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.
- Gene Synthesis
- Codon Optimization
- Construct Design
- Plasmid Preparation
- Antibody Development and Engineering
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