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Virology Research Journal | Volume 2
May 18-19, 2018 | Montreal, Canada
2
nd
World Conference on
STDs, STIs & HIV/AIDS
P
resently, HIV patients ingest combination antiretroviral
therapy (cART), has proven to significantly reduce plasma
viremia below detection limits. Patients are able to live fairly
normal lives on cART. However, some serious long-term side
effects due to high cARV drug levels are produced. Additionally,
another concern is low-level replication of HIV-1 primarily in
tissue reservoirs of suppressed individuals. Subsequently, even
a brief interruption in treatment may allow HIV-1 rebound
from the reservoirs into the plasma. Hence, a highly motivated,
adherent patient taking cARV daily is needed to achieve a
nondetectable plasma viral load (pVL). Therefore, cARV therapy
faces major challenges including adherence, a daily large oral
dose, with associated drug side effects, and costs. Here, cARV
nanomedicine could be a potential alternative. Currently, HIV-
1 research is focused on formulation ARV drugs that prolong
bioavailability of drugs to improve drug-adherence and
improves therapeutic or prophylactic opportunities of HIV-
1 patient populations. The other major issue is to suppress
HIV-1 replication in the reservoirs. To achieve these goals,
our research is focused to formulate anti-CCR5 antibody
loaded cARV nanoparticles (NPs), with the aim to prolong
cARV bioavailability and to block HIV replication within the
HIV reservoir to improve drug efficacy to prevent/treat HIV-1
infection. We formulated, cARV drugs (i.e. dolutegravir (DTG) +
emtricitabine (FTC)) loaded Poly (lactic-co-glycolic acid) (PLGA)
NPs (DTG+FTC NPs) and to target HIV-1 infected cells (a HIV-1
reservoir model), these NPs were surface labelling with anti-
CCR5 antibody. For bio distribution study of cARV NPs, IRDye
800CW loaded NPs were formulated and administration
subcutaneously (SubQ) in humanized mice model, Hu-CD34-
NSG mice (n=3) with functional human immune reconstitution.
The mice were imaged for 14 days under IVIS Lumina XR
In
Vivo
Imaging System. After 14th day, animals were sacrificed
and organ of interest (female reproductive track (FRT), colon,
lymph nodes, spleen and brain) were imaged. Bio distribution
of IRD NPs demonstrated whole body distribution within 1 h of
SubQ administration. Overtime accumulation of IR NPs reveals
high accumulation at the HIV-1 virus infection site (FRT and
colon), and reservoirs (lymph nodes, spleen, and brain), even
after 14 days of study. Positively, the injection site shows high
NPs presence even at day 14 of study, conferring the depo and
slow release properties of NPs. To target the HIV-1 infected cells
(a HIV-1 reservoir model), DTG+FTC loaded NPs were surface
labeled with anti-CCR5 antibody and their binding efficacy was
evaluated by flow cytometry. Further, CCR5 targeting analysis
after treatment with anti-CCR5-DTG+FTC NPs shows enhance
binding efficacy with the CCR5 receptor expressing cells (i.e.
HIV-1 reservoir cell type). At the tissue level, NPs accelerates
prolonged penetration. Whereas
in-vivo
study demonstrates
NPs results in enhanced and prolonged accumulation at the site
of infection and within latent reservoirs in this animal model
of HIV-1 for entire study period. Moreover, targeted cARV NPs
enhances latent cells at theHIV-1 reservoirs. Present focus of our
study is to evaluate potency of the HIV-1 protective/treatment
efficacy of the target specific cARV NPs. Our cARV encapsulated
polymeric nanoparticle (NPs) as nanodrug delivery system
shows slow drug release and protects drugs from systemic
clearance as well as HIV-1 reservoir organ accumulation.
Therefore, we predict use of targeted cARV NPs will lead to
monthly dosing in humans that potentially could overcome
the adherence burden of the HIV patient and potentially could
achieve functional HIV-1 cure.
Speaker Biography
Subhra Mandal has graduated from International School of Advanced Studies-SISSA,
Trieste, Italy with her Doctorate degree. Soon after completion, she joined Prof. Carl
Figdor, a world-class immunologist in Radboud University Nijmegen Medical Centre,
Nijmegen, The Netherlands, as Post-Doctoral researcher for European Research
Council (ERC) Advanced grant project. Since 2015, she is working as co-investigator
with Dr. Chris Destache as a NIAID (R01) grant, she has more than 10 years of research
experience in design, characterization and application of various types of nanocarriers
for effective drug delivery system and nano-drugs for cancer, neurodegenerative
diseases and HIV/AIDS theranostics. She is active editorial board member of various
journals and participates in peer-reviewing manuscripts for various journals. She is an
active member in various scientific societies such as RSB, ASM and AAPS.
e:
SubhraMandal@creighton.eduSubhra Mandal
Creighton University, USA
Targeting HIV-1 reservoir by combination antiretroviral drug loaded nanoformulation:
Towards functional HIV cure