Human Immunodeficiency Virus Life Cycle Research Articles

Investigating the Current and Novel Methods for the Treatment of HIV

Human immunodeficiency virus (HIV), a retrovirus that primarily infects CD4 receptor-bearing cells, can cause significant immune system dysfunction in humans. Although antiretroviral therapy (ART) has extended the life expectancy of individuals with HIV, challenges persist due to drug resistance, adherence issues, and side effects. This review examines both established and emerging HIV treatment strategies, including ART and novel agents like fostemsavir and ibalizumab. It also explores innovative approaches such as therapeutic vaccines, transdermal drug delivery systems (TDDS), hematopoietic stem cell transplantation (HSCT), and chimeric antigen receptor T (CAR-T) cell therapy. The role of artificial intelligence (AI) and machine learning (ML) in optimizing patient care and predicting treatment outcomes is also highlighted. A comprehensive understanding of HIVs life cycle and the challenges of current therapies is crucial for developing more effective treatments and interventions for HIV prevention and management

Involvement of Human Cellular Proteins and Structures in Realization of the HIV Life Cycle: A Comprehensive Review, 2024.

Human immunodeficiency virus (HIV) continues to be a global health challenge, with over 38 million people infected by the end of 2022. HIV-1, the predominant strain, primarily targets and depletes CD4+ T cells, leading to immunodeficiency and subsequent vulnerability to opportunistic infections. Despite the progress made in antiretroviral therapy (ART), drug resistance and treatment-related toxicity necessitate novel therapeutic strategies. This review delves into the intricate interplay between HIV-1 and host cellular proteins throughout the viral life cycle, highlighting key host factors that facilitate viral entry, replication, integration, and immune evasion. A focus is placed on actual findings regarding the preintegration complex, nuclear import, and the role of cellular cofactors such as FEZ1, BICD2, and NPC components in viral transport and genome integration. Additionally, the mechanisms of immune evasion via HIV-1 proteins Nef and Vpu, and their interaction with host MHC molecules and interferon signaling pathways, are explored. By examining these host-virus interactions, this review underscores the importance of host-targeted therapies in complementing ART, with a particular emphasis on the potential of genetic research and host protein stability in developing innovative treatments for HIV/AIDS.

The role of heat shock proteins in HIV-1 pathogenesis: a systematic review investigating HSPs-HIV-1 correlations and interactions.

The human immunodeficiency virus (HIV) pandemic is a global health emergency. Studies suggest a connection between heat shock proteins (HSPs) and HIV-1 infection pathogenesis. This systematic review aims to summarize HSPs' role in HIV-1 infection pathogenesis. A systematic literature search was undertaken across the National Library of Medicine (MEDLINE-PubMed), Science Direct, Web of Science, Scopus, SpringerLink, Sage, ProQuest, and Google Scholar databases, using related keywords to synthesize the HSPs' role in HIV-1 infection pathogenesis. This literature review was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, and the protocol was registered in the Open Science Framework (OSF) database under DOI 10.17605/OSF.IO/VK3DJ. A database search revealed 3,332 articles, with 14 in vitro studies analysing the interaction between HSPs and HIV-1 across different cell types. HSPs are involved in HIV-1 infection through direct interactions and indirect responses to cellular stress, including HSP40, HSP70, HSPBP1, and HSP90. The study explores HSP interactions at various stages of the viral life cycle, including entry, uncoating, replication, transmission, and latency reactivation. HSPs are crucial for the HIV lifecycle and immune response, offering the potential for new therapeutic strategies. Further research is needed to understand the clinical significance and target potential.

Hybrid Virtual Screening Approach to Predict Novel Natural Compounds against HIV-1 CCR5.

Human immunodeficiency virus (HIV) infection continues to pose a major global health challenge. HIV entry into host cells via membrane fusion mediated by the viral envelope glycoprotein gp120/gp41 is a key step in the HIV life cycle. CCR5, expressed on CD4+ T cells and macrophages, acts as a coreceptor facilitating HIV-1 entry. The CCR5 antagonist maraviroc is used to treat HIV infection. However, it can cause adverse effects and has limitations such as only inhibiting CCR5-tropic viruses. There remains a need to develop alternative CCR5 inhibitors with improved safety profiles. Natural products may offer advantages over synthetic inhibitors including higher bioavailability, binding affinity, effectiveness, lower toxicity, and molecular diversity. However, screening the vast chemical space of natural compounds to identify novel CCR5 inhibitors presents challenges. This study aimed to address this gap through a hybrid ligand-based pharmacophore modeling and molecular docking approach to virtually screen large natural product databases. A reliable pharmacophore model was developed based on 311 known CCR5 antagonists and validated against an external data set. Five natural product databases containing over 306,000 compounds were filtered based on drug-likeness rules. The validated pharmacophore model screened the databases to identify 611 hits. Key residues of the CCR5 receptor crystal structure were identified for docking. The top hits were docked, and interactions were analyzed. Molecular dynamics simulations were conducted to examine complex stability. Computational prediction evaluated pharmacokinetic properties. Three compounds exhibited similar interactions and binding energies to maraviroc. MD simulations demonstrated complex stability comparable to maraviroc. One compound showed optimal predicted absorption, minimal metabolism, and a lower likelihood of interactions than maraviroc. This computational screening workflow identified three natural compounds with promising CCR5 inhibition and favorable pharmacokinetic profiles. One compound emerged as a lead based on bioavailability potential and minimal interaction risk. These findings present opportunities for developing alternative CCR5 antagonists and warrant further experimental investigation. Overall, the hybrid virtual screening approach proved effective for mining large natural product spaces to discover novel molecular entities with drug-like properties.

Modeling and Analysis of HIV-1 Pol Polyprotein as a Case Study for Predicting Large Polyprotein Structures.

Acquired immunodeficiency syndrome (AIDS) is caused by human immunodeficiency virus (HIV). HIV protease, reverse transcriptase, and integrase are targets of current drugs to treat the disease. However, anti-viral drug-resistant strains have emerged quickly due to the high mutation rate of the virus, leading to the demand for the development of new drugs. One attractive target is Gag-Pol polyprotein, which plays a key role in the life cycle of HIV. Recently, we found that a combination of M50I and V151I mutations in HIV-1 integrase can suppress virus release and inhibit the initiation of Gag-Pol autoprocessing and maturation without interfering with the dimerization of Gag-Pol. Additional mutations in integrase or RNase H domain in reverse transcriptase can compensate for the defect. However, the molecular mechanism is unknown. There is no tertiary structure of the full-length HIV-1 Pol protein available for further study. Therefore, we developed a workflow to predict the tertiary structure of HIV-1 NL4.3 Pol polyprotein. The modeled structure has comparable quality compared with the recently published partial HIV-1 Pol structure (PDB ID: 7SJX). Our HIV-1 NL4.3 Pol dimer model is the first full-length Pol tertiary structure. It can provide a structural platform for studying the autoprocessing mechanism of HIV-1 Pol and for developing new potent drugs. Moreover, the workflow can be used to predict other large protein structures that cannot be resolved via conventional experimental methods.

HIV and Drug-Resistant Subtypes

Acquired Immunodeficiency Syndrome (AIDS) is a human viral infectious disease caused by the positive-sense single-stranded (ss) RNA Human Immunodeficiency Virus (HIV) (Retroviridae family, Ortervirales order). HIV-1 can be distinguished into various worldwide spread groups and subtypes. HIV-2 also causes human immunodeficiency, which develops slowly and tends to be less aggressive. HIV-2 only partially homologates to HIV-1 despite the similar derivation. Antiretroviral therapy (ART) is the treatment approved to control HIV infection, based on multiple antiretroviral drugs that belong to different classes: (i) NNRTIs, (ii) NRTIs, (iii) PIs, (iv) INSTIs, and (v) entry inhibitors. These drugs, acting on different stages of the HIV life cycle, decrease the patient's total burden of HIV, maintain the function of the immune system, and prevent opportunistic infections. The appearance of several strains resistant to these drugs, however, represents a problem today that needs to be addressed as best as we can. New outbreaks of strains show a widespread geographic distribution and a highly variable mortality rate, even affecting treated patients significantly. Therefore, novel treatment approaches should be explored. The present review discusses updated information on HIV-1- and HIV-2-resistant strains, including details on different mutations responsible for drug resistance.

Molecular Modeling and Docking Studies of 2,4,5-Trisubstituted Pyrimidines as HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitors

Human immunodeficiency virus (HIV) reverse transcriptase (RT) works in the life cycle of HIV and is one of the key targets for anti-HIV-1 drug development. Recently, a novel series of diarylpyrimidine derivatives (DAPYs) have been reported as potent HIV-1 non-nucleoside RT inhibitors (NNRTIs), and they exhibit potent antiviral activity. Here we explored the binding interaction patterns of a set of 2,4,5-trisubstituted pyrimidine derivatives using molecular docking, three-dimensional quantitative structure–activity relationships (3D-QSAR), and molecular dynamics (MD) simulations. Molecular docking for exploring the mechanism of action of small molecule ligands with receptor proteins. Comparative molecular field (CoMFA q 2 = 0.828, r 2 = 0.988, r 2 pred = 0.981) and comparative molecular similarity index (CoMSIA q2 = 0.859, r 2 = 0.968, r 2 pred = 0.980) were performed to build stable and reliable 3D-QSAR models. The contour plots revealed the relationship between structural features and inhibitory activities. Based on the molecular docking analysis and contour maps, some novel compounds with higher predicted activities were designed and further MD simulations and bind free energy calculations were performed. Our models results may provide an essential reference for the design and development of effective novel HIV-1 NNRTIs.

A functional map of HIV-host interactions in primary human T cells

Human Immunodeficiency Virus (HIV) relies on host molecular machinery for replication. Systematic attempts to genetically or biochemically define these host factors have yielded hundreds of candidates, but few have been functionally validated in primary cells. Here, we target 426 genes previously implicated in the HIV lifecycle through protein interaction studies for CRISPR-Cas9-mediated knock-out in primary human CD4+ T cells in order to systematically assess their functional roles in HIV replication. We achieve efficient knockout (>50% of alleles) in 364 of the targeted genes and identify 86 candidate host factors that alter HIV infection. 47 of these factors validate by multiplex gene editing in independent donors, including 23 factors with restrictive activity. Both gene editing efficiencies and HIV-1 phenotypes are highly concordant among independent donors. Importantly, over half of these factors have not been previously described to play a functional role in HIV replication, providing numerous novel avenues for understanding HIV biology. These data further suggest that host-pathogen protein-protein interaction datasets offer an enriched source of candidates for functional host factor discovery and provide an improved understanding of the mechanics of HIV replication in primary T cells.

An in silico molecular modeling approach of halolactone derivatives as potential inhibitors for human immunodeficiency virus type-1 reverse transcriptase enzyme

Acquired Immune Deficiency Syndrome (AIDS) is an infectious disease caused by Human Immunodeficiency Virus (HIV) infection and its replication requires the Reverse Transcriptase (RT) enzyme. RT plays a key role in the HIV life cycle, making it one of the most important targets for designing new drugs. Thus, in order to increase therapeutic options against AIDS, halolactone derivatives (D-halolactone) that have been showed as potential non-nucleoside inhibitors of the RT enzyme were studied. In the present work, a series of D-halolactone were investigated by molecular modeling studies, combining Three-dimensional Quantitative Structure-Activity Relationship (3 D-QSAR), molecular docking and Molecular Dynamics (MD) techniques, to understand the molecular characteristics that promote biological activity. The internal and external validation parameters indicated that the 3 D-QSAR model has good predictive capacity and statistical significance. Contour maps provided useful information on the structural characteristics of compounds for anti-HIV-1 activity. The docking results showed that D-halolactone present good complementarity by the RT allosteric site. In MD simulations it was observed that the formation of enzyme-ligand complexes were favorable, and from the free energy decomposition it was found that Leu100, Val106, Tyr181, Try188, and Trp229 are key residues for stabilization in the enzymatic site. Thus, the results showed that the proposed models can be used to design promising HIV-1 RT inhibitors. Communicated by Ramaswamy H. Sarma

In Vitro Antiviral Activity of Mentha cordifolia Plant Extract in HIV-1 Latently Infected Cells Using an Established Human Cell Line.

Emergence of drug resistance demands new therapeutic strategies against the human immunodeficiency virus (HIV). Currently, there is an increasing research focus on targeting gene expression-the crucial step wherein new viruses and new viral strains are amplified. Moreover, natural products are also being considered as potential candidates for new antivirals. We screened the extract obtained from a Philippine medicinal plant, Mentha cordifolia (Mc). In this study, we demonstrated that Mc ammonium sulfate extract has antiretroviral activity against HIV. HIV-1 latently infected cells (OM10.1) were pretreated with Mc extract and activated with TNFα. In treated cells, viral replication was inhibited in both cell culture supernatant and whole cell lysates. The level of viral production, as measured by the viral p24 protein concentration, was very much inhibited under noncytotoxic concentrations to the similar level without addition of TNFα. Luciferase assays, however, showed that Mc does not inhibit the HIV-1 long terminal repeat-driven gene expression. IκBα degradation and p65 nuclear translocation was also not affected as visualized through Western blot and immunofluorescence. These observations demonstrated that Mc possessed an antiviral component against HIV-1 and warrant further work to explore its target of action at a later step of gene expression. Our study introduces a potential source of a lead compound that targets steps in the HIV life cycle.

HIV-1 Latency and Viral Reservoirs: Existing Reversal Approaches and Potential Technologies, Targets, and Pathways Involved in HIV Latency Studies.

Eradication of latent human immunodeficiency virus (HIV) infection is a global health challenge. Reactivation of HIV latency and killing of virus-infected cells, the so-called “kick and kill” or “shock and kill” approaches, are a popular strategy for HIV cure. While antiretroviral therapy (ART) halts HIV replication by targeting multiple steps in the HIV life cycle, including viral entry, integration, replication, and production, it cannot get rid of the occult provirus incorporated into the host-cell genome. These latent proviruses are replication-competent and can rebound in cases of ART interruption or cessation. In general, a very small population of cells harbor provirus, serve as reservoirs in ART-controlled HIV subjects, and are capable of expressing little to no HIV RNA or proteins. Beyond the canonical resting memory CD4+ T cells, HIV reservoirs also exist within tissue macrophages, myeloid cells, brain microglial cells, gut epithelial cells, and hematopoietic stem cells (HSCs). Despite a lack of active viral production, latently HIV-infected subjects continue to exhibit aberrant cellular signaling and metabolic dysfunction, leading to minor to major cellular and systemic complications or comorbidities. These include genomic DNA damage; telomere attrition; mitochondrial dysfunction; premature aging; and lymphocytic, cardiac, renal, hepatic, or pulmonary dysfunctions. Therefore, the arcane machineries involved in HIV latency and its reversal warrant further studies to identify the cryptic mechanisms of HIV reservoir formation and clearance. In this review, we discuss several molecules and signaling pathways, some of which have dual roles in maintaining or reversing HIV latency and reservoirs, and describe some evolving strategies and possible approaches to eliminate viral reservoirs and, ultimately, cure/eradicate HIV infection.

Exploring the Mechanisms of Drug Resistance with a 3D Molecular Model of HIV Protease

Human immunodeficiency virus (HIV) affects 37 million people worldwide. HIV causes Acquired Immunodeficiency Syndrome (AIDS) by impairing the immune functions in the human body and is transmitted through contact of body fluid. HIV attacks the body’s immune system, specifically CD4 T cells which help the immune system fight off infection. Antiretroviral therapy (ART) has prolonged the life expectancy of those under the treatment process. ART is a combination of antiretroviral drugs that keep the virus from replicating. The drug combination “cocktail” combines the power of multiple drugs to block multiple targets in HIV replication. HIV‐1 protease is an essential enzyme for the life cycle of HIV. Therefore, HIV‐1 protease is an important target used in antiretroviral therapy. However, under the selective pressure of protease inhibitors, mutations may occur at the active site, crippling inhibitor binding and leading to drug resistance. Umass6 is an analog of the HIV protease inhibitor, duranovir, with a bulky P1′ moiety that allows enhanced overall van der Waals interactions at the active site. Here, we design a 3D model of the drug resistant HIV protease mutant I50V bound to UMass6 using Jmol based on the crystal structure described by Gordon J. Lockbaum and colleagues (1). HIV protease is a homodimer with the active site located in the interface between the subunits. Our model highlights the location of the I50V mutation within the active site and the resulting structural changes that cause the loss of inhibitor potency. Our 3D model also highlights the critical residues involved in inhibitor binding and the catalytic residue, D25, within the active site. Designing 3D model exposes students to protein structure, mutations, and tools for understanding drug resistance.Support or Funding InformationThis work is supported by NSF‐DUE1725940 and NSF‐HRD1623340.

Role of medicinal plants in HIV/AIDS therapy.

Human immunodeficiency virus (HIV) causes the potentially life-threatening and chronic disease called acquired immune deficiency syndrome (AIDS). The main target of this viral disease is to suppress the immune system and make the body unresponsive to external stimuli. According to global health observatory data since epidemic, more than 78 million people were affected by HIV and 39 million people died globally. Until 2017, 36.5 million people were living with HIV. An estimated 0.8% (0.6%-0.9%) of adults aged 15-49years worldwide is living with HIV. The World Health Organization (WHO) reported that the African region remains most severely affected, with nearly one in every 25 adults (4.1%) living with HIV and accounting for nearly two-thirds of the people living with HIV worldwide. WHO reported that globally only 21.7 million (19.1 million-22.6 million) people have had access to antiretroviral therapy up to 2017. Currently, antiretroviral therapy (ART) is available for the control of HIV but has serious associated side effects such as lipodystrophy. Because of the limitations, associated with ART, researchers throughout the world are trying to explore and develop more reliable and safe drugs from natural resources to manage HIV infection. A wide range of medicinal plants have been studied and have reported significant potential against HIV. Plants like Rheum palmatum L., Rheum officinale, Trigonostem axyphophylloides, Vatica astrotricha, Vernonia amygdalina, Hypoxias pelargonium, Sidoides hemerocallidea and Sutherlandia frutescens etc. have high efficacy to cure HIV. The exact mechanism of action is still not known but various phytoconstituents isolated from medicinal plants such as alkaloids, flavonoids, polyphenols, terpenoids, tannins, proteins and coumarins have the potential to interrupt the life cycle of HIV as well as act as immunomodulators to enhance the immune system of infected patients with no well reported side effects. It could be concluded that medicinal plants have potential for the management of HIV/AIDS but more studies are needed to reveal rigorous efficacy and safety concerns by conducting clinical trials at vast level to explore therapeutic impact of medicinal plants.

Anti-HIV/AIDS Drugs: An Overview

Human Immunodeficiency Virus (HIV) is an enveloped virus, belonging to the viral family Retroviridae. It is a highly evolved virus which has grasped the attention of all researchers with its special features like morphology, genetics and also by its emerging nature3. The special feature of all retro viruses is the presence of an enzyme called Reverse transcriptase which plays major role in reverse transcription process4. HIV enters the host body, damages immune system and will cause life-threatening opportunistic infections finally leads to AIDS (Acquired Immunodeficiency Syndrome).Many advances have been made in the prevention of HIV transmission and management of HIV/AIDS since the virus was discovered in the early 1980s7. One of the most important discoveries has been antiretroviral treatment, which can halt the replication of HIV and ease symptoms, turning AIDS into a chronic condition instead of a rapidly terminal illness. Despite advances, HIV remains a major public health challenge. This article reviews the genus, life cycle, and transmission of HIV, as well as workplace issues surrounding the virus and the challenges of developing an HIV vaccine12. Keywords: Acquired Immunodeficiency Syndrome.

Molecular dissection of an inhibitor targeting the HIV integrase dependent preintegration complex nuclear import.

Human immunodeficiency virus (HIV) continues to be a major contributor to morbidity and mortality worldwide, particularly in developing nations where high cost and logistical issues severely limit the use of current HIV therapeutics. This, combined HIV's high propensity to develop resistance, means that new antiviral agents against novel targets are still urgently required. We previously identified novel anti‐HIV agents directed against the nuclear import of the HIV integrase (IN) protein, which plays critical roles in the HIV lifecycle inside the cell nucleus, as well as in transporting the HIV preintegration complex (PIC) into the nucleus. Here we investigate the structure activity relationship of a series of these compounds for the first time, including a newly identified anti‐IN compound, budesonide, showing that the extent of binding to the IN core domain correlates directly with the ability of the compound to inhibit IN nuclear transport in a permeabilised cell system. Importantly, compounds that inhibited the nuclear transport of IN were found to significantly decrease HIV viral replication, even in a dividing cell system. Significantly, budesonide or its analogue flunisolide, were able to effect a significant reduction in the presence of specific nuclear forms of the HIV DNA (2‐LTR circles), suggesting that the inhibitors work though blocking IN, and potentially PIC, nuclear import. The work presented here represents a platform for further development of these specific inhibitors of HIV replication with therapeutic and prophylactic potential.

Nano-Medicine as a Newly Emerging Approach to Combat Human Immunodeficiency Virus (HIV)

Human Immuno deficiency Virus (HIV) infection has attained pandemic level due to its complexity on both the HIV infection cycle and on the targets for drug delivery. This limits medication and consequently requires prominent and promising drug delivery systems to be invented. Notably, various nanomaterial have been studied to enhance effective delivery of the antiretroviral drugs for HIV prevention, diagnosis and cure. Some of these nanomaterials are liposomes, dendrimers, inorganic nanoparticles (NPs), polymeric micelles, natural and synthetic polymers. The present study aimed to review the recent progress in nanomedicine as a newly emerging approach to combat HIV. The scientific data bases reviewed carefully to find both in vitro and in vivo studies representing the role of nonomedicine to combat HIV. Impressively, nanomedicine drug delivery systems have been commendable in various models ranging from in vitro to in vivo. It gives notion about the application of nano-carrier systems for the delivery of anti-retroviral drugs which ideally should provide better distribution to surpass Blood- Brain Barrier (BBB) and other tissue or to overcome innate barriers such as mucus. Considerably, nanomaterials such as dendrimers and many other inorganic NPs such as silver, gold, iron, and zinc can be used for HIV treatment by interfering in varying stages of HIV life cycle. Furthermore, NPs could best act as adjuvants, convoys during vaccine delivery, as intra-vaginal microbicides and for the early detection of HIV-1 p24 antigen. Nanomedicine may be a proper approach in HIV/AIDS therapy by means of offering lower dosage and side effect, better patient-to-patient consistency, bioavailability, target specificity and improved sensitivity of HIV diagnosis.

Multiple Inhibitory Factors Act in the Late Phase of HIV-1 Replication: a Systematic Review of the Literature.

The use of lentiviral vectors for therapeutic purposes has shown promising results in clinical trials. The ability to produce a clinical-grade vector at high yields remains a critical issue. One possible obstacle could be cellular factors known to inhibit human immunodeficiency virus (HIV). To date, five HIV restriction factors have been identified, although it is likely that more factors are involved in the complex HIV-cell interaction. Inhibitory factors that have an adverse effect but do not abolish virus production are much less well described. Therefore, a gap exists in the knowledge of inhibitory factors acting late in the HIV life cycle (from transcription to infection of a new cell), which are relevant to the lentiviral vector production process. The objective was to review the HIV literature to identify cellular factors previously implicated as inhibitors of the late stages of lentivirus production. A search for publications was conducted on MEDLINE via the PubMed interface, using the keyword sequence "HIV restriction factor" or "HIV restriction" or "inhibit HIV" or "repress HIV" or "restrict HIV" or "suppress HIV" or "block HIV," with a publication date up to 31 December 2016. Cited papers from the identified records were investigated, and additional database searches were performed. A total of 260 candidate inhibitory factors were identified. These factors have been identified in the literature as having a negative impact on HIV replication. This study identified hundreds of candidate inhibitory factors for which the impact of modulating their expression in lentiviral vector production could be beneficial.

Chemokines and Chemokine Receptors: Accomplices for Human Immunodeficiency Virus Infection and Latency.

Chemokines are small chemotactic cytokines that are involved in the regulation of immune cell migration. Multiple functional properties of chemokines, such as pro-inflammation, immune regulation, and promotion of cell growth, angiogenesis, and apoptosis, have been identified in many pathological and physiological contexts. Human immunodeficiency virus (HIV) infection is characterized by persistent inflammation and immune activation during both acute and chronic phases, and the “cytokine storm” is one of the hallmarks of HIV infection. Along with immune activation after HIV infection, an extensive range of chemokines and other cytokines are elevated, thereby generating the so-called “cytokine storm.” In this review, the effects of the upregulated chemokines and chemokine receptors on the processes of HIV infection are discussed. The objective of this review was to focus on the main chemokines and chemokine receptors that have been found to be associated with HIV infection and latency. Elevated chemokines and chemokine receptors have been shown to play important roles in the HIV life cycle, disease progression, and HIV reservoir establishment. Thus, targeting these chemokines and receptors and the other proteins of related signaling pathways might provide novel therapeutic strategies, and the evidence indicates a promising future regarding the development of a functional cure for HIV.

Current Status of the Pharmacokinetics and Pharmacodynamics of HIV-1 Entry Inhibitors and HIV Therapy.

Human Immunodeficiency Virus (HIV) entry inhibitors target the first step of the HIV life cycle and efficiently inhibit HIV from infecting the immune cells which is a key prerequisite for viral spread. Because of their unique mechanism of action on cell-cell transmission, they may provide a promising perspective for the treatment of AIDS. Maraviroc (MVC) and Enfuvirtide (ENF) have been approved by the FDA for the treatment of HIV-1 infection. Attachment inhibitors (BMS-663068 and TNX-355) and co-receptor inhibitors (PRO-140 and cenicriviroc (CVC)) have reached phase II or III clinical trials. These entry inhibitors show beneficial pharmacokinetics and substantial reductions of plasma HIV-1 RNA load in HIV infected patients. Most entry inhibitors are generally safe, without serious Adverse Event (AE) or AE leading to discontinuation. The pharmacokinetics of MVC, CVC and BMS-663068 was affected by CYP3A4 inhibitors or inducers. The FDA has proposed that the dosage of MVC (300 mg, BID, orally) be adjusted to half or two-fold for patients if it is combined with a major CYP3A4 inhibitor or inducer, respectively. Researchers suggested that the dosage of CVC (50-75 mg, QD, orally) may also need adjustment but the dosage of BMS-663068 (600 mg, BID, orally) does not. The standard, recommended ENF dosage is 90 mg BID, injected subcutaneously for adults, and 2 mg/kg BID, up to a maximum dose of 90 mg, injected subcutaneously for pediatric patients. TNX-355 (10-15 mg/kg, BID, intravenously) and PRO-140(5-10 mg/kg, BID, intravenously; 324 mg, biweekly, subcutaneously) are administered by intravenous infusion or subcutaneous injection.

Quantitative Temporal Viromics of an Inducible HIV-1 Model Yields Insight to Global Host Targets and Phospho-Dynamics Associated with Protein Vpr

The mechanisms by which human immunodeficiency virus (HIV) circumvents and coopts cellular machinery to replicate and persist in cells are not fully understood. HIV accessory proteins play key roles in the HIV life cycle by altering host pathways that are often dependent on post-translational modifications (PTMs). Thus, the identification of HIV accessory protein host targets and their PTM status is critical to fully understand how HIV invades, avoids detection and replicates to spread infection. To date, a comprehensive characterization of HIV accessory protein host targets and modulation of their PTM status does not exist. The significant gap in knowledge regarding the identity and PTMs of HIV host targets is due, in part, to technological limitations. Here, we applied current mass spectrometry techniques to define mechanisms of viral protein action by identifying host proteins whose abundance is affected by the accessory protein Vpr and the corresponding modulation of down-stream signaling pathways, specifically those regulated by phosphorylation. By utilizing a novel, inducible HIV-1 CD4+ T-cell model system expressing either the wild type or a vpr-negative viral genome, we overcame challenges associated with synchronization and infection-levels present in other models. We report identification and abundance dynamics of over 7000 proteins and 28,000 phospho-peptides. Consistent with Vpr's ability to impair cell-cycle progression, we observed Vpr-mediated modulation of spindle and centromere proteins, as well as Aurora kinase A and cyclin-dependent kinase 4 (CDK4). Unexpectedly, we observed evidence of Vpr-mediated modulation of the activity of serine/arginine-rich protein-specific kinases (SRPKs), suggesting a possible role for Vpr in the regulation of RNA splicing. This study presents a new experimental system and provides a data-resource that lays the foundation for validating host proteins and phosphorylation-pathways affected by HIV-1 and its accessory protein Vpr.