There is no specific technology for the treatment of AIDS. Some drugs of specific composition are given to the patients which are able to increase the life time to a few years only. To make the treatment more specific we use the new technology called Nanotechnology which has bio-medical application. The size of nanorobots is about times lesser than the size of an animal cell and hence it can easily monitor the behavior of cell inside the body. It operates at specific sites and has no side effects. Nanorobotics is the technology of creating machines or robots at or close to the microscopic scale of nanometers 10 -9 meters.
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Combination antiretroviral therapy has dramatically improved treatment, but it has to be taken for a lifetime, has major side effects and is ineffective in patients in whom the virus develops resistance.
Nanotechnology is an emerging multidisciplinary field that is revolutionizing medicine in the 21st century. At the end of , around 33 million people were living with the virus, with 2. This has caused tremendous social and economic damage worldwide, with developing countries, particularly Sub-Saharan Africa, heavily affected.
Early treatments focused on antiretroviral drugs that were effective only to a certain degree. The first drug, zidovudine, was approved by the US FDA in , leading to the approval of a total of 25 drugs to date, many of which are also available in fixed-dose combinations and generic formulations for use in resource-limited settings to date, only zidovudine and didanosine are available as true generics in the USA [ 8 , 9 ].
This launched the era of highly active antiretroviral therapy HAART , where a combination of three or more different classes of drugs are administered simultaneously [ 11 ]. The use of the HAART regimen, particularly in the developed world, has resulted in tremendous success in improving the expectancy and quality of lives for patients [ 12 ]. Some patients also develop resistance to certain combinations of drugs, resulting in failure of the treatment.
In addition to treatment, the best way to fight global infections is through preventive strategies, vaccines being the most effective agents. Vaccines have historically been very effective at controlling other major infectious diseases such as measles, mumps, rubella and polio, with smallpox completely eradicated.
However, the pursuit has been very daunting so far, with recent failures of clinical trials for major candidate vaccines [ 13 — 15 ]. Despite this debate, it is clear that novel approaches for identifying new antigens and adjuvants as well as better delivery systems are necessary. Another preventive strategy that has been under investigation is the development of effective intravaginal microbicides that can be used by women.
There has been remarkable progress in the understanding and design of technologies for microbicide development. However, recent clinical trials failed to show efficacy, indicating the need for more research and development to design better systems [ 16 , 17 ]. Nanotechnology is a new discipline of science and engineering that is advancing many areas of medicine.
It involves the understanding, design, engineering and fabrication of materials at the atomic and molecular level. The National Nanotechnology Initiative defines nanotechnology as the study of structures with roughly 1— nm in size in at least one dimension but structures up to several hundred nanometers are also considered under nanotechnology applications [ 18 ]. The application of nanotechnology to medicine, commonly referred to as nanomedicine, involves the use of nanoscale materials for preventive, therapeutic and diagnostic purposes [ 19 ].
There have been major advances in nanomedicine over the last few decades, particularly in cancer diagnosis and therapy [ 20 — 22 ]. There are emerging novel approaches in which nanotechnology can enhance current treatment as well as advance new therapeutic strategies, such as gene therapy and immunotherapy. Moreover, some nanomaterials have therapeutic effects by themselves.
Nanotechnology can also play a major role in preventive strategies for developing vaccines and microbicides. The drugs used in combination are in most cases from different classes that work based on different mechanisms.
The major difficulty has been the failure of the treatment, typically due to poor patient compliance [ 23 ]. Due to the need to take the medication daily for a lifetime, patients fail to adhere to the treatment schedule, leading to ineffective drug levels in the body and rebound of viral replication [ 11 , 24 , 25 ].
Moreover, in some patients, the virus develops resistance to particular combinations of drugs even with good adherence. Drug resistance is mainly caused by the high genetic diversity of HIV-1 and the continuous mutation it undergoes [ 26 ]. This problem is being addressed with individualized therapy, whereby resistance testing is performed to select a combination of drugs that is most effective for each patient [ 26 ]. In addition, side effects due to toxicities of the drugs are also a concern.
There are reports that patients taking HAART experience increased rates of heart disease, diabetes, liver disease, cancer and accelerated aging [ 11 ]. Most experts agree that these effects could be due to the HIV infection itself or co-infection with another virus, such as co-infection with hepatitis C virus resulting in liver disease.
However, the toxicities resulting from the drugs used in HAART could also contribute to these effects. Under current treatment, complete eradication of the virus from the body has not been possible. A major study recently found that, in addition to acting as latent reservoirs, macrophages significantly contribute to the generation of elusive mutant viral genotypes by serving as the host for viral genetic recombination [ 27 ].
The cells that harbor latent HIV are typically concentrated in specific anatomic sites, such as secondary lymphoid tissue, testes, liver, kidney, lungs, gut and the CNS [ 11 , 28 — 31 ]. Therefore, there is a great need to explore new approaches for developing nontoxic, lower-dosage treatment modalities that provide more sustained dosing coverage and effectively eradicate the virus from the reservoirs, avoiding the need for lifetime treatments.
The use of nanotechnology platforms for delivery of drugs is revolutionizing medicine in many areas of disease treatment [ 32 ]. Cancer patients have been the biggest beneficiaries of this revolution so far, with significant advances in the last few decades. Many nanoscale systems for systemic cancer therapy are either FDA approved or in clinical trials [ 19 , 33 ]. This tremendous success has been due to the unique features that nanotechnology imparts on drug delivery systems.
Using nanotechnology, it has become possible to achieve improved delivery of poorly water-soluble drugs, targeted delivery of drugs to specific cells or tissues and intracellular delivery of macromolecules [ 18 , 32 ]. Nanotechnology-based platforms for systemic delivery of antiretroviral drugs could have similar advantages. Controlled-release delivery systems can enhance their half-lives, keeping them in circulation at therapeutic concentrations for longer periods of time.
This could have major implications in improving adherence to the drugs. Nanoscale delivery systems also enhance and modulate the distribution of hydrophobic and hydrophilic drugs into and within different tissues due to their small size. This particular feature of nanoscale delivery systems appears to hold the most promise for their use in clinical treatment and prevention of HIV. Moreover, by controlling the release profiles of the delivery systems, drugs could be released over a longer time and at higher effective doses to the specific targets.
Various nanoscale drug delivery systems shown in Figure 1 could be explored for these purposes. The use of nanotechnology systems for delivery of antiretroviral drugs has been extensively reviewed by Nowacek et al. In this section, we only highlight a few of the most recent and significant examples of nanotechnology-based drug delivery.
In a recent study based on polymeric systems, nanosuspensions nm of the drug rilpivirine TMC stabilized by polyethylene-polypropylene glycol poloxamer and PEGylated tocopheryl succinate ester TPGS were studied in dogs and mice [ 35 ]. A single-dose administration of the drug in nanosuspensions resulted in sustained release over 3 months in dogs and 3 weeks in mice, compared with a half-life of 38 h for free drug.
These results serve as a proof-of-concept that nanoscale drug delivery may potentially lower dosing frequency and improve adherence. A series of experiments by Dou et al. The indinavir nanosuspensions were loaded into macrophages and their uptake was investigated.
Macrophages loaded with indinavir nanosuspensions were then injected intravenously into mice, resulting in a high distribution in the lungs, liver and spleen. More significantly, the intravenous administration of a single dose of the nanoparticle-loaded macrophages in a rodent mouse model of HIV brain infection resulted in significant antiviral activity in the brain and produced measureable drug levels in the blood up to 14 days post-treatment [ 38 ].
These studies serve as a proof of concept for indinavir delivery to the brain and the sustained drug levels for up to 14 days, which is important when considering that the half-life of indinavir in its conventional dosage form is 2 h. The demonstration that macrophages could be used to target drugs to the brain could be utilized for in vivo nanoparticle-targeted delivery of other drugs to the brain in the future.
Active targeting strategies have also been employed for antiretroviral drug delivery. Macrophages, which are the major HIV reservoir cells, have various receptors on their surface such as formyl peptide, mannose, galactose and Fc receptors, which could be utilized for receptor-mediated internalization. The drug stavudine was encapsulated using various liposomes — nm conjugated with mannose and galactose, resulting in increased cellular uptake compared with free drug or plain liposomes, and generating significant level of the drug in liver, spleen and lungs [ 39 — 41 ].
Stavudine is a water-soluble drug with a very short serum half-life 1 h. Hence, the increased cellular uptake and sustained release in the tissues afforded by targeted liposomes is a major improvement compared with free drug. The drug zidovudine, with half-life of 1 h and low solubility, was also encapsulated in a mannose-targeted liposome made from stearylamine, showing increased localization in lymph node and spleen [ 42 ].
An important factor to consider here is that although most of the nucleoside drugs such as stavudine and zidovudine have short serum half-lives, the clinically relevant half-life is that of the intracellular triphosphate form of the drug. Therefore, future nanotechnology-based delivery systems will have to focus in showing significant increase of the half-lives of the encapsulated drugs to achieve a less frequent dosing such as once weekly, once-monthly or even less.
The targeted nanocarrier resulted in fold increase in cellular uptake compared with free drug. A similar system was used to deliver the drug lamivudine in vitro , resulting in significantly higher anti-HIV activity for the targeted and nontargeted dendrimer systems compared with free drugs [ 44 ].
In a more recent study, the tetra-peptide tuftsin Thr-Lys-Pro-Arg was conjugated to the same dendrimer to target the drug efavirenz to macrophages in vitro [ 45 ]. The targeted dendrimer system resulted in sixfold prolonged release, fold increased cellular uptake and sevenfold increase in anti-HIV activity compared with free drug.
In a new approach to target macrophage HIV reservoirs, a peptide nanocarrier was proposed as a model where a drug is conjugated to the backbone of peptide-PEG and N -formyl-methionyl-leucyl-phenylalanine fMLF , a bacterial peptide sequence for which macrophages express a receptor, is attached to the PEG for targeting [ 46 ].
The study found that fMLF-targeted peptide-PEG nanocarriers show increased cellular uptake and increased accumulation in macrophages of liver, kidney and spleen compared with those which are nontargeted [ 30 , 46 ]. All the aforementioned efforts are examples of the potential nanotechnology platforms hold for improving targeted delivery of antiretroviral drugs to the cellular and anatomical reservoirs of HIV.
These early efforts provide evidence for the potential of nanotechnology to improve delivery of antiretroviral therapy and support ongoing efforts to initiate clinical trials.
Although the early efforts have not reached clinical trials yet, the works so far provide encouraging evidence that a subset of these preclinical technologies may enter clinical evaluation in the future. In addition to being used as delivery agents, nanomaterials have also been shown to have therapeutic effects of their own.
Studies have shown that the capsid of HIV could be a target for structure-based drug design for inhibiting viral replication [ 47 , 48 ]. As a result, both computational and experimental studies have identified compounds that could inhibit the assembly of the HIV capsid.
Various nanomaterials have been found to inhibit viral replication in vitro and it is suggested that these effects are based on structural interference with viral assembly. Various fullerene C -based structures, dendrimers and inorganic nanoparticles, such as gold and silver, have been shown to have anti-HIV activity in vitro [ 49 — 60 ]. While these efforts have not yet progressed beyond in vitro studies, they illustrate the potential of therapeutic nanomaterials to inhibit HIV replication.
One promising alternative approach is gene therapy, in which a gene is inserted into a cell to interfere with viral infection or replication. Other nucleic acid-based compounds, such as DNA, siRNA, RNA decoys, ribozymes and aptamers or protein-based agents such as fusion inhibitors and zinc-finger nucleases can also be used to interfere with viral replication [ 61 , 62 ].
In one of these studies, Benitec Ltd and City of Hope are collaborating in an ongoing clinical trial to study the safety and feasibility of a gene therapy strategy based on the combination of three different inhibitory genes in a single lentiviral vector that utilizes stem cells in the delivery process [ 65 ]. Recently, scientists from UCLA reported that a Phase II gene therapy clinical trial showed that cell-derived gene transfer is safe and biologically active in HIV-infected individuals [ 69 ].
However, lessons learned over the past two decades indicate that the use of viral vectors for gene delivery poses fundamental problems such as toxicity, immunogenicity, insertion mutagenesis and limitations with scale-up procedures [ 70 , 71 ]. These problems have encouraged the investigation of nonviral vectors for gene delivery, where nanotechnology platforms are showing great promise [ 70 — 72 ].
In recent years, the Nobel prize-winning discovery of RNA interference RNAi in by Fire, Mello and colleagues has gained much attention in the clinical therapeutics field and is generating billion dollar investments in therapeutic applications [ 73 , 74 ]. Ongoing clinical trials for the treatment of age-related macular degeneration and respiratory syncytial virus have provided data that are creating tremendous excitement in the field [ 74 ].
These two mechanisms are shown in Figure 2. The siRNA acts by degrading mRNA in at least two major ways: A Inhibit entry and fusion by interfering with production of receptors or co-receptors and B interfere with translation and transcription of viral genes preventing production of proteins and genomic RNA.
The viral entry and replication stages shown here are also the targets for the antiretroviral drugs discussed above [ 29 ]. As with other gene therapy techniques, delivery of siRNA to specific cells and tissues has been the major challenge in realizing the potential of RNAi [ 74 ]. New nanotechnology platforms are tackling this problem by providing nonviral alternatives for effective and safe delivery. The first nontargeted delivery of siRNA in humans via self-assembling, cyclodextrin polymer-based nanoparticles for cancer treatment have recently entered Phase I clinical trials [ 76 ].
A fusion protein, with a peptide transduction domain and a double stranded RNA-binding domain, was used to encapsulate and deliver siRNA to T cells in vivo [ 77 ].
Emerging nanotechnology approaches for HIV/AIDS treatment and prevention
Nanorobots are nanodevices that will be used for the purpose of maintaining and protecting the human body against pathogens. Nano is one billionth of one. Nanotechnology is the technology in which the operations are performed on nanometrics. It is the application of different technologies primarily interested in the reduction of size. The credential part of this paper gives the theoretical application of nanodevices in the treatment of AIDS. There is no technology for the treatment of AIDS.
Anti-HIV using Nanorobots