Current HIV Research (v.10, #4)
Editorial: HIV-1 Vpu and BST-2/Tetherin: Enemies at the Gates by Kenzo Tokunaga (275-276).
Adaptation of Human and Simian Immunodeficiency Viruses for Resistance to Tetherin/BST-2 by Ruth Serra-Moreno (277-282).
Tetherin (BST-2 or CD317) is an interferon-inducible cellular factor that prevents the detachment of enveloped viruses from infected cells. The primate lentiviruses have evolved different countermeasures to tetherin. The majority of SIVs use Nef to antagonize the tetherin proteins of their nonhuman primate hosts. However, due to the absence of sequences in human tetherin required for antagonism by Nef, HIV-1 Vpu and HIV-2 Env evolved to serve this function in humans. We recently identified compensatory changes in the Env cytoplasmic domain of a pathogenic nef-deleted SIV that confers resistance to rhesus macaque tetherin. These observations highlight the extraordinary plasticity of the primate lentiviruses in adapting to the tetherin proteins of their respective hosts, and reveal a prominent role for tetherin in shaping the evolution of the primate lentiviruses.
Sites of Action of HIV-1 Vpu in BST-2/Tetherin Downregulation by Juan F. Arias (283-291).
The interferon-inducible host restriction factor bone marrow stromal antigen 2 (BST-2/tetherin) blocks the release of human immunodeficiency virus type 1 (HIV-1) by directly cross-linking virions to the membrane of infected cells. This antiviral effect is counteracted by the HIV-1 accessory protein viral protein U (Vpu) through mechanisms that remain unclear. Accumulating evidence suggests that Vpu antagonizes BST-2 by removing it from the plasma membrane; however, neither the cellular sites of interaction nor the effector mechanisms that result in the downregulation of BST-2 cell-surface expression have been fully determined. Based on current evidence regarding the subcellular localization of Vpu and BST-2 and the latter's trafficking defects induced by their interaction, three models have been proposed. In the first, Vpu is hypothesized to block the traffic of newly synthesized BST-2 towards the cell surface by retaining it in the biosynthetic/secretory compartment. The second model suggests that Vpu sequesters BST-2 within intracellular compartments corresponding to recycling endosomes and the trans-Golgi network by blocking its recycling after endocytosis. In the third model, we and others have proposed that Vpu directly internalizes BST-2 from the plasma membrane and induces its enhanced endolysosomal trafficking and degradation. As for its intracellular fate, the viral antagonism of BST-2 is likely dependent on the intracellular sequestration, or the proteasomal/lysosomal degradation of the restriction factor. This review summarizes the current advances in our understanding of the cellular pathways and sites of action of Vpu in the downregulation of cell-surface BST-2.
Transmembrane Interactions of HIV-1 Vpu and Tetherin by Fei Guo (292-297).
Tetherin is a type II membrane protein that bears a N-terminal transmembrane domain, an extracellular coiledcoil structure and a C-terminal GPI anchor. This unique topology allows tetherin to block the release of a wide range of enveloped viruses from the cell surface. In order to overcome this host restriction, viruses have evolved various counter measures. In the case of human immunodeficiency virus type 1 (HIV-1), the viral protein U (Vpu) is able to downmodulate cell surface tetherin, thus removing tetherin molecules from the site of virus budding. This activity of Vpu depends on its direct interaction with tetherin. In this review, we summarize the known molecular details of the interaction between Vpu and tetherin, and also discuss how tetherin is targeted by other viral antagonists. Following our summary, it is evident that each of the intracellular, transmembrane and extracellular domains of tetherin can become the target of viral antagonists for counteraction.
Structural Basis of Tetherin Function by Winfried Weissenhorn (298-306).
HIV-1 employs its structural proteins to orchestrate assembly and budding at the plasma membrane of host cells, which depends on numerous cellular factors. Although cells evolved interferon inducible restriction factors such as tetherin that act as a first line of defense, enveloped viruses, including HIV-1, developed countermeasures in the form of tetherin antagonists such as Vpu that decrease the effect of tetherin and permits normal viral replication in vivo. Here we review recent advances in the understanding of the dynamic structural properties of tetherin that provide the basis to physically retain HIV-1 by bridging plasma and virion membranes after completion of budding.
β-TrCP Dependency of HIV-1 Vpu-Induced Downregulation of CD4 and BST-2/Tetherin by Fabien P. Blanchet (307-314).
During evolution, pathogens have evolved strategies to counteract key cellular restriction mechanisms in order to efficiently invade target cells and fulfill essential steps of their replication cycle. Human Immunodeficiency Virus-1 and some Simian counterparts express a small multifunctional protein, Vpu, which influences viral replication. By acting as a multifunctional adapter, Vpu enhances viral particle release and infectivity. Therefore Vpu, an accessory protein, contributes to pathogenesis while avoiding superinfection. These effects rely mainly on the ability of Vpu to target the host proteins CD4 and BST-2/tetherin. Indeed, Vpu downregulates the cell surface expression of these receptors and subsequently induces their proteolysis via a mechanism involving a β -TrCP-containing E3 ubiquitin ligase complex. In this review, we will detail recent research aimed at elucidating the mechanism of Vpu-mediated CD4 and BST-2/tetherin downregulation and degradation as well as their subsequent consequences on viral pathogenesis.
Role of the Endosomal ESCRT Machinery in HIV-1 Vpu-Induced Down- Regulation of BST2/Tetherin by Katy Janvier (315-320).
The cellular protein “Bone marrow stromal antigen 2” (BST2 also called Tetherin, CD317, HM1.24) was identified as a major mediator of the innate immune defense against the dissemination of enveloped viruses. BST2 was shown to physically trap the de novo formed viral particles at the surface of infected cells, thereby reducing viral release. Lentiviruses have evolved specific strategies to down-regulate the expression level of BST2 from the surface of the cells and as such promote viral egress. In Human Immunodeficiency Virus-1 (HIV-1), the accessory protein Vpu counters BST2 antiviral activity. However, the cellular and molecular mechanisms involved are not fully understood. Vpumediated antagonism of BST2 antiviral activity seems to involve complex interplay between the viral protein and host components regulating protein turnover and vesicular trafficking. This review focuses on the interplay between Vpu and the ubiquitin/endosomal pathway in countermeasures of HIV-1 to BST2 restriction, with a particular emphasis on the “Endosomal Sorting Complexes Required for Transport” (ESCRT) machinery.
Intracellular Logistics of BST-2/Tetherin by Hideaki Fujita (321-326).
Bone marrow stromal antigen 2 (BST-2) is a type II membrane protein with two targeting signals, one of which is located in the cytoplasmic domain and contains a non-canonical dual tyrosine-based motif responsible for its endocytosis from the plasma membrane, and the other is a C-terminal glycosylphosphatidylinositol anchor that facilitates its association with detergent-resistant membranes/lipid rafts and targeting to the apical domain in polarized epithelial cells. Due to its unusual topology at the membrane, BST-2 takes unique and complicated trafficking routes in cells. Recently, a physiological role for BST-2 as the “tetherin” molecule for viruses, especially for HIV-1, has been extensively examined. These studies have shown that the biosynthesis, intracellular trafficking, localization, and structure of human BST-2 are closely related to its antiviral activity. This review provides an overview of the intracellular logistics of human BST-2.
HIV-1 Vpu Interference with Innate Cell-mediated Immune Mechanisms by Johan K. Sandberg (327-333).
The HIV-1 accessory protein Vpu is emerging as a viral factor with a range of activities devoted to counteracting host innate immunity. Here, we review recent findings concerning the role of Vpu in hampering activation of cellular immune responses mediated by CD1d-restricted invariant natural killer T (iNKT) cells and natural killer (NK) cells. The two key findings are that Vpu interferes with CD1d expression and antigen presentation, and also with expression of the NK cell activation ligand NK-T and B cell antigen (NTB-A). Both these activities are mechanistically distinct from CD4 and Tetherin (BST-2) down-modulation. We summarize the mechanistic insights gained into Vpu interference with CD1d and NTB-A, as well as important challenges going forward, and discuss these mechanisms in the context of the role that iNKT and NK cells play in HIV-1 immunity and immunopathogenesis
Response to Antiretroviral Treatment After Failure of NNRTI Plus NRTIs-Based Therapy. Data from the ARCA Collaborative Group by Elena Seminari (334-340).
Objective: The aim of the present study was to evaluate the virological response to a new antiretroviral treatment (ART2) after failure of a nonnucleoside reverse transcriptase inhibitor (NNRTI) plus two nucleoside reverse transcriptase inhibitors (NRTIs)-containing regimen. Design: Retrospective observational study based on the Italian ARCA cohort database. Adult patients were included if they had a virological failure (defined as plasma viral load above 500 copies/ml in two subsequent visits) while on a treatment with one NNRTI plus 2 NRTIs, had an available HIV genotype. Results: Patients on ART2 were followed up for 791 person/year and median follow up was 10.8 months(IQR 5.2-26). Variables associated with reduced risk of ART2 virological failure at univariable analysis had started the treatment in recent years (HR 0.90; 95% CI 0.86-0.94, p < 0.0001) and duration of previous NNRTI treatment (HR 0.995; 95%CI 0.990-0.990, p=0.045). Variables associated with increased risk of virological failure of ART2 were a higher plasma viral load (pVL) at baseline(HR 1.2; 95% CI 1.07-1.34, p=0.002) and the type of treatment, in particular an unboosted PIcontaining regimen vs. a boosted PI-containing regimen(HR 1.6; 95%CI 1.25-2.04 p < 0.0001) and a non–PI-containing vs. a boosted PI-containing regimen (HR 1.56; 95% CI 1.25-1.96, p < 0.0001). At multivariable analysis, year of ART2 start, pVL at NNRTI failure as well as using a boosted PI remained statistically significant predictors. Conclusion: This study highlights the role of drugs with high genetic barrier, such as boosted PI as a cornerstone to build a new antiretroviral treatment in patients failing a NNRTI based regimen.
Interleukin-7 Biology in HIV Disease and the Path to Immune Reconstitution by Scott F. Sieg (341-347).
Interleukin-7 (IL-7) is a cytokine that plays a critical role in T cell homeostasis by promoting proliferation and survival of mature T cells and also by enhancing thymic output for the generation of new T cells. IL-7 receptor expression and signaling function is perturbed in HIV infection and could contribute to disease pathogenesis. Even though highly active anti-retroviral therapy has markedly reduced morbidity and mortality in HIV-infected persons, there remains concern that a significant proportion of treated patients may experience relatively poor CD4+ T cell recovery despite sustained viral suppression. Recent human trials and animal studies suggest that IL-7 administration may provide a powerful tool to enhance T cell reconstitution in HIV-infected persons. The role of IL-7/IL-7 receptor perturbations in HIV pathogenesis and the potential to reconstitute immunity with IL-7 administration in the setting of HIV infection are important areas of investigation.
Minority HIV Patients’ Perceptions of Barriers and Facilitators to Participation in Clinical Research by Caitlin Wolak (348-355).
HIV clinical trials play an essential role in producing new HIV medications, developing guidelines for the appropriate timing of antiretroviral treatment, and evaluating behavioral interventions that aim to increase the quality of life of HIV-infected individuals. It is critical to have participation from all demographic groups, yet minorities are disproportionately underrepresented in HIV clinical research. This study assessed HIV+ minority patient perceptions of the barriers and benefits of participating in HIV clinical trials in an HIV clinic of a large, urban teaching hospital. Twentysix, age-eligible (18-65), minority patients were recruited and participated in three focus groups, separated by clinical research participation status. Results suggest differences in perceptions between those who had and had not participated. Facilitators for those who had participated included doctor recommendation and receiving extra medical attention. Those who had not participated indicated disclosure of HIV status, fear of losing the stability that their current medication regimen provided, distrust of the medical system and doubt about the origin of HIV were major deterrents of participation. Both groups indicated a need to better educate minority patients about what clinical research is and its benefits. To increase minority participation, it is vital to examine the perceptions of minority HIV-infected patients and develop culturally competent, developmentally appropriate messages that address these barriers.
Effectiveness of Antiretroviral Therapy in HIV-1-Infected Active Drug Users Attended in a Drug Abuse Outpatient Treatment Facility Providing a Multidisciplinary Care Strategy by Gabriel V. Sanchez (356-363).
Objective: HIV-1-infected active drug users (ADU) obtain smaller clinical benefits with antiretroviral therapy (HAART) compared to non-ADU subjects with sexually-transmitted HIV-1 infection. Therefore treatment strategies are required to address the specific issues arising in this challenging scenario. We describe the effectiveness of HAART provided in a drug abuse outpatient treatment facility through a comprehensive integrated care that includes medical, drug dependence, and psychosocial support. Methods: We included all consecutive HIV-1-infected ADU admitted for drug dependency treatment and who started their first HAART. A comparator arm consisted of a control group of sexually transmitted HIV-1-infected subjects attended in a reference hospital under standard care. The strategy did not include directly observed treatment. Results: A total of 71 ADU and 48 matched subjects infected through sexual transmission were included. ADU had lower baseline CD4+ T-cell counts (196 vs 279 cells/μL, P=.001), and more advanced CDC stages (P=.001). The estimated probabilities of patients with virological response ( < 50 copies/mL) at weeks 48 and 96 were 92.9% (95%-CI: 87.1%—99.1%) and 87.3% (95%-CI: 78.7%—95.2% for ADU, and 93.7%(95%-CI: 84.1%—99.8%) and 87.5% (95%-CI: 77.5%—97.3%) for sexually-infected subjects (P= .1325 and .241). Kaplan-Meier estimates of time to loss of virological response did not show differences between groups (log rank test, P=.965). Conclusions: An integrated multidisciplinary care of HIV-1-infected antiretroviral naïve ADU provided in a drug abuse treatment center obtains high rates of virological suppression, similar to those observed in a comparison group of sexually-transmitted HIV-1-infected subjects. This strategy should be further evaluated in public health programs and assessed in randomized trials.