Drug-resistant Human Immunodeficiency Virus Strains Research Articles

The anti-HIV potential of imidazole, oxazole and thiazole hybrids: A mini-review

Human immunodeficiency virus (HIV) especially HIV-1 infection and its progression to acquired immune deficiency syndrome (AIDS) remains a significant global health challenge. The advent of the highly active antiretroviral therapy (HAART) has greatly extended the life expectancy of patients living with HIV, but it has become evident that long-term HAART will not eliminate the HIV reservoir and cure the infection. Moreover, the drug resistance and undesirable side effects hamper efficacious therapy, creating an urgent need to develop novel, more effective and less toxic anti-HIV therapeutics. Imidazole, oxazole and thiazole with two heteroatoms at meta-position of five-membered rings are fascinating structures and constitute an important class of heterocycles in drug discovery. Their derivatives could exert the anti-HIV activity through diverse mechanisms and possess promising antiviral activity against both drug-sensitive and drug-resistant HIV strains. This review summarizes the research progress made regarding the anti-HIV potential of imidazole, oxazole and thiazole hybrids, and the structure–activity relationships (SARs) are also discussed to facilitate further rational design of more effective candidates, covering articles published from 2012 to 2022.

A Literature Review on Recent Advancements in the Treatment of Human Immunodeficiency Virus

Abstract: The aim of this study is to conduct an extensive literature review on recent advancements in the treatment of human immunodeficiency virus (HIV). This is because in extant studies, the care of the HIV infected patient has changed dramatically in the last few years. Potent new antiretroviral drugs combined with updated treatment strategies have now achieved efficient inhibition of HIV replication in most patients. Classes of drugs include both nucleoside and non-nucleoside inhibitors of the viral enzyme reverse transcriptase (RT) and inhibitors of the viral protease and integrase enzymes. The methodology used in this study was reviewed from secondary sources of information including journals, articles, newspaper, and textbooks. In this study, authors found that a major drawback of the highly active antiretroviral therapy (HAART) is the selection of resistant mutants under suboptimal dosage, in advanced stages of disease or after pre-treatment with mono- or double-combination regimens. In addition, monitoring of antiretroviral therapy is achieved by measurement of viral load using nucleic acid amplification techniques. Strict adherence to HIV drug regimens was reported to be essential for reaching and maintaining therapeutic levels of anti-retro-virals and avoiding development of drug-resistant HIV strains. This strict dosage-taking adherence makes HIV therapies among the most challenging treatments with which to adhere. Future researchers are encouraged to adopt a scientific approach in investigating the various constructs that have emerged in this study in other to provide more generalized findings for the research community and public policy makers. Keywords: Antiretroviral Drugs: Combination Therapy: Medication: Transmission: Inhibitors: Immune System.

Natural Products with Inhibitory Activity against Human Immunodeficiency Virus Type 1.

Infections caused by human immunodeficiency virus (HIV) are considered one of the main public health problems worldwide. Antiretroviral therapy (ART) is the current modality of treatment for HIV-1 infection. It comprises the combined use of several drugs and can decrease the viral load and increase the CD4+ T cell count in patients with HIV-1 infection, thereby proving to be an effective modality. This therapy significantly decreases the rate of morbidity and mortality owing to acquired immunodeficiency syndrome (AIDS) and prolongs and improves the quality of life of infected patients. However, nonadherence to ART may increase viral resistance to antiretroviral drugs and transmission of drug-resistant strains of HIV. Therefore, it is necessary to continue research for compounds with anti-HIV-1 activity, exhibiting a potential for the development of an alternative or complementary therapy to ART with low cost and fewer side effects. Natural products and their derivatives represent an excellent option owing to their therapeutic potential against HIV. Currently, the derivatives of natural products available as anti-HIV-1 agents include zidovudine, an arabinonucleoside derivative of the Caribbean marine sponge (Tectitethya crypta), which inhibits the reverse transcriptase of the virus. This was the first antiviral agent approved for treatment of HIV infection. Additionally, bevirimat (isolated from Syzygium claviflorum) and calanolide A (isolated from Calophyllum sp.) are inhibitors of viral maturation and reverse transcription process, respectively. In the present review, we aimed to describe the wide repertoire of natural compounds exhibiting anti-HIV-1 activity that can be considered for designing new therapeutic strategies to curb the HIV pandemic.

Drug Resistance During HIV Pre-Exposure Prophylaxis.

Clinical studies have demonstrated that use of tenofovir disoproxil fumarate with or without emtricitabine as antiretroviral pre-exposure prophylaxis (PrEP) can decrease the risk of human immunodeficiency virus (HIV) acquisition when medication adherence is high. However, the potential for PrEP to promote antiretroviral resistance remains an important public health consideration. We performed a search of the medical literature to identify studies that address HIV drug resistance during PrEP use. In this review, we summarize findings about emergent drug resistance during clinical trials of PrEP, case reports of seroconversions in patients adherent to PrEP, and animal studies of PrEP effectiveness against drug-resistant viral strains. We also discuss the potential utility of novel PrEP formulations for protection against drug-resistant HIV, the impact of drug resistance on HIV treatment options, and mathematical models that estimate the potential contribution of PrEP to population-level drug resistance. Evidence suggests that selection for HIV drug resistance with PrEP use is infrequent and most likely to occur when PrEP is used during undiagnosed acute HIV infection. Breakthrough infections during PrEP use with high adherence are possible, but appear to be rare. The prevalence of drug-resistant HIV strains needs to be monitored as PrEP is scaled up. However, the benefit of a decreased HIV incidence with wider PrEP use is likely to outweigh the risk of harms from possible increases in the prevalence of HIV drug resistance.

Review of Real-World Implementation Data on Emtricitabine-Tenofovir Disoproxil Fumarate as HIV Pre-exposure Prophylaxis in the United States.

The antiretroviral combination of emtricitabine-tenofovir disoproxil fumarate (FTC/TDF) was approved by the U.S. Food and Drug Administration for use as pre-exposure prophylaxis (PrEP) in individuals at high risk for acquiring human immunodeficiency virus (HIV) in July 2012. Since then, Centers for Disease Control and Prevention guidelines for the use of PrEP have been published and implemented into clinical practice throughout the United States. A number of published open-label and PrEP demonstration projects have evaluated the real-world use of PrEP including analysis of the barriers to its use and addressing major concerns. Despite the approval of FTC/TDF for PrEP, its use for this indication relies on patient and provider acceptance, and its effectiveness requires patient adherence and retention in care during periods of high-risk behaviors. Concerns regarding the use of PrEP in healthy individuals persist and include medication adverse effects including renal dysfunction and bone mineral density loss; risk compensation leading to HIV infections, sexually transmitted infections, and unintended pregnancies; and the development of drug resistance in the event of seroconversion. The cost-effectiveness of PrEP continues to be assessed with the greatest cost-effectiveness remaining in those at highest risk of acquiring HIV. Additionally, cases of HIV acquisition in individuals who are adherent to PrEP highlight scenarios in which PrEP is not 100% effective including against the transmission of drug-resistant HIV strains. This review examines data on the implementation of PrEP outside the setting of clinical trials with the aim of providing clinicians with a summary of the current barriers and opportunities for PrEP use with a specific focus on the role of pharmacists in the optimization of PrEP implementation.

Combining 25-Hydroxycholesterol with an HIV Fusion Inhibitor Peptide: Interaction with Biomembrane Model Systems and Human Blood Cells.

The fusion between the viral and the target cell membrane is a crucial step in the life cycle of enveloped viruses. The blocking of this process is a well-known therapeutic approach that led to the development of the fusion inhibitor peptide enfuvirtide, clinically used against human immunodeficiency virus (HIV) type 1. Despite this significant advance on viral treatment, the appearance of resistance has limited its clinical use. Such a limitation has led to the development of other fusion inhibitor peptides, such as C34, that present the same structural domain as enfuvirtide (heptad repeat sequence) but have different functional domains (pocket-binding domain in the case of C34 and lipid-binding domain in the case of enfuvirtide). Recently, the antiviral properties of 25-hydroxycholesterol were demonstrated, which boosted the interest in this oxysterol. The combination of two distinct antiviral molecules, C34 and 25-hydroxycholesterol, may help to suppress the emergence of resistant viruses. In this work, we characterized the interaction of the C34-25-hydroxycholesterol conjugate with biomembrane model systems and human blood cells. Lipid vesicles and monolayers with defined lipid compositions were used as biomembrane model systems. The conjugate interacts preferentially with membranes rich in sphingomyelin (a lipid enriched in lipid rafts) and presents a poor partition to membranes composed solely of phosphatidylcholine and cholesterol. We hypothesize that cholesterol causes a repulsive effect that is overcome in the presence of sphingomyelin. Importantly, the peptide shows a preference for human peripheral blood mononuclear cells relative to erythrocytes, which shows its potential to target CD4+ cells. Antiviral activity results against different wild-type and drug-resistant HIV strains further demonstrated the potential of C34-HC as a good candidate for future studies.

Imidazolidinones and Imidazolidine-2,4-diones as Antiviral Agents.

Imidazolidinones and imidazolidine-2,4-diones are important classes of heterocyclic compounds that possess potent activities against several viruses such as dengue virus, enterovirus, hepatitis C virus (HCV), and human immunodeficiency virus (HIV). The first imidazolidinone derivative as an anti-HIV agent was reported in 1996. Imidazolidinones inhibit HIV aspartic protease activity, and also act as CCR5 co-receptor antagonists. Significant effort has been devoted to the design of various imidazolidinone analogues that are active against drug-resistant HIV strains, with fewer side effects. Different scaffolds have been designed through both rational drug design strategies and computer-aided drug design. Imidazolidinones have been found to be potent against HIV, and preclinical studies are currently in progress. There are some reports of imidazolidinones as having both anti-HCV and anti-dengue virus activity, and more research has yet to be done along these lines. These compounds inhibit NS3 serine protease of HCV, and NS2B-NS3 protease of dengue virus. Pyridyl-imidazolidinones possess very specific and potent activity against human enterovirus 71 (EV71) by targeting the EV71 capsid protein VP1, and inhibiting viral adsorption and/or viral RNA uncoating.

Recombinant antibodies targeting HIV-1 capsid protein (p24): the development of single-chain variable fragment

Event Abstract Back to Event Recombinant antibodies targeting HIV-1 capsid protein (p24): the development of single-chain variable fragment Siti Aisyah Mualif1* and Mohammad Tasyriq Che Omar2 1 School of Biomedical Engineering & Health Sciences, Faculty of Engineering, University of Technology Malaysia, Malaysia 2 University of Science, Malaysia, Malaysia Background Human immunodeficiency virus (HIV) is the causative agent of acquired immune deficiency syndrome (AIDS) disease. The increasing morbidity and mortality due to HIV/AIDS in the past decades has sparked an interest to combat HIV/AIDS. However, ongoing research against the HIV/AIDS pandemic has failed to completely eradicate the infection. Introduction of highly active anti-retroviral therapy (HAART) in early 1990s has reduced the death rate of HIV/AIDS, but it has also resulted in the development of drug-resistant strains of HIV. Therefore, there is a pressing need to develop new and improved therapeutic modalities. HIV-1 capsid protein (p24) plays important roles in both early and late stages of HIV-1 replication. Small molecule inhibitors and peptides targeting p24 have shown to inhibit viral infection. However, rapid clearance and toxicity are major drawbacks associated with the aforementioned therapeutic modalities. The potential of monoclonal antibodies (mAbs) targeting p24 was discovered and found out that p24-targeting antibodies can be developed into novel therapeutic modalities. However, natural or hybridoma-derived mAbs are large molecules and difficult to engineer. Recombinant DNA technology allows the engineering of antibodies in multiple formats. Therefore, the aim of this study was to generate, characterize, and evaluate recombinant antibodies targeting HIV-1 p24. Methods Recombinant anti-p24 antibodies were generated from a combinatorial library of variable domains cloned from a hybridoma cell line and subsequently expressed on the surface of filamentous bacteriophage. Recombinant scFvs reacting specifically with HIV-1 p24 were isolated, expressed, and characterized. Results Out of 50 clones, three specific binders were identified via initial ELISA screening. Specificity of the binders was confirmed through competition studies and the selected clones were expressed in E. coli. The recombinant scFvs markedly inhibited p24 polymerization in vitro and HIV replication in Jurkat T cell lines when expressed as intracellular antibodies (intrabodies). Conclusion The anti-p24 scFvs engineered in this study have potential to be developed into novel antibody-based therapeutics against HIV. Acknowledgements This work was supported by a FRGS grant (203/CIPPT/67 11206) from the Ministry of Higher Education of Malaysia and Research Student Fund (USM/IPPT/2000/G-2/xiv) from AMDI, USM. Not forgetting the MOHE scholarship (KPT (BS) 841003015520) for the author to complete the work and a PAS grant (PY/2017/01374) from UTM, Johor Bahru to support the presentation. Keywords: HIV-1 p24, scFv, Phage display antibody library, anti-p24 scFv, therapeutic Conference: International Conference on Drug Discovery and Translational Medicine 2018 (ICDDTM '18) “Seizing Opportunities and Addressing Challenges of Precision Medicine”, Putrajaya, Malaysia, 3 Dec - 5 Feb, 2019. Presentation Type: Poster Presentation Topic: Infectious diseases Citation: Mualif S and Che Omar M (2019). Recombinant antibodies targeting HIV-1 capsid protein (p24): the development of single-chain variable fragment. Front. Pharmacol. Conference Abstract: International Conference on Drug Discovery and Translational Medicine 2018 (ICDDTM '18) “Seizing Opportunities and Addressing Challenges of Precision Medicine”. doi: 10.3389/conf.fphar.2018.63.00104 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 31 Oct 2018; Published Online: 17 Jan 2019. * Correspondence: Dr. Siti Aisyah Mualif, School of Biomedical Engineering & Health Sciences, Faculty of Engineering, University of Technology Malaysia, Johor Bahru, Malaysia, aisyahmualif@utm.my Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Siti Aisyah Mualif Mohammad Tasyriq Che Omar Google Siti Aisyah Mualif Mohammad Tasyriq Che Omar Google Scholar Siti Aisyah Mualif Mohammad Tasyriq Che Omar PubMed Siti Aisyah Mualif Mohammad Tasyriq Che Omar Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

An integrated chemical biology approach reveals the mechanism of action of HIV replication inhibitors

Continuous flow (microfluidic) chemistry was employed to prepare a small focused library of dihydropyrimidinone (DHPM) derivatives. Compounds in this class have been reported to exhibit activity against the human immunodeficiency virus (HIV), but their molecular target had not been identified. We tested the initial set of DHPMs in phenotypic assays providing a hit (1i) that inhibited the replication of the human immunodeficiency virus HIV in cells. Flow chemistry-driven optimization of 1i led to the identification of HIV replication inhibitors such as 1l with cellular potency comparable with the clinical drug nevirapine (NVP). Mechanism of action (MOA) studies using cellular and biochemical assays coupled with 3D fingerprinting and in silico modeling demonstrated that these drug-like probe compounds exert their effects by inhibiting the viral reverse transcriptase polymerase (RT). This led to the design and synthesis of the novel DHPM 1at that inhibits the replication of drug resistant strains of HIV. Our work demonstrates that combining flow chemistry-driven analogue refinement with phenotypic assays, in silico modeling and MOA studies is a highly effective strategy for hit-to-lead optimization applicable to the discovery of future therapeutic agents.

Using Hierarchical Virtual Screening To Combat Drug Resistance of the HIV-1 Protease.

Human immunodeficiency virus (HIV) protease inhibitors (PIs) are important components of highly active anti-retroviral therapy (HAART) that block the catalytic site of HIV protease, thus preventing maturation of the HIV virion. However, with two decades of PI prescriptions in clinical practice, drug-resistant HIV mutants have now been found for all of the PI drugs. Therefore, the continuous development of new PI drugs is crucial both to combat the existing drug-resistant HIV strains and to provide treatments for future patients. Here we purpose an HIV PI drug design strategy to select candidate PIs with binding energy distributions dominated by interactions with conserved protease residues in both wild-type and various drug-resistant mutants. On the basis of this strategy, we have constructed a virtual screening pipeline including combinatorial library construction, combinatorial docking, MM/GBSA-based rescoring, and reranking on the basis of the binding energy distribution. We have tested our strategy on lopinavir by modifying its two functional groups. From an initial 751 689 candidate molecules, 18 candidate inhibitors were selected using the pipeline for experimental validation. IC50 measurements and drug resistance predictions successfully identified two ligands with both HIV protease inhibitor activity and an improved drug resistance profile on 2382 HIV mutants. This study provides a proof of concept for the integration of MM/GBSA energy analysis and drug resistance information at the stage of virtual screening and sheds light on future HIV drug design and the use of virtual screening to combat drug resistance.

Early initiation of antiretroviral treatment: Challenges in the Middle East and North Africa.

New World Health Organization guidelines recommend the initiation of antiretroviral treatment (ART) for asymptomatic patients with CD4+ T-cell counts of ≤ 500 cells/mm(3). Substantial reduction of human immunodeficiency virus (HIV) transmission is addressed as a major public health outcome of this new approach. Middle East and North Africa (MENA), known as the area of controversies in terms of availability of comprehensive data, has shown concentrated epidemics among most of it's at risk population groups. Serious challenges impede the applicability of new guidelines in the MENA Region. Insufficient resources restrict ART coverage to less than 14%, while only one fourth of the countries had reportable data on patients' CD4 counts at the time of diagnosis. Clinical guidelines need to be significantly modified to reach practical utility, and surveillance systems have not yet been developed in many countries of MENA. Based on available evidence in several countries people who inject drugs and men who have sex with men are increasingly vulnerable to HIV and viral hepatitis, while their sexual partners - either female sex workers or women in monogamous relationships with high-risk men - are potential bridging populations that are not appropriately addressed by regional programs. Research to monitor the response to ART among the mentioned groups are seriously lacking, while drug resistant HIV strains and limited information on adherence patterns to treatment regimens require urgent recognition by health policymakers. Commitment to defined goals in the fight against HIV, development of innovative methods to improve registration and reporting systems, monitoring and evaluation of current programs followed by cost-effective modifications are proposed as effective steps to be acknowledged by National AIDS Programs of the countries of MENA Region.

HIV behind Bars: Human Immunodeficiency Virus Cluster Analysis and Drug Resistance in a Reference Correctional Unit from Southern Brazil

People deprived of liberty in prisons are at higher risk of infection by the human immunodeficiency virus (HIV) due to their increased exposure through intravenous drug use, unprotected sexual activity, tattooing in prison and blood exposure in fights and rebellions. Yet, the contribution of intramural HIV transmission to the epidemic is scarcely known, especially in low- and middle-income settings. In this study, we surveyed 1,667 inmates incarcerated at Presídio Central de Porto Alegre, located in southern Brazil, for HIV infection and molecular characterization. The HIV seroprevalence was 6.6% (110/1,667). Further analyses were carried out on 40 HIV-seropositive inmates to assess HIV transmission clusters and drug resistance within the facility with the use of molecular and phylogenetic techniques. The molecular epidemiology of HIV-1 subtypes observed was similar to the one reported for the general population in southern Brazil, with the predominance of HIV-1 subtypes C, B, CRF31_BC and unique BC recombinants. In particular, the high rate (24%) of URF_BC found here may reflect multiple exposures of the population investigated to HIV infection. We failed to find HIV-infected inmates sharing transmission clusters with each other. Importantly, the analysis of HIV-1 pol genomic fragments evidenced high rates of HIV primary and secondary (acquired) drug resistance and an alarming proportion of virologic failure among patients under treatment, unveiling suboptimal access to antiretroviral therapy (ARV), low ARV adherence and dissemination of drug resistant HIV strains in primary infections. Our results call for immediate actions of public authority to implement preventive measures, serological screening and, for HIV-seropositive subjects, clinical and treatment follow-up in order to control HIV infection and limit the spread of drug resistance strains in Brazilian prisons.

Inhibitory effect of aqueous dandelion extract on HIV-1 replication and reverse transcriptase activity

BackgroundAcquired immunodeficiency syndrome (AIDS), which is caused by the human immunodeficiency virus (HIV), is an immunosuppressive disease that results in life-threatening opportunistic infections. The general problems in current therapy include the constant emergence of drug-resistant HIV strains, adverse side effects and the unavailability of treatments in developing countries. Natural products from herbs with the abilities to inhibit HIV-1 life cycle at different stages, have served as excellent sources of new anti-HIV-1 drugs. In this study, we aimed to investigate the anti-HIV-1 activity of aqueous dandelion extract.MethodsThe pseudotyped HIV-1 virus has been utilized to explore the anti-HIV-1 activity of dandelion, the level of HIV-1 replication was assessed by the percentage of GFP-positive cells. The inhibitory effect of the dandelion extract on reverse transcriptase activity was assessed by the reverse transcriptase assay kit.ResultsCompared to control values obtained from cells infected without treatment, the level of HIV-1 replication and reverse transcriptase activity were decreased in a dose-dependent manner. The data suggest that dandelion extract has a potent inhibitory activity against HIV-1 replication and reverse transcriptase activity. The identification of HIV-1 antiviral compounds from Taraxacum officinale should be pursued.ConclusionsThe dandelion extract showed strong activity against HIV-1 RT and inhibited both the HIV-1 vector and the hybrid-MoMuLV/MoMuSV retrovirus replication. These findings provide additional support for the potential therapeutic efficacy of Taraxacum officinale. Extracts from this plant may be regarded as another starting point for the development of an antiretroviral therapy with fewer side effects.

Prevalence of Genotypic Resistance to Antiretroviral Drugs in Treatment-Naive Youths Infected with Diverse HIV Type 1 Subtypes and Recombinant Forms in Dar es Salaam, Tanzania

As human immunodeficiency virus (HIV) diversity may have an impact on both vaccine efficacy and drug resistance, it is important to have knowledge of circulating genetic variants. With widespread use of antiretroviral (ARV) drugs in Africa, one of the major potential challenges is the risk of emergence of ARV drug-resistant HIV strains. This study aimed to determine the circulating HIV subtypes and recombinant forms, as well as the prevalence of ARV drug resistance mutations, among 75 treatment-naive HIV-infected youths in Dar es Salaam, Tanzania. Gag (n = 48), partial pol (n = 44), and partial env (n = 35) sequencing was performed; all three regions were sequenced in 26 samples. Evidence of infection with recombinant viruses was found in 12 (46%) participants; AC recombinants were the most commonly detected and they were identified in six (23%) participants. Of individuals infected with nonrecombinant strains, subtype A was most commonly detected in seven (27%) participants, followed by subtype C detected in six (23%) participants and subtype D detected in one (4%) participant. Among the pol sequences from 44 individuals, three (7%) had resistance to nucleoside reverse transcriptase (RT) inhibitors and four (9%) had nonnucleoside RT inhibitor resistance mutations. Of these, three (7%) individuals were infected with viruses with cross-resistance mutations to both classes of RT inhibitors. These resistant mutations were all associated with drugs currently used in first-line therapy and in the prevention of vertical transmission. This high prevalence of resistance mutations is of considerable concern in apparently drug-naive populations as it may result in treatment failure and the spread of ARV-resistant strains.

NeuroAIDS: An Evolving Epidemic

Over 60,000 Canadians are infected with human immunodeficiency virus (HIV). Greater than 50% of these individuals will develop a neurological disorder despite the availability of highly active antiretroviral therapy. HIV causes nervous system disease at all stages of infection with adverse effects on quality of life, adherence to medications, employment and survival. These disorders include opportunistic infections in addition to distinct HIV-associated neurological syndromes and undesirable treatment-related effects. The latter two groups of disorders are often undiagnosed and untreated in both adolescents and adults. Direct HIV infection of central nervous system causes HIV-associated dementia, which is a progressive subcortical dementia. HIV infection of the peripheral nervous system produces a painful sensory neuropathy termed distal sensory polyneuropathy, which may be exacerbated by several antiretroviral drugs. Other important HIV-induced neurological disorders include vacuolar myelopathy and an increased risk of seizures. Future issues that will confound the presentation and treatment of HIV-induced nervous system disorders include the increasing prevalence of drug-resistant HIV strains, increasing age of HIV-infected patients, hepatitis C virus co-infection and the Immune Reconstitution Inflammatory Syndrome. Herein, we review the clinical presentations, underlying pathogenesis and treatments of this burgeoning group of neurological disorders.

Mutation and control of the human immunodeficiency virus

We examine the dynamics of infection by the human immunodeficiency virus ( HIV), as well as therapies that minimize viral load, restore adaptive immunity, and use minimal dosage of anti-HIV drugs. Virtual therapies for wild-type infections are demonstrated; however, the HIV infection is never cured, requiring continued treatment to keep the condition in remission. With high viral turnover and mutation rates, drug-resistant strains of HIV evolve quickly. The ability of optimal therapy to contain drug-resistant strains is shown to depend upon the relative fitness of mutant strains.

Design of HIV Protease Inhibitors Targeting Protein Backbone: An Effective Strategy for Combating Drug Resistance

The discovery of human immunodeficiency virus (HIV) protease inhibitors (PIs) and their utilization in highly active antiretroviral therapy (HAART) have been a major turning point in the management of HIV/acquired immune-deficiency syndrome (AIDS). However, despite the successes in disease management and the decrease of HIV/AIDS-related mortality, several drawbacks continue to hamper first-generation protease inhibitor therapies. The rapid emergence of drug resistance has become the most urgent concern because it renders current treatments ineffective and therefore compels the scientific community to continue efforts in the design of inhibitors that can efficiently combat drug resistance. The present line of research focuses on the presumption that an inhibitor that can maximize interactions in the HIV-1 protease active site, particularly with the enzyme backbone atoms, will likely retain these interactions with mutant enzymes. Our structure-based design of HIV PIs specifically targeting the protein backbone has led to exceedingly potent inhibitors with superb resistance profiles. We initially introduced new structural templates, particulary nonpeptidic conformationally constrained P 2 ligands that would efficiently mimic peptide binding in the S 2 subsite of the protease and provide enhanced bioavailability to the inhibitor. Cyclic ether derived ligands appeared as privileged structural features and allowed us to obtain a series of potent PIs. Following our structure-based design approach, we developed a high-affinity 3( R),3a( R),6a( R)-bis-tetrahydrofuranylurethane (bis-THF) ligand that maximizes hydrogen bonding and hyrophobic interactions in the protease S 2 subsite. Combination of this ligand with a range of different isosteres led to a series of exceedingly potent inhibitors. Darunavir, initially TMC-114, which combines the bis-THF ligand with a sulfonamide isostere, directly resulted from this line of research. This inhibitor displayed unprecedented enzyme inhibitory potency ( K i = 16 pM) and antiviral activity (IC 90 = 4.1 nM). Most importantly, it consistently retained is potency against highly drug-resistant HIV strains. Darunavir's IC 50 remained in the low nanomolar range against highly mutated HIV strains that displayed resistance to most available PIs. Our detailed crystal structure analyses of darunavir-bound protease complexes clearly demonstrated extensive hydrogen bonding between the inhibitor and the protease backbone. Most strikingly, these analyses provided ample evidence of the unique contribution of the bis-THF as a P 2-ligand. With numerous hydrogen bonds, bis-THF was shown to closely and tightly bind to the backbone atoms of the S 2 subsite of the protease. Such tight interactions were consistently observed with mutant proteases and might therefore account for the unusually high resistance profile of darunavir. Optimization attempts of the backbone binding in other subsites of the enzyme, through rational modifications of the isostere or tailor made P 2 ligands, led to equally impressive inhibitors with excellent resistance profiles. The concept of targeting the protein backbone in current structure-based drug design may offer a reliable strategy for combating drug resistance.

Overcoming HIV drug resistance through rational drug design based on molecular, biochemical, and structural profiles of HIV resistance

There are 20 available drugs for the treatment of human immunodeficiency virus (HIV) infection. With a single exception, all of these drugs inhibit either HIV reverse transcriptase or protease. Reverse transcriptase inhibitors can be further categorized as nucleoside/nucleotide analogs or non-nucleoside reverse transcriptase inhibitors. Resistance that has emerged against all available antiretroviral drugs represents a major challenge in the therapy of HIV infection. Nevertheless, extensive analysis of the molecular and structural mechanisms by which such mutations confer resistance has accumulated over the years. This understanding has driven the development and refinement of novel compounds capable of maintaining antiviral activity against both wild-type and drug-resistant HIV strains. The molecular, biochemical, and structural profiles of reverse transcriptase inhibitor and protease inhibitor resistance are discussed. In addition, how this knowledge has been utilized to generate a new generation of antiviral drugs with activity against drug-resistant HIV is reviewed.

New antiretroviral drugs in clinical use

The advent of combination antiretroviral therapy for the treatment of human immunodeficiency virus (HIV) infection has dramatically changed the prognosis and quality of life of HIV-infected adults and children. To date, there are 21 antiretroviral agents available with only 11 agents being approved for the use in young children less than 6 years of age. The currently available antiretroviral agents belong to four different classes; nucleoside/nucleotide reverse transcriptase inhibitors (NRTI, NtRTI), non-nucleoside reverse transcriptase inhibitors (NNRTI), protease inhibitors (PI), and a new class of fusion inhibitors (FI). It is recommended that the treatment regimen should be a combination of at least 3 drugs from different drug classes as this has been shown to slow disease progression, improve survival, and result in better virologic and immunologic responses. Treatment with antiretroviral agents is frequently complicated by the issues of adherence, tolerability, long term toxicity and drug resistance. Many efforts have been made to develop new antiretroviral agents with greater potency, higher tolerability profiles and better convenience. Some new agents are also effective against drug-resistant strains of HIV. Since 2001, there were 7 new antiretroviral agents and 2 fixed-dose multidrug formulations being approved for the treatment of HIV infection, most are approved only for use in adults. In this article, we will review new antiretroviral agents including emtricitabine, tenofovir disoproxil fumarate, atazanavir, fosamprenavir, tipranavir and enfuvirtide. Pediatric information on these drugs will be provided when available.

New Drug Targets for HIV

A significant number of human immunodeficiency virus (HIV) infections have become resistant to antiretroviral treatment, which means that there is a paramount need for novel drug targets to defeat the virus. Until recently, all HIV drugs inhibited HIV replication by mechanisms operating inside infected cells. In contrast, new antiretroviral drugs operate outside infected cells. Their mechanism of action consists in inhibiting entry of the virus into cells, thereby halting the very first step of HIV replication. Examples of this new class of drugs include entry inhibitors, coreceptor antagonists, and fusion inhibitors. In addition to their novel mechanism of action, this new class of drugs also has potential action against drug-resistant HIV strains, causes minimal adverse effects, and may be administered in a simplified, once-daily dosing regimen. New classes of anti-HIV drugs--and new drugs in existing classes--represent the best hope for people infected with HIV, especially those who have exhausted current therapies.