Posts Tagged ‘CD8+ T cells’

NIH Considers Guidelines for CAR-T therapy: Report from Recombinant DNA Advisory Committee

Reporter: Stephen J. Williams, Ph.D.

In the mid to late 1970’s a public debate (and related hysteria) had emerged surrounding two emerging advances in recombinant DNA technology;

  1. the development of vectors useful for cloning pieces of DNA (the first vector named pBR322) and
  2. the discovery of bacterial strains useful in propagating such vectors

As discussed by D. S, Fredrickson of NIH’s Dept. of Education and Welfare in his historical review” A HISTORY OF THE RECOMBINANT DNA GUIDELINES IN THE UNITED STATES” this international concern of the biological safety issues of this new molecular biology tool led the National Institute of Health to coordinate a committee (the NIH Recombinant DNA Advisory Committee) to develop guidelines for the ethical use, safe development, and safe handling of such vectors and host bacterium. The first conversations started in 1974 and, by 1978, initial guidelines had been developed. In fact, as Dr. Fredrickson notes, public relief was voiced even by religious organizations (who had the greatest ethical concerns)

On December 16, 1978, a telegram purporting to be from the Vatican was hand delivered to the office of Joseph A. Califano, Jr., Secretary of Health, Education,

and Welfare. “Habemus regimen recombinatum,” it proclaimed, in celebration of the

end of a long struggle to revise the NIH Guidelines for Research Involving

Recombinant DNA Molecules

The overall Committee resulted in guidelines (2013 version) which assured the worldwide community that

  • organisms used in such procedures would have limited pathogenicity in humans
  • vectors would be developed in a manner which would eliminate their ability to replicate in humans and have defined antibiotic sensitivity

So great was the success and acceptance of this committee and guidelines, the NIH felt the Recombinant DNA Advisory Committee should meet regularly to discuss and develop ethical guidelines and clinical regulations concerning DNA-based therapeutics and technologies.

A PowerPoint Slideshow: Introduction to NIH OBA and the History of Recombinant DNA Oversight can be viewed at the following link:

Please see the following link for a video discussion between Dr. Paul Berg, who pioneered DNA recombinant technology, and Dr. James Watson (Commemorating 50 Years of DNA Science):

The Recombinant DNA Advisory Committee has met numerous times to discuss new DNA-based technologies and their biosafety and clinical implication including:

A recent Symposium was held in the summer of 2010 to discuss ethical and safety concerns and discuss potential clinical guidelines for use of an emerging immunotherapy technology, the Chimeric Antigen Receptor T-Cells (CART), which at that time had just been started to be used in clinical trials.

Considerations for the Clinical Application of Chimeric Antigen Receptor T Cells: Observations from a Recombinant DNA Advisory Committee Symposium Held June 15, 2010[1]

Contributors to the Symposium discussing opinions regarding CAR-T protocol design included some of the prominent members in the field including:

Drs. Hildegund C.J. Ertl, John Zaia, Steven A. Rosenberg, Carl H. June, Gianpietro Dotti, Jeffrey Kahn, Laurence J. N. Cooper, Jacqueline Corrigan-Curay, And Scott E. Strome.

The discussions from the Symposium, reported in Cancer Research[1]. were presented in three parts:

  1. Summary of the Evolution of the CAR therapy
  2. Points for Future Consideration including adverse event reporting
  3. Considerations for Design and Implementation of Trials including mitigating toxicities and risks

1. Evolution of Chimeric Antigen Receptors

Early evidence had suggested that adoptive transfer of tumor-infiltrating lymphocytes, after depletion of circulating lymphocytes, could result in a clinical response in some tumor patients however developments showed autologous T-cells (obtained from same patient) could be engineered to express tumor-associated antigens (TAA) and replace the TILS in the clinical setting.

However there were some problems noticed.

  • Problem: HLA restriction of T-cells. Solution: genetically engineer T-cells to redirect T-cell specificity to surface TAAs
  • Problem: 1st generation vectors designed to engineer T-cells to recognize surface epitopes but engineered cells had limited survival in patients.   Solution: development of 2nd generation vectors with co-stimulatory molecules such as CD28, CD19 to improve survival and proliferation in patients

A summary table of limitations of the two types of genetically-modified T-cell therapies were given and given (in modified form) below

                                                                                                Type of Gene-modified T-Cell

Limitations aβ TCR CAR
Affected by loss or decrease of HLA on tumor cells yes no
Affected by altered tumor cell antigen processing? yes no
Need to have defined tumor target antigen? no yes
Vector recombination with endogenous TCR yes no

A brief history of construction of 2nd and 3rd generation CAR-T cells given by


Differences between  second- and third-generation chimeric antigen receptor T cells. (Adapted by permission from the American Association for Cancer Research: Lee, DW et al. The Future Is Now: Chimeric Antigen Receptors as New Targeted Therapies for Childhood Cancer. Clin Cancer Res; 2012;18(10); 2780–90. doi:10.1158/1078-0432.CCR-11-1920)

Constructing a CAR T Cell (from

The first efforts to engineer T cells to be used as a cancer treatment began in the early 1990s. Since then, researchers have learned how to produce T cells that express chimeric antigen receptors (CARs) that recognize specific targets on cancer cells.

The T cells are genetically modified to produce these receptors. To do this, researchers use viral vectors that are stripped of their ability to cause illness but that retain the capacity to integrate into cells’ DNA to deliver the genetic material needed to produce the T-cell receptors.

The second- and third-generation CARs typically consist of a piece of monoclonal antibody, called a single-chain variable fragment (scFv), that resides on the outside of the T-cell membrane and is linked to stimulatory molecules (Co-stim 1 and Co-stim 2) inside the T cell. The scFv portion guides the cell to its target antigen. Once the T cell binds to its target antigen, the stimulatory molecules provide the necessary signals for the T cell to become fully active. In this fully active state, the T cells can more effectively proliferate and attack cancer cells.

2. Adverse Event Reporting and Protocol Considerations

The symposium had been organized mainly in response to two reported deaths of patients enrolled in a CART trial, so that clinical investigators could discuss and formulate best practices for the proper conduct and analysis of such trials. One issue raised was lack of pharmacovigilence procedures (adverse event reporting). Although no pharmacovigilence procedures (either intra or inter-institutional) were devised from meeting proceedings, it was stressed that each institution should address this issue as well as better clinical outcome reporting.

Case Report of a Serious Adverse Event Following the Administration of T Cells Transduced With a Chimeric Antigen Receptor Recognizing ERBB2[2] had reported the death of a patient on trial.

In A phase I clinical trial of adoptive transfer of folate receptor-alpha redirected autologous T cells for recurrent ovarian cancer[3] authors: Lana E Kandalaft*, Daniel J Powell and George Coukos from University of Pennsylvania recorded adverse events in pilot studies using a CART modified to recognize the folate receptor, so it appears any adverse event reporting system is at the discretion of the primary investigator.

Other protocol considerations suggested by the symposium attendants included:

  • Plan for translational clinical lab for routine blood analysis
  • Subject screening for pulmonary and cardiac events
  • Determine possibility of insertional mutagenesis
  • Informed consent
  • Analysis of non T and T-cell subsets, e.g. natural killer cells and CD*8 cells

3. Consideration for Design of Trials and Mitigating Toxicities

  • Early Toxic effectsCytokine Release Syndrome– The effectiveness of CART therapy has been manifested by release of high levels of cytokines resulting in fever and inflammatory sequelae. One such cytokine, interleukin 6, has been attributed to this side effect and investigators have successfully used an IL6 receptor antagonist, tocilizumab (Acterma™), to alleviate symptoms of cytokine release syndrome (see review Adoptive T-cell therapy: adverse events and safety switches by Siok-Keen Tey).


Below is a video form Dr. Renier Brentjens, M.D., Ph.D. for Memorial Sloan Kettering concerning the finding he made that the adverse event from cytokine release syndrome may be a function of the tumor cell load, and if they treat the patient with CAR-T right after salvage chemotherapy the adverse events are alleviated..

Please see video below:

http link:

  • Early Toxic effects – Over-activation of CAR T-cells; mitigation by dose escalation strategy (as authors in reference [3] proposed). Most trials give billions of genetically modified cells to a patient.
  • Late Toxic Effectslong-term depletion of B-cells . For example CART directing against CD19 or CD20 on B cells may deplete the normal population of CD19 or CD20 B-cells over time; possibly managed by IgG supplementation

 Please look for a Followup Post concerning “Developing a Pharmacovigilence Framework for Engineered T-Cell Therapies”


  1. Ertl HC, Zaia J, Rosenberg SA, June CH, Dotti G, Kahn J, Cooper LJ, Corrigan-Curay J, Strome SE: Considerations for the clinical application of chimeric antigen receptor T cells: observations from a recombinant DNA Advisory Committee Symposium held June 15, 2010. Cancer research 2011, 71(9):3175-3181.
  2. Morgan RA, Yang JC, Kitano M, Dudley ME, Laurencot CM, Rosenberg SA: Case report of a serious adverse event following the administration of T cells transduced with a chimeric antigen receptor recognizing ERBB2. Molecular therapy : the journal of the American Society of Gene Therapy 2010, 18(4):843-851.
  3. Kandalaft LE, Powell DJ, Jr., Coukos G: A phase I clinical trial of adoptive transfer of folate receptor-alpha redirected autologous T cells for recurrent ovarian cancer. Journal of translational medicine 2012, 10:157.

Other posts on this site on Immunotherapy and Cancer include

Report on Cancer Immunotherapy Market & Clinical Pipeline Insight

New Immunotherapy Could Fight a Range of Cancers

Combined anti-CTLA4 and anti-PD1 immunotherapy shows promising results against advanced melanoma

Molecular Profiling in Cancer Immunotherapy: Debraj GuhaThakurta, PhD

Pancreatic Cancer: Genetics, Genomics and Immunotherapy

$20 million Novartis deal with ‘University of Pennsylvania’ to develop Ultra-Personalized Cancer Immunotherapy

Upcoming Meetings on Cancer Immunogenetics

Tang Prize for 2014: Immunity and Cancer

ipilimumab, a Drug that blocks CTLA-4 Freeing T cells to Attack Tumors @DM Anderson Cancer Center

Juno’s approach eradicated cancer cells in 10 of 12 leukemia patients, indicating potential to transform the standard of care in oncology


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Nanotechnology and HIV/AIDS Treatment

Author: Tilda Barliya, PhD


AIDS was first reported in 1981 followed by the identification of HIV as the cause of the disease in 1983 and is now a global pandemic that has become the leading infectious killer of adults worldwide. By 2006, more than 65 million people had been infected with the HIV virus worldwide and 25 million had died of AIDS (Merson MH. The HIV-AIDS pandemic at 25 – the global response. (1, 2). This has caused tremendous social and economic damage worldwide, with developing countries, particularly Sub-Saharan Africa, heavily affected.

A cure for HIV/AIDS has been elusive in almost 30 years of research. 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 1987, 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).

However, it was the advent of a class of drugs known as protease inhibitors and the introduction of triple-drug therapy in the mid-1990s that revolutionized HIV/AIDS treatment (3,4). This launched the era of highly active antiretroviral therapy (HAART), where a combination of three or more different classes of drugs are administered simultaneously.

Challenges of HIV/AIDS treatment

  • HIV resides in latent cellular and anatomical reservoirs where current drugs are unable to completely eradicate the virus.
  • Macrophages are major cellular reservoirs, which also contribute to the generation of elusive mutant viral genotypes by serving as the host for viral genetic recombination.
  • Anatomical latent reservoirs include secondary lymphoid tissue, testes, liver, kidney, lungs, the gut and the brain.
  • The major challenge facing current drug regimens is that they do not fully eramacrdicate the virus from these reservoirs; requiring patients take medications for life. Under current treatment, pills are taken daily, resulting in problems of patient adherence. The drugs also have side effects and in some people the virus develops resistance against certain drugs.

Current treatment in HIV/AIDS

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. However, some HAART regimens have serious side effects and, in all cases, HAART has to be taken for a lifetime, with daily dosing of one or more pills. 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.Some patients also develop resistance to certain combinations of drugs, resulting in failure of the treatment. The absence of complete cure under current treatment underscores the great need for continued efforts in seeking innovative approaches for treatment of HIV/AIDS.

Drug resistance is mainly caused by the high genetic diversity of HIV-1 and the continuous mutation it undergoes. 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 (5). 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. 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. The major cause for this is that the virus resides in ‘latent reservoirs’ within memory CD4+ T cells and cells of the macrophage–monocyte lineage. 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 (6).  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. The eradication of the virus from such reservoirs is critical to the effective long-term treatment of HIV/AIDS patients.

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.

Nanotechnology for HIV/AIDS treatment

The use of nanotechnology platforms for delivery of drugs is revolutionizing medicine in many areas of disease treatment.

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. Specifically, targeted delivery of antiretroviral drugs to CD4+ T cells and macrophages as well as delivery to the brain and other organ systems could ensure that drugs reach latent reservoirs
  • 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. Figure 1. Various nanoscale drug delivery systems.

Optional treatments:

  •    Antiretroviral drugs
  •    Gene Therapy
  •    Immune Therapy
  •    Prevention

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The use of nanotechnology systems for delivery of antiretroviral drugs has been extensively reviewed by Nowacek et al. and Amiji et al. (7,8).

In a recent study based on polymeric systems, nanosuspensions (200 nm) of the drug rilpivirine (TMC278) stabilized by polyethylene. A series of experiments by Dou et al. showed that nanosuspension of the drug indinavir can be stabilized by a surfactant system comprised of Lipoid E80 for effective delivery to various tissues. 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.polypropylene glycol (poloxamer 338) and PEGylated tocopheryl succinate ester (TPGS 1000) were studied in dogs and mice. 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.

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 (120–200 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. 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. 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. For example, despite zidovudine’s 1 h half-life in plasma, it is dosed twice daily based on intracellular pharmacokinetic and clinical efficacy data. 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.

Gene Therapy for HIV/AIDS

In addition to improving existing antiretroviral therapy, there are ongoing efforts to discover alternative approaches for treatment of HIV/AIDS. 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.

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RNAi is also considered to have therapeutic potential for HIV/AIDS. Gene silencing is induced by double stranded siRNA, which targets for destruction

he mRNA of the gene of interest. For HIV/AIDS, RNAi can either target the various stages of the viral replication cycle or various cellular targets involved in viral infection such as CD4, CCR5, and/or CXCR4, the major cell surface co-receptors responsible for viral entry. HIV replicates by reverse transcription to form DNA and uses the DNA to produce copies of its mRNA for protein synthesis; siRNA therapy could be used to knock down this viral mRNA. 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.

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.

Although at an early stage, nonviral delivery of siRNA for treatment of HIV infection is also gaining ground. 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. CD4- and CD8-specific siRNA delivery caused RNAi responses with no adverse effects such as cyto-toxicity or immune stimulation. Similarly, a protamine-antibody fusion protein-based siRNA delivery demonstrated that siRNA knockdown of the gag gene can inhibit HIV replication in primary T cells

Single-walled nanotubes were shown to deliver CXCR4 and CD4 specific siRNA to human T cells and peripheral blood mononuclear cells. Up to 90% knockdown of CXCR4 receptors and up to 60% knockdown of CD4 expression on T cells was observed while the knockdown of CXCR4 receptors on peripheral blood mononuclear cells was as high as 60%. In a separate study, amino-terminated carbosilane dendrimers (with interior carbon-silicon bonds) were used for delivery of siRNA to HIV-infected lymphocytes.

These pioneering studies demonstrate that nonviral siRNA delivery is possible for HIV/AIDS treatment. However, more work needs to be done in optimizing the delivery systems and utilizing designs for efficient targeting and intracellular delivery. The recent developments in polymer- and liposome-based siRNA delivery systems could be optimized for targeting cells that are infected with HIV, such as T cells and macrophages. Moreover, since HIV mutates and has multiple strains with different genetic sequences, combination siRNA therapy targeting multiple genes should be pursued. For these applications, nanotechnology platforms with capability for co-delivery and targeting need to be developed specifically for HIV-susceptible cells. A macrophage and T-cell-targeted and nanotechnology-based combination gene therapy may be a promising platform for efficient HIV/AIDS treatment.

Immunotherapy for HIV/AIDS

The various treatment approaches described above focus on treating HIV/AIDS by directly targeting HIV at the level of the host cell or the virus itself. An alternative approach is immunotherapy aimed at modulating the immune response against HIV. CD8+ cytotoxic T-cell responses to acute HIV infection appear to be relatively normal, while neutralizing antibody production by B cells is delayed or even absent.

Immunotherapy is a treatment approach involving the use of immunomodulatory agents to modulate the immune response against a disease. Similar to vaccines, it is based on immunization of individuals with various immunologic formulations; however, the purpose is to treat HIV-infected patients as opposed to protect healthy individuals (preventive vaccines will be discussed in an upcoming section). The various immunotherapy approaches for HIV/AIDS could be based on delivering cytokines (such as IL-2, IL-7 and IL-15) or antigens. The development of cellular immunity, and to a large degree humoral immunity, requires antigen-presenting cells (APCs) to process and present antigens to CD4+and CD8+ T cells. Dendritic cells (DCs) are the quintessential professional APCs responsible for initiating and orchestrating the development of cellular and humoral (antibody) immunity.

Various polymeric systems have been explored for in vivo targeting of DCs and delivery of small molecules, proteins or DNAs showing potential for immunotherapy. Poly(ethylene glycol) (PEG) stabilized poly(propylene sulfide) polymer nanoparticles accumulated in DCs in lymph nodes. Following nanoparticle injection, DCs containing nanoparticles accumulated in lymph nodes, peaking at 4 days with 40–50% of DCs and other APCs having internalized nanoparticles.

In another study, nanoparticles of the copolymer poly(D,L-lacticide-co-glycolide) (PLGA) showed efficient delivery of antigens to murine bone marrow-derived DCs in vitro, suggesting their potential use in immunotherapy. More recently, a very interesting work showed that HIV p24 protein adsorbed on the surface of surfactant-free anionic poly(D,L-lactide) (PLA) nanoparticles were efficiently taken-up by mouse DCs, inducing DC maturation. he p24-nanoparticles induced enhanced cellular and mucosal immune responses in mice. Although this targeting is seen in ex vivo-generated DCs and not in vivo DCs, the efficient delivery of the antigen to DCs through the nanoparticles is an important demonstration that may eventually be applied to in vivo DC targeting.

Clinical Trial

he most clinically advanced application of nanotechnology for immunotherapy of HIV/AIDS is the DermaVir patch that has reached Phase II clinical trials (9). DermaVir is a targeted nanoparticle system based on polyethyleimine mannose (PEIm), glucose and HIV antigen coding DNA plasmid formulated into nanoparticles (~100 nm) and administered under a patch after a skin preparation. The nanoparticles are delivered to epidermal Langerhans cells that trap the nanoparticles and mature to become highly immunogenic on their way to the lymph nodes. Mature DCs containing the nanoparticles present antigens to T cells inducing cellular immunity. Preclinical studies and Phase I clinical trials showed safety and tolerability of the DermaVir patch, which led the progression to Phase II trials. This is the first nanotechnology-based immunotherapy for HIV/AIDS that has reached the clinic and encourages further work in this area.

Table 1

Summary of nanotechnology-based treatment approaches for HIV/AIDS.

Type of therapy Therapeutic agent (drug or gene) Nanotechnology delivery platform Development stage Refs.
Antiretroviral therapy Rilpivirine (TMC278) Poloxamer 338/TPGS 1000 Preclinical [35]
Indinavir Liposome-laden macrophages Preclinical [3638]
Stavudine Mannose- and galactose-targeted liposome Preclinical [3941]
Zidovudine Mannose-targeted liposome Preclinical [42]
Efavirenz Mannose-targeted dendrimer Preclinical [43,45]
Lamivudine Mannose-targeted dendrimer Preclinical [46]
Nanomaterials Fullerene derivatives Preclinical [4955]
Dendrimers Preclinical [56,57]
Silver nanoparticles Preclinical [58,59]
SDC-1721/gold nanoparticles Gold nanoparticles Preclinical [60]
Gene therapy siRNA Peptide fusion proteins, protamine–antibody fusion proteins, dendrimers, single walled carbon nanotubes, peptide–antibody conjugates Preclinical [7781]
Immunotherapy P24 protein Poly (D,L-lactide) nanoparticles/dendritic cells Preclinical [98]
Plasmid DNA Mannose-targeted polyethyleimine polymers Phase II clinical trials [99]

Note:  to open the references in the table 1, please go to ref 1 in this post to see full ref info.

Nanotechnology for HIV/AIDS prevention

The search for a safe and effective HIV/AIDS vaccine has been challenging in the almost three decades since the discovery of the disease. Recently, high-profile clinical trial failures have prompted great debate over the vaccine research, with some suggesting the need for a major focus on fundamental research, with fewer efforts on clinical trials.

The major challenges in the development of a preventive HIV/AIDS vaccine have been the extensive viral strain and sequence diversity, viral evasion of humoral and cellular immune responses, coupled with the lack of methods to elicit broadly reactive neutralizing antibodies and cytotoxic T cells. The challenge associated with delivery of any exogenous antigen (such as nanoparticles) to APCs, is that exogenous antigens require specialized ‘cross-presentation’ in order to be presented by MHC class I and activate CD8+cytotoxic T cells.

his requirement for cytosolic delivery of antigens and cross-presentation represents yet another hurdle for HIV intracellular antigen vaccine, but potentially an advantage of nanodelivery. Humoral responses (neutralizing antibodies produced by B cells) are generated to intact antigen presented on the surface for the virus, or nanoparticles, but these humoral responses typically require ‘help’ from CD4+ T cells, but rather both. Nanoparticles have potential as adjuvants and delivery systems for vaccines. Table 2 present the different approaches.

Table 2

Summary of nanotechnology developments for prevention of HIV/AIDS.

Type of preventive agent Antigen/adjuvant or drug Nanotechnology platform Development stage Refs.
Protein or peptide vaccine gp41, gp120, gp160, p24, Env, Gag, Tat Liposomes, nanoemulsion, MF59, PLA nanoparticles, poly(γ-glutamic acid) nanoparticles Preclinical [108111]
DNA vaccine env, rev, gag, tat, CpG ODN Liposomes, nanoemulsion, PLA nanoparticles Preclinical [115,121]
Inactivated viral particle Inactivated HIV viral particle Polystyrene nanospheres Preclinical [126127]
Microbicides L-lysine dendrimer L-lysine dendrimer Phase I/II [136138]
PLGA nanoparticles
PSC-RANTES PLGA Preclinical [139]
siRNA Nanoparticles, lipids, cholesterol conjugation Preclinical [141144]

ODN: Oligonucleotides; PLA: Poly(D,L-lactide); PLGA: Poly(D,L-lacticide-co-glycolide).

Note:  to open the references in the table 2, please go to ref 1 in this post to see full ref info.



Nanotechnology can impact the treatment and prevention of HIV/AIDS with various innovative approaches. Treatment options may be improved using nanotechnology platforms for delivery of antiretroviral drugs. Controlled and sustained release of the drugs could improve patient adherence to drug regimens, increasing treatment effectiveness.

While there is exciting potential for nanomedicine in the treatment of HIV/AIDS, challenges remain to be overcome before the potential is realized. These include toxicity of nanomaterials, stability of nanoparticles in physiological conditions and their scalability for large-scale production. These are challenges general to all areas of nanomedicine and various works are underway to tackle them.

Another important consideration in investigating nanotechnology-based systems for HIV/AIDS is the economic aspect, as the hardest hit and most vulnerable populations reside in underdeveloped and economically poor countries. In the case of antiretroviral therapy, nanotherapeutics may increase the overall cost of treatment, reducing the overall value. However, if the nanotherapeutics could improve patient adherence by reducing dosing frequency as expected, and furthermore, if they can eradicate viral reservoirs leading to a sterile immunity, these advantages may effectively offset the added cost.



1. Mamo T, Moseman EA., Kolishetti N., Salvadoe-Morales C., Shi J., Kuritzkes DR., Langer R., von-Adrian U and Farokhzad OF.   Emerging nanotechnology approaches for HIV/AIDS treatment and prevention. Nanomedicine (Lond) 2010; 5(2): 269-295.

2. Merson MH. The HIV-AIDS pandemic at 25 – the global response. N Engl J Med.2006;354(23):2414–2417

3. Walensky RP, Paltiel AD, Losina E, et al. The survival benefits of AIDS treatment in the United States. J Infect Dis. 2006;194(1):11–19

4. Richman DD, Margolis DM, Delaney M, Greene WC, Hazuda D, Pomerantz RJ. The challenge of finding a cure for HIV infection. Science. 2009;323(5919):1304–1307)

5.Sax PE, Cohen CJ, Kuritzkes DR. HIV Essentials. Physicians’ Press; Royal Oak, MI, USA: 2007.

6. Lamers SL, Salemi M, Galligan DC, et al. Extensive HIV-1 intra-host recombination is common in tissues with abnormal histopathology. PLoS One. 2009;4(3):E5065.

7. Vyas TK, Shah L, Amiji MM. Nanoparticulate drug carriers for delivery of HIV/AIDS therapy to viral reservoir sites. Expert Opin Drug Deliv. 2006;3(5):613–628.

8. Amiji MM, Vyas TK, Shah LK. Role of nanotechnology in HIV/AIDS treatment: Potential to overcome the viral reservoir challenge. Discov Med. 2006;6(34):157–162

9. Lori F, Calarota SA, Lisziewicz J. Nanochemistry-based immunotherapy for HIV-1. Curr Med Chem. 2007;14(18):1911–1919

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