inoculation is potentially accessible to researchers via an array of microscopy techniques. Because of the potential insights organoids may provide in this context, we offer this review to highlight key physiological factors of HIV-1 transmission at common mucosal sites and a discussion to highlight how many of these factors can be recapitulated in organoids, their current limitations and what questions can initially be addressed, particularly using a selective inclusion of quantitative light microscopy techniques. Harnessing organoids for direct observation of HIV-1 entry at mucosal sites may uncover potential therapeutic targets which prevent the establishment of HIV-1 infection.