Article: Fc-dependent functions are redundant to efficacy of anti-HIV antibody PGT121 in macaques (2019)
https://www.jci.org/articles/view/122466
Authors
Matthew S. Parsons,1 Wen Shi Lee,1 Anne B. Kristensen,1 Thakshila Amarasena,1 Georges Khoury,1 Adam K. Wheatley,1,2 Arnold Reynaldi,3 Bruce D. Wines,4 P. Mark Hogarth,4 Miles P. Davenport,3 and Stephen J. Kent1,2,5 1 Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, and 2 ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, The University of Melbourne, Parkville, Victoria, Australia. 3 Kirby Institute, University of New South Wales, Sydney, New South Wales, Australia. 4 Centre for Biomedical Research, Burnet Institute, Melbourne, Victoria, Australia. 5 Melbourne Sexual Health Centre and Department of Infectious Diseases, Alfred Health, Central Clinical School, Monash University, Melbourne, Victoria, Australia.
Funding
Funded by grants from the Australian National Health and Medical Research Council (NHMRC) and the Australian Centre for HIV and Hepatitis Virology Research.
Terminology
Simian-human immunodeficiency virus– An HIV-like virus that can infect monkeys and apes and can cause a disease similar to AIDS.
Broadly neutralizing antibodies (BnAbs)- A type of antibody that can recognize and block many types of HIV from entering healthy cells. Broadly neutralizing antibodies (bNAbs) may also activate other immune cells to help destroy HIV-infected cells. This research utilises a number of BnAbs, including WT PGT121 and LALA PGT121,
Fc-dependent function– Fc-dependent functions improve the capacity of broadly neutralizing antibodies (BnAbs) to protect against and control HIV-1 infection.
Cell-associated virus– a virus passed on by direct cell-cell contact.
HIV-1- there are two main types of HIV – HIV-1 (the most common) and HIV-2 (relatively uncommon and less infectious) and they are 2 distinct viruses.
NK cell–depleting– natural killer cells provide innate defence against viruses and tumour cells by killing target cells and producing immunoregulatory cytokine
Plasma viremia– virologic marker of the clinical stage of HIV infection and viral replication
PBMC– a peripheral blood mononuclear cell (PBMC) is any peripheral blood cell having a round nucleus. These cells consist of lymphocytes (T cells, B cells, NK cells) and monocytes, PBMCs are widely used in research and toxicology applications. Peripheral blood mononuclear cells (PBMC) give selective responses to the immune system and are the major cells in the human body immunity.
Method
To assess the importance of Fc-dependent functions of the BnAB PGT121, macaques were administered WT PGT121 or a version of the Ab with greatly diminished Fc-dependent functionality (i.e., LALA PGT121) and then challenged with cell-associated SHIVSF162P3. In a second experiment, macaques were administered an NK cell–depleting Ab prior to WT PGT121 administration and cell-associated SHIVSF162P3 challenge (Two control animals were infused with saline). Last, a series of SHIVSF162P3-infected macaques were administered WT or LALA PGT121 and followed up for determination of plasma viremia and viral DNA within PBMCs.
In total, 26 macaques were used in this research. Juvenile pigtail macaques were sourced from the Monash University Animal Research Platform, the Australian National macaque breeding facility. The research varied in length according to the experiment and group assigned, but was up to 11 weeks.
Ultimately, the macaques were presumably killed to obtain their spleens for analysis.Â
Relevance to Humans
Analyses of the relevance of monkey studies to human biology indicate that genetic similarity does not result in sufficient physiological similarity for monkeys to constitute good models for research, and that monkey data do not translate well to progress in clinical practice for humans.
The major molecular differences underlying these inter-species phenotypic disparities have been revealed by comparative genomics and molecular biology — there are key differences in all aspects of gene expression and protein function, from chromosome and chromatin structure to post-translational modification. The collective effects of these differences are striking, extensive and widespread, and they show that the superficial similarity between human and monkey genetic sequences is of little benefit for biomedical research.
This research does not equate to studying an illness in humans; but studying a different illness in primates. Because HIV and simian immunodeficiency virus (SIV) are closely related viruses, researchers study SIV as a way to learn more about HIV. In fact, SIV differs from the genetics of HIV by a staggering 50% (2). SIV cannot infect humans, and HIV cannot infect monkeys. In fact, infection with HIV-1 does not progress to AIDS in chimpanzees, or any other animal species except humans (1).
Macaques infected with a hybrid of SIV and HIV (SHIV) progress to AIDS but the time to progression is significantly different from that observed in humans infected with HIV. The pathology revealed in SIV- or SHIV-infected monkeys does not duplicate human HIV (3). This is indicative of the failing of 100 different types of HIV vaccines tested in monkeys with positive results, none of which provided protection or therapeutic benefit in humans, due to major differences in SIV-infected macaques compared to HIV-infected humans (1).
Animal Welfare Concerns
Monkey species have rich social lives taking place in diverse groups and mixed habitats. Their behaviour is complex and varied. Their mental abilities are developed to the point that they can reflect on what is happening to them. Cuthbertson notes that any animal with a nervous system suffers from events such as removal from its own kind, fear, and being subjected to invasive and often painful tests with no knowledge of what is going to happen next (4).
One animal had to be euthanized ‘2 weeks after the challenge for non- SHIV related reasons’. It is not stated what the reason was. There is no mention of monitoring for adverse welfare effects, vet care or interventions such as analgesics/humane endpoints.
There is also no reference to the symptoms that may affect the animals, which can range from anorexia, chronic diarrhea, SHIV-related encephalitis, or SAIDS-associated neurologic symptoms, nor their welfare implications.
Cost-Benefit Assessment
The small sample of primates may not extrapolate to wider populations of primates.
Discussion states that “data presented is consistent with those of previous studies” and again, “the in vivo observation is consistent with several in vitro studies (references 10,14,25). If this is existing information, why was there a need for repeat studies?
There is some new knowledge claimed: data are in apparent contradiction with the literature highlighting a role for Fc-dependent functions (2). In macaques, the b12 BnAb partially loses protective efficacy after mutation to the LALA format. The reason (or reasons) why b12 LALA loses protective efficacy but PGT121 LALA retains protective efficacy is unknown.
However, this relates to macaques and SHIV and may not translate to humans and HIV, due to the aforementioned reasons.
Alternatives to animals in HIV research
Human cells and tissues can be used in HIV research, as well as more sophisticated methods such as genetic engineering techniques and reconstituted human tissue models.
Human-focussed research method are in use. For example, scientists from The Scripps Research Institute (TSRI), the International AIDS Vaccine Initiative (IAVI) and the La Jolla Institute for Allergy and Immunology published a study where they improved the affinity of a previously known bnAb-inducing immunogen by mutating every single position on this protein to find most optimal binding sequence. The newly optimized immunogen they identified by yeast display library screening and next-generation sequencing has a binding affinity 2,100 times greater than the original immunogen. Using donated blood from 15 healthy volunteers, they subsequently demonstrated that about 96 percent of people have sufficient precursor B cells that would respond to this new immunogen. This human-based approach offers a promising new vaccine candidate for HIV with data supporting its effectiveness in humans while also serving as a model strategy to develop similar vaccine candidates for other diseases (5).
What You Can Do
Please write to the University of Melbourne to express your concerns about the use of primates in unnecessary experiments. Ask how they justify the use of animals in experimental procedures when these animals do not appropriately model humans.
Professor Duncan Maskell
Vice Chancellor University of Melbourne
9th Floor, Raymond Priestley Building
The University of Melbourne
Victoria 3010 Australia
Email: vc@unimelb.edu.au
References
[1]Â Â Bailey J. Monkey-based research on human disease: the implications of genetic differences. Altern Lab Anim. 2014;42(5):287-317. doi:10.1177/026119291404200504
[2] Taylor (2016) Monkeys are still suffering for ineffective HIV research https://www.crueltyfreeinternational.org/what-we-do/blog/monkeys-are-still-suffering-ineffective-hiv-research
[3] Animal Models and the Development of an HIV Vaccine (Greek, 2012) J AIDS Clinic Res 2012, S8 https://www.hilarispublisher.com/open-access/animal-models-and-the-development-of-an-hiv-vaccine-2155-6113.S8-001.pdf
[4] Cuthbertson, J 2012, ‘Primates and HIV Research – Infecting our closest relatives’. Available at: https://animalfreescienceadvocacy.org.au/_literature_101603/Primates_and_HIV_Research_-_Infecting_our_closest_relatives
[5] PCRM (2016) Promising HIV Vaccine Candidate Identified Through Human-Focused Research https://www.pcrm.org/news/ethical-science/promising-hiv-vaccine-candidate-identified-through-human-focused-research