It
has been almost 40 years since the first reported case of human
immunodeficiency virus (HIV) infection leading to acquired immunodeficiency
syndrome (AIDS) in US in 1981. Since then many research laboratories around the
world have tirelessly worked to find ways to prevent, treat or even cure AIDS
patients. Supported by private and government agencies, millions of dollars
were spent to support the research. In US alone, $26,945.4M and $28,021.4M were
respectively allocated for 2018 and 2019 through NIH, in addition to specific
funds for supporting the global investigation through the U.S. President’s
Emergency Plan for AIDS Relief (PEPFAR) program.
With the latest reports on novel treatments leading to undetectable viral levels in patients’ bodies, let’s review the most prominent achievements in recent years as well as the enabling tools that made such developments possible. Our hope is that by knowing where we are and how we reached the current status we will be inspired to think more creatively towards further advancing the field.Key Milestones in HIV Research
a. Berlin Patient (Hütter, et al., 2009)
Perhaps
the most interesting news in the history of HIV research is the successful
treatment of the Timothy Ray Brown, the well-known “Berlin Patient” who seems
to have been cured by cell therapy. After being diagnosed with HIV in 1995, he
moved to Berlin from his hometown of Seattle, Washington, US. For many years he
took antiretroviral drugs to manage his HIV infection before being diagnosed
with leukemia in 2006. A year later, after undergoing two unsuccessful courses
of induction chemotherapy and one course of consolidation chemotherapy, he
received two transplants of bone marrow stem cells in Berlin, one of which was
from an HIV-immune donor (i.e. carrying CCR5-Δ32 mutation). This treatment was
based on previous studies reporting that the presence of CD4 and chemokine
receptors, such as CCR5, were required for successful HIV infection. Therefore,
a CCR5 allele with a homozygous 32-bp deletion (i.e. CCR5 deficient genotype)
would render humans resistant to the virus. In 2008, almost 20 months after Tim
received the transplant, Dr. Gero Hütter publicly broke the news about this
successful treatment in the CROI Conference in Boston, US. To this day, Tim
seems to be cancer and HIV free, holding the promise for other patients
awaiting to receive a similar treatment.
b. London Patient (Gupta, et al., 2019)
In
early March of 2019, a decade after the Berlin Patient, Nature released a
groundbreaking publication on an anonymous "London Patient". The
patient was a male adult who was diagnosed with Hodgkin’s lymphoma in late 2012
following an HIV-1 infection in 2003. Similar to the Berlin Patient, the London
Patient received CCR5Δ32/Δ32 haematopoietic stem-cell transplantation in 2016
and stopped taking antiretroviral therapy 16 months after his transplantation.
At the time researchers disclosed this study, patient had been in HIV-1
remission for 18 months after the cessation of antiviral therapy. The fact that
this patient achieved remission with two rounds of allogeneic haematopoietic
stem-cell transplantation (allo-HSCT) with homozygous CCR5Δ32/Δ32 donor cells
along with a mild chemotherapy rather than one round of transplantation and a
harsh total body irradiation as the Berlin Patient received, suggests that a
single allo-HSCT may be sufficient to achieve HIV-1 remission. Future reports
on similar treatment regiments will demonstrate if this approach can be established
as the gold standard for treating HIV patients or not.
c. Anti-HIV Broadly Neutralizing Antibodies
(Mendoza, et al. 2018)
In
the last several decades, monoclonal antibodies (mAb) have been used as a
therapeutic agent for treating AIDS. Among them, those with high neutralizing
activity against the majority of HIV isolates are named Broadly Neutralizing
Antibodies (bNAbs) and have been employed to design anti-HIV vaccines. While
bNAbs showed great promise as a potential alternative to antiretroviral drugs,
results from numerous clinical studies showed that HIV can be resistant to
bNAbs monotherapy. In 2018, however, Mendoza et al. reported that three rounds
of administration of two bNAbs - a combination of 3BNC117 and 10-1074 – in nine
patients enrolled in a Phase 1b clinical trial had led to viral suppression
from 15 to >30 weeks with a median of 21 weeks. This promising result
initiated a series of clinical trials on combinatorial bNAb treatment to
maintain long-term HIV suppression without any antiretroviral treatment in
patients carrying antibody-sensitive viral reservoirs.
d. Miami Monkey (Martinez-Navio, et al.,
2019)
Effectiveness of mAbs as anti-HIV therapeutic agents were also tested in animal models. A study led by Dr. Desrosiers recently reported progress on HIV prevention and treatment through the use of adeno assisted virus (AAV)-encoded monoclonal antibodies in rhesus monkeys. Results from triple mAb treatment of four HIV-infected rhesus monkeys for 86 weeks showed the viral load in one monkey to be undetectable for over three years. Further study on additional 12 monkeys was later performed using AAV delivery of four mAbs to the "quad group" and two mAbs to the "bi group", in which two monkeys from the quad group were observed with virologic suppression at a reasonable level in the 4-mAb cocktail treatment. Results from these two studies provide proof of concept for AAV delivery of anti-HIV mAb therapy to achieve a functional cure for AIDS patients. Moreover, this study highlights the importance of further understanding the anti-drug antibody (ADA) towards future application of this new approach in humans.
Removing
Obstacles for a Promising Future
Though
the Berlin and London Patients are lucky to be functionally cured by stem cell
therapy and combinatorial bNAb immunotherapy holds great promise, there are
still several challenges towards routine application of these approaches in
clinics. For one, stem cell therapy is highly risky due to medical complication,
such as Graft-versus-host disease (GvHD). Recipients need to take
immunosuppressive drugs which render patients more susceptible to bacterial and
viral infection. On the other hand, to ensure successful transplantation, it is
vital to monitor self-recognition by matching the surface molecules of the
donor cell and the recipient cell; posing another impediment for routine
clinical application. Moreover, the HIV tolerance induced by CCR5 mutation may
allow the virus to use the CXCR4 receptor and hence, increase the possibility
of CCR5 deficient genotype to be HIV infected.
Lastly, the envelope glycoprotein GP120, which is critical for HIV-1 to enter CD4+ cells, is reported to undergo rapid changes in its amino acid sequence. Such increased diversity would trigger the evolution of virus, by binding to CXCR4 instead of CCR5, and consequently increasing the complexity of HIV-1 prevention and treatment strategies. Similar concerns over HIV-1 as a highly diverse virus with varying levels of sensitivity to bNAbs as well as differences in viral reservoir in patients undergoing immunotherapy pose challenges in treating patients with combinatorial bNAbs. Creative approaches to solve these obstacles will ensure effective and universal application of these novel treatments for patients in all clinics.
Past
and Present HIV Research Support by GenScript
To this date, GenScript has provided up to 1 million synthetic genes to support research projects led by the global scientific community. Among them are scientific achievements of Feng Zhang’s CRIPSR genome editing, development of novel HIV vaccine by the Vaccine Research Center (VRC) at the National Institute of Allergy and Infectious Diseases (NIAID), and the design, optimization and synthesis of construct for AAV vectors harboring mAb-coding sequences reported in the "Miami Monkey" study. GenScript is honored to have its services, such as gene synthesis and cloning, enabled these scientists and strives to provide more advanced and reliable reagents for groundbreaking research in the future.
Voice
of Supported Researchers
"GenScript
provides excellent services in a variety of research needs. I have been using
GenScript services for over 10 years now, and the products and services
provided have been to my highest satisfaction, and that at blazing speed and
reasonable costs. I mostly used GenScript's molecular biology services, but
also protein analysis and expression services. Our regional customer support
specialist has provided exceptional help and superb assistance. Thank you
GenScript for making our research faster and smoother."
-
Dr. Sebastian P. Fuchs, University of Miami – Miller School of Medicine
"GenScript
delivers excellent quality and reliability in DNA synthesis and cloning
services at a very competitive price. Generating our constructs with them saved
us plenty of time and headaches. Moreover, they flawlessly adapt to our
specific needs on every occasion, and the customer experience is always
superb."
- Dr. Jose Martinez-Navio, University of Miami – Miller School of Medicine
Reference:
1.
https://www.hiv.gov/federal-response/funding/budget
2.
https://physician-news.umiamihealth.org/new-hiv-treatment-strategy-can-provide-long-term-viral-suppression-according-to-miller-school-study/
3.
https://americansforcures.org/patient_story/tim-brown-hiv-aids-cured-stem-cells/
4.
Gupta, et al. (2019) HIV-1 remission following CCR5Δ32/Δ32 haematopoietic
stem-cell transplantation. Nature. doi: 10.1038/s41586-019-1027-4
5.
Hütter, et al. (2009) Long-Term Control of HIV by CCR5 Delta32/Delta32
Stem-Cell Transplantation. N Engl J Med, 360: 692-698
6.
Martinez-Navio, et al. (2019) Adeno-Associated Virus Delivery of Anti-HIV
Monoclonal Antibodies Can Drive Long-Term Virologic Suppression. Immunity 50:
567-575
7. Mendoza, et al. (2018) Combination therapy with anti-HIV-1 antibodies maintains viral suppression. Nature 568: 479-484
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