19-02-2013, 03:10 PM
Emerging nanotechnology approaches for HIV/AIDS treatment and prevention
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ABSTRACT
Currently, there is no cure and no preventive vaccine for HIV/AIDS. 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. It has a vast potential to radically advance the
treatment and prevention of HIV/AIDS. In this review, we discuss the challenges with the current treatment
of the disease and shed light on the remarkable potential of nanotechnology to provide more effective
treatment and prevention for HIV/AIDS by advancing antiretroviral therapy, gene therapy, immunotherapy,
vaccinology and microbicides.
INTRODUCTION
The emergence of AIDS was first reported in
1981 followed by the identification of HIV as
the cause of the disease in 1983 [1–4]. HIV/AIDS
is now a global pandemic that has become the
leading infectious killer of adults worldwide [5].
By 2006, more than 65 million people had been
infected with the HIV virus worldwide and
25 million had died of AIDS [6]. At the end of
2007, around 33 million people were living with
the virus, with 2.7 million new infections and
2 million deaths each year [7]. 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 fixeddose
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]. 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 [10,11]. 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].
Current HIV/AIDS treatment
The current state-of-the-art treatment modality
for HIV/AIDS is HAART, where three or more
antiretroviral drugs are given to patients simultaneously.
The drugs used in combination are in
most cases from different classes that work based
on different mechanisms. Despite the remarkable
successes with the current HAART treatment
for HIV/AIDS, there are still various challenges
remaining. 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].
Nanotechnology for antiretroviral
drug delivery
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 watersoluble
drugs, targeted delivery of drugs to specific
cells or tissues and intracellular delivery of
macromolecules [18,32].
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 [25,61]. 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].
Early efforts in gene therapy for HIV/AIDS
have been focused on viral vectors as the
delivery agents with various clinical trials
in progress [61,63–68]. 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].
These efforts are encouraging and support the
growing excitement around gene therapy for
the treatment of HIV/AIDS.
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 [83]. Over time, viral mutation leads to
loss of the CD8+ T cell cytotoxic function.
However, the major effect of an infection by
HIV is the loss of CD4+ T cells. These ‘helper’
T cells are responsible for a number of supportive
functions for other immune populations
and their loss leads to profound immunosuppression,
manifested by the presence of
dysfunctional B-cells, natural killer cells and
the macrophages in chronically HIV-infected
patients [84]. In recent years, there has been
increasing interest in the therapeutic use of
immune responses to restore the regular function
of the immune system as an effective way to
treat HIV/AIDS [85–87].
Vaccine delivery
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 [13–15,100,101].
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 [102]. In order to generate
T cell responses, protein antigens must
enter APCs (such as DCs) where peptides are
processed and loaded into MHC molecules
for presentation to CD4+ T cells (extracellular
antigen in MHC class II) and CD8+ T cells
(intracellular antigen in MHC class I) [103].
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 [104]. This 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 [105], and thus the challenge is not
to achieve either a single cellular or humoral
response, but rather both.
Intravaginal microbicides
Although vaccines that induce sterilizing immunity
are the most ideal way to prevent the spread
of HIV/AIDS, other approaches are also being
pursued until a safe and effective vaccine is
developed. Since sexual transmission is the
major route of infection, prevention methods
aimed at behavioral changes as well as the use
of personal protection such as condoms have
helped in reducing the spread of the disease in
some countries [131]. However, effective protection
methods that can be utilized by women have
not been readily available, making women more
vulnerable to the disease. Among people infected
with HIV/AIDS, women account for nearly 50%
of infections worldwide and 60% in Sub-Saharan
Africa [132,133]. As a result, there are major efforts
focused on developing effective microbicides for
HIV/AIDS prevention. Microbicides are preventive
agents that are topically applied into the
vagina to prevent the transmission of HIV/AIDS
or other sexually transmitted diseases.
Conclusion & future perspective
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. Targeted nanoparticles
utilizing ligands such as mannose, galactose,
tuftsin and fMLF peptides have been used to
target macrophages, major HIV viral reservoirs.
In the future, targeted co-delivery of two or
more antiviral drugs in a nanoparticle system
could radically improve treatment of viral reservoirs.
Our group and other investigators have
developed nanoparticles with the potential to codeliver
both hydrophobic and hydrophilic drugs
or genes and these may provide versatility for
codelivery of antiviral drugs [145–148].