Current HIV Research - Volume 14, Issue 3, 2016

Background: Similar to other animal viruses, HIV-1 relies on the contributions of the cellular machinery to ensure efficient virus propagation. However, human cells have evolved refined mechanisms to block key steps of the virus life-cycle, thereby suppressing viral replication. These cellular proteins are generally known as restriction factors, and they provide an early antiviral defense. So far, five potent restriction factors have been shown to effectively block HIV and/or SIV replication. These are TRIM5 proteins, SAMHD-1, members of the APOBEC3 (A3) family, Mx2 and Tetherin/BST-2. Results: Here, we review the antiviral mechanisms of these and other antiviral factors, their interaction with the innate immune responses, and how their functions might be exploited to clear and prevent HIV infection. Conclusion: Since the majority of vaccine approaches against HIV have failed so far, it is imperative to start looking at alternative strategies for vaccine and therapy development. By better understanding how HIV hijacks the cellular machinery for its own benefit in completing its life-cycle, and how the virus adapts to circumvent our intrinsic immunity, we will be better equipped to design compounds that specifically interrupt virus replication and spread.

Background: Human immunodeficiency virus 1 (HIV-1) infection is the primary cause of the acquired immunodeficiency syndrome (AIDS). Worldwide, approximately 37 million people are infected (UNAIDS, 2014), most of them in developing countries. A vaccine is not available and current treatment strategies and diagnostics are expensive and require appropriate medical infrastructure. As a lentivirus of the family Retroviridae, HIV-1 reverse transcribes its RNA into double stranded DNA that integrates into the host genome during infection, establishing a stably integrated provirus that serves as a template for the production of progeny virus. The earliest steps during infection are critical for onset of disease, progression and clinical outcome. Methods: Here we review the current literature of known interactions between host cell factors and HIV-1 in the early infection steps and discuss them as possible targets for new treatment strategies. Results: Targeting the earliest interactions of the virus with host cell factors is an attractive way to prevent provirus formation, underlined by the evolution of multiple antiviral host cell barriers at this stage. HIV-1 has to overcome these restrictions by either counteracting them directly or by escape mutations. At the same time, viral fitness requires preservation of viral structures that interact with host components, thereby avoiding recognition of viral nucleic acids, like reverse transcription intermediates, by innate pattern recognition receptors. Conclusion: Future drug development, improvement of existing drugs acting in the earliest stages of the HIV-1 replication cycle as well as specifically targeting interactions of viral components with host cell factors required for HIV-1 infection will likely advance current therapy strategies.

Background: In the past decade, the identification and characterization of antiviral genes with the ability to interfere with virus replication has established cell-intrinsic innate immunity as a third line of antiviral defense in addition to adaptive and classical innate immunity. Understanding how cellular factors have evolved to inhibit HIV-1 reveals particularly vulnerable points of the viral replication cycle. Many, but not all, antiviral proteins share type I interferon-upregulated expression and sensitivity to viral counteraction or evasion measures. Whereas well-established restriction factors interfere with early post-entry steps and release of HIV-1, recent research has revealed a diverse set of proteins that reduce the infectious quality of released particles using individual, to date poorly understood modes of action. These include induction of paucity of mature glycoproteins in nascent virions or self-incorporation into the virus particle, resulting in poor infectiousness of the virion and impaired spread of the infection. Conclusion: A better understanding of these newly discovered antiviral factors may open new avenues towards the design of drugs that repress the spread of viruses whose genomes have already integrated.

Background: To suppress HIV infection, host cells have evolved numerous defenses that generally belong to the innate and adaptive immune responses. Over the last decade, extensive efforts have been focused on understanding HIV restriction factors and mechanisms of evasion. The host protein APOBEC3G (A3G) was identified as a member of cytidine deaminase family in 2002, and it was shown that, in the absence of HIV encoded Vif, A3G can block the replication of HIV-1 by introducing viral hypermutations during reverse transcription, also conferring innate immunity to the virus. Hence, therapeutic exploitation of A3G as an antiviral therapy has received an increasing amount of attention. Recent studies have developed a series of strategies to abolish the interaction between Vif and A3G or facilitate A3G expression, thus enhancing active A3G formation and delivering A3G into virion. Conclusion: Here we present a review that discuss the role of A3G as a host innate immunity factor and its application in HIV therapy.

Background: The antiviral restriction factor SAM domain and HD domain-containing protein 1 (SAMHD1) is a dNTP triphosphohydrolase and thereby contributes to the regulation of intracellular dNTP levels. SAMHD1 blocks retroviral infection at the level of reverse transcription in myeloid cells and resting CD4+ T cells and is counteracted by the accessory protein Vpx, which is encoded by human immunodeficiency virus 2 (HIV-2) and several simian immunodeficiency virus (SIV) strains. Recently, it has been shown that the antiviral activity of SAMHD1 in myeloid dendritic cells (DC) hampers the induction of an efficient immune response directed against HIV-1. Conclusion: Within this review, we will summarize recent advances on the biology of SAMHD1 and its function as an antiviral restriction factor. In addition, we will discuss its role in autoimmunity and the antiviral immune response directed against HIV-1 and will evaluate the possibility of modulating SAMHD1 activity to generate an enhanced antiretroviral immune response.

Background: Cell-mediated immune (CMI) responses are critical for the control of HIV-1 infection and their importance was highlighted by the existence of viral proteins, particularly Vpu and Nef, that antagonize these responses. Pandemic HIV-1 Vpu counteracts Tetherin/BST-2, a host factor that could prevent the release of HIV-1 virions by tethering virions on the cell surface, but a link between Tetherin and HIV-1 CMI responses has not yet been demonstrated in vivo. In vitro, the virological and immunological impact of Tetherin-mediated accumulation of virions ranged from enhanced or diminished cell-to-cell spread to enhanced recognition by virus-specific antibodies for natural killer cellmediated lysis. However, Tetherin-restricted virions could be internalized through an endocytosis motif in the Tetherin cytoplasmic tail. Methods: Given the uncertainties on which in vitro results manifest in vivo and the dearth of knowledge on how Tetherin influences retroviral immunity, in vivo retrovirus infections in mice encoding wild-type, null and endocytosis-defective Tetherin were performed. Here, we review and highlight the results from these in vivo studies. Results: Current data suggests that endocytosis-defective Tetherin functions as a potent innate restriction factor. By contrast, endocytosis-competent Tetherin, the form found in most mammals including humans and the form counteracted by HIV-1 Vpu, was linked to stronger CMI responses in mice. Conclusion: We propose that the main role of endocytosis-competent Tetherin is not to directly restrict retroviral replication, but to promote a more effective CMI response against retroviruses.

Background: Most of HIV infections occur via the genital tract or the rectum and HIV replicates at high levels in lymphoid organs and intestinal mucosa, likely requiring a more diversified immunity than pathogens restricted to a single mucosal site, such as the gastrointestinal tract for Vibrio cholera, or the respiratory airways for the influenza virus. Results: Numerous AIDS vaccine candidates are under development and a general observation obtained from preclinical trials in non-human primates that failed to provide sterilizing immunity is that some infection protection or delayed onset of disease is observed in the presence of anti-SIV immunity. Recent clinical trials support difficulties to reproduce in humans the results observed in simian models, but at least one of them indicated that some protection of infection can be achieved. However, given the limited efficacy observed in the RV144 trial and concerns voiced in its statistical interpretation, preclinical trials should explore more effective immunogens, whether new or as combinations of existing ones, and mucosal routes of vaccinations in addition to the systemic routes, with the goal to maximize vaccination-mediated protection. Conclusion: The rationale for generating both strong mucosal and systemic immunity comes from animal experiments, recent clinical trials, and other successful vaccines currently in use. Mucosal responses against SIV have been induced with a variety of SIV antigens and via different mucosal routes with a spectrum of effects on protection. This review covers the rational and the experimental data that support the validity to explore mucosal immunization for HIV infection and AIDS prevention.

Background: Over the years, numerous studies have been carried out demonstrating the role of antibodies in HIV control leading to the development of antibody-based therapeutic and prophylactic strategies. Objective: The objective of this review is to provide updated information on the role of antibodies in the prevention and control of HIV infection and the strategies against HIV that have been designed based on this information. Results: Passive transfer of anti-HIV antibodies in animal models has proven the efficacy of certain antibodies in the prevention and treatment of infection. The capacity of antibodies to control the virus was first attributed to their neutralizing capacity. However, we now know that there are other Fc-mediated antibody activities associated with virus protection. When it comes to better understanding protection against HIV, we ought to pay particular attention to mucosal immune responses. The evidence accumulated so far indicates that an effective vaccine against HIV should generate both mucosal IgAs and systemic IgGs. Due to the problematic induction of protective anti-HIV antibodies, several groups have developed alternative approaches based on antibody delivery via gene therapy vectors. Experiments in animal models with these vectors have shown impressive protection levels and this strategy is now being clinically trialed. Conclusion: Taking into account all the information included in this review, it seems evident that anti-HIV-1 antibodies play an important role in virus control and prevention. This review aims to give an overview of the strategies used and the advances in antibody-based preventive and therapeutic strategies against HIV-1.

Background: The infectious human immunodeficiency virus (HIV) particle is characterized by a conical capsid that encloses the viral RNA genome. The capsid is essential for HIV-1 replication and plays crucial roles in both early and late stages of the viral life cycle. Early on, upon fusion of the viral and cellular membranes, the viral capsid is released into the host cell cytoplasm and dissociates in a process known as uncoating, tightly associated with the reverse transcription of the viral genome. During the late stages of viral replication, the Gag polyprotein, precursor of the capsid protein, assemble at the plasma membrane to form immature non-infectious viral particles. After a maturation step by the viral protease, the capsid assembles to form a fullerene-like conical shape characteristic of the mature infectious particle. Mutations affecting the uncoating process, or capsid assembly and maturation, have been shown to hamper viral infectivity. The key role of capsid in viral replication and the absence of approved drugs against this protein have promoted the development of antiretrovirals. Screening based on the inhibition of capsid assembly and virtual screening for molecules binding to the capsid have successfully identified a number of potential small molecule compounds. Unfortunately, none of these molecules is currently used in the clinic. Conclusion: Here we review the discovery and the mechanism of action of the small molecules and peptides identified as capsid inhibitors, and discuss their therapeutic potential.

Background: The transmembrane subunit of the HIV envelope protein, gp41 is a vulnerable target to inhibit HIV entry. There is one fusion inhibitor T20 (brand name: Fuzeon, generic name: enfuvirtide) available by prescription. However, it has several drawbacks such as a high level of development of drug resistance, a short-half life in vivo, rapid renal clearance, low oral bioavailability, and it is only used as a salvage therapy. Therefore, investigators have been studying a variety of different modalities to attempt to overcome these limitations. Methods: Comprehensive literature searches were performed on HIV gp41, inhibition mechanisms, and inhibitors. The latest structural information was collected, and multiple inhibition strategies targeting gp41 were reviewed. Results: Many of the recent advances in inhibitors were peptide-based. Several creative modification strategies have also been performed to improve inhibitory efficacy of peptides and to overcome the drawbacks of T20 treatment. Small compounds have also been an area of intense research. There is a wide variety in development from those identified by virtual screens targeting specific regions of the protein to natural products. Finally, broadly neutralizing antibodies have also been important area of research. The inaccessible nature of the target regions for antibodies is a challenge, however, extensive efforts to develop better neutralizing antibodies are ongoing. Conclusion: The fusogenic protein, gp41 has been extensively studied as a promising target to inhibit membrane fusion between the virus and target cells. At the same time, it is a challenging target because the vulnerable conformations of the protein are exposed only transiently. However, advances in biochemical, biophysical, structural, and immunological studies are coming together to move the field closer to an understanding of gp41 structure and function that will lead to the development of novel drugs and vaccines.