“We have been privileged to have worked with community members who are so committed to the research that could one day realize our shared vision of a world without AIDS.”
Professor Salim Abdool Karim, Director of CAPRISA, South Africa.
Since HIV was found to be the cause of acquired immune deficiency syndrome (AIDS) in 1983, scientists have been working endlessly towards the development of an effective vaccine to end the global HIV pandemic which has claimed more than 32 million lives[1] and impacted millions more. Unfortunately, the best vaccine candidate we have had to date was from the famous Thai RV144 trial which only resulted in 31.2% efficacy (Rerks-Ngarm et al., 2009[2]). However, hope remains and more than 30 years after the discovery of HIV, we have uncovered many vulnerabilities of the virus which could lead to the development of an effective HIV vaccine to solve one of the big global challenges of our age.
One of the keys to a successful vaccine is the use of broadly neutralizing antibodies (bNAbs). These special antibodies bind to the HIV envelope protein and prevent the virus from infecting host cells. What makes them even more special is that they can bind numerous mutated versions of the virus and therefore overcome the problem of the HIV variability. Understanding the diverse ways that antibodies use to target the HIV envelope is important to the development of an HIV vaccine which can produce such unique and unusual antibodies and effectively protect vaccinated individuals from HIV infection.
My name is Dr Thandeka Moyo and I am a GCRF START grant-funded Postdoctoral Research Fellow at South Africa’s National Institute for Communicable Diseases (NICD), affiliated to the University of the Witwatersrand (Wits). Over the past few years, my colleagues and I have gained new insights into bNAbs in chronic HIV infection, insights which contribute significantly to the worldwide hunt for an HIV vaccine. Most recently, with access to the UK’s national synchrotron – Diamond Light Source (Diamond) – facilitated by the GCRF START grant, we were able to solve the structure for one member of a family of antibodies which has revealed a uniquely long loop in the light chain of the antibody – a loop up to three times longer than other published anti-HIV antibodies![3] Such insights are exciting, providing opportunities not only to expand my skills and knowledge as an early career scientist but also to inspire further hope that we will one day have all the necessary information to design an effective vaccine to end the global HIV pandemic.
South Africa has the biggest HIV epidemic in the world, with an estimated 7.5 million people infected nationally according to UNAIDS[4]. In this article, I will outline some of the insights achieved over several years of investigating broadly neutralizing antibodies through women participating in the CAPRISA Cohort – a research programme based in the KwaZulu-Natal province of South Africa. Without these women enabling us to study their donated samples, we would still have many unanswered questions.
“The experiences of the CAPRISA bnAb cohort studies epitomize the strength of the relationship between CAPRISA researchers and the local communities – a relationship of respect and equality.”
Professor Salim Abdool Karim, Director of CAPRISA, South Africa.
Investigating broadly neutralizing antibodies in chronic HIV infection
A subset of individuals who are infected with HIV develop broadly neutralizing antibodies (bNAbs) in chronic HIV infection. Unfortunately, these special antibodies are very unusual with characteristics not found in most other antibodies that we have in our bodies. For example, these antibodies are highly mutated and have longer “arms” that reach out and bind to the virus. Most antibodies do not have these characteristics, so researchers have spent years studying these unique bNAbs to get a better sense of how to produce them with an HIV vaccine.
In our laboratory at the NICD, we study antibodies in HIV-infected women from KwaZulu-Natal who participate in the CAPRISA Cohort. Established in 2003, this Cohort has tracked women over several years from before HIV infection, through to when a subset of them were just infected (acute stage), and years after infection (chronic stage). Throughout the course of the study, the women received healthcare and HIV counselling through the Cohort and have continued to participate in it for years. Blood samples were taken at various time points and from these samples we have been able to track the evolution of the viruses in these women as well as the way their antibodies have adapted throughout infection – with some women developing these special bNAbs.
The CAPRISA Cohort has been invaluable in providing us with novel information on how bNAbs develop as the virus mutates, as well as how we can engineer a vaccine strategy more widely to make these antibodies. This has helped us understand the development of bNAbs and how we can use these antibodies for an effective HIV vaccine. Outlined below are examples from three women in the Cohort (referred to as CAP256, CAP248 and CAP314 respectively) who have developed special antibodies.
CAPRISA Cohort participants CAP256 and CAP248
CAPRISA Cohort participant CAP256 became infected with HIV during the study and then re-infected with another variant form of HIV 15 weeks after initial infection – a phenomenon referred to as superinfection. A related virus to the superinfecting virus changed the immune response in this woman and she developed bNAbs after this event. Scientists in the USA isolated antibodies from the blood donated by CAP256[5] and discovered that the best antibody isolated bound to the apex (the top region) of the HIV envelope protein. This antibody is the most potent antibody isolated to date that binds to this target and the exact mode of binding for this antibody was not understand until recently. Led by our collaborators at the National Institute of Health in the USA, a study of the high-resolution structure of this antibody bound to the HIV envelope using cryo-electron microscopy revealed that it uses two distinct mechanisms to bind to this region (Gorman et al., 2020[6]). The use of these diverse strategies is likely the cause of its extremely high potency. The antibodies from CAP256 are currently in an HIV prevention clinical trial with results expected in the next few years.
Another CAPRISA Cohort participant, CAP248, also developed bNAbs. Researchers isolated an antibody from this participant which was unusual in the HIV envelope site that it targeted. Using negative stain electron microscopy (Scarff et al., 2018[7]), they showed that this antibody from CAP248 bound to a target proximal to the viral membrane and parts of the antibody interacted directly with viral membrane (Wibmer et al., 2017[8]). This mode of binding is unique and represents a novel way an antibody can bind to the HIV envelope protein. This novel binding mechanism may provide insight into the design of an HIV vaccine candidate that can produce this type of antibody response.
Solving a unique antibody structure with the help of the GCRF START grant – CAPRISA Cohort participant CAP314
The last participant to highlight in this article is CAP314. CAP314 developed bNAbs within two years of infection which is a relatively short time for HIV-infected individuals to develop these special antibodies. We isolated antibodies from three families of antibodies that developed in this individual. One family of antibodies mutated over time in response to the mutating HIV variants circulating in CAP314 at the same time. We were able to solve the structure for one member of this antibody family by X-ray crystallography on Diamond’s i03 beamline, in 2019, with Dr Dave Hall as our local contact in the UK for the beamline session and access provided by the GCRF START grant. Solving the structure of this antibody has revealed its uniqueness in that it has an extremely long light chain loop. The loops of antibodies are like arms which reach out and attach to their target on the HIV Envelope. Most anti-HIV antibodies have long loops on the heavy chain of the antibody, but this antibody has a uniquely long loop – up to three times longer than other published anti-HIV antibodies – in the light chain of the antibody. This long light chain loop reaches into the HIV envelope protein and makes the necessary contacts for this antibody to bind to the virus and stop it from infecting cells. Novel and unique binding mechanisms of antibodies like these give us important insights which could help us in our quest to design an HIV vaccine.
Global solidarity, shared responsibility through phenomenal CAPRISA Cohort and collaborations
We are very grateful to the women in the CAPRISA Cohort who make our vital work towards the goal of HIV prevention possible, and to our collaboration with the GCRF-funded START grant. START is a phenomenal initiative supporting capacity development of structural biologists throughout Africa by providing improved access to world class synchrotron equipment, mentoring and expertise. I have been fortunate to have found extremely supportive mentors in START Co-Investigator’s (CoI’s), Prof. Penny Moore and Prof. Lynn Morris, who have encouraged my independence and supported me throughout my Postdoctoral studies.
“Over the last decade, we have learned an incredible amount about how some HIV infected women make broadly neutralizing antibodies. These insights have significantly contributed to HIV vaccine design. This has only been possible because of the extraordinary commitment shown by CAPRISA Cohort donors who come back again and again, and the clinical staff who care for them. We are truly indebted to them.”
GCRF START Co-I, Prof. Penny Moore, University of the Witwatersrand and the National Institute for Communicable Diseases.
The UN states that a core principle of the 17 Sustainable Development Goals (SDGs), and of the AIDS response, is that “no one should be left behind.“ The AIDS epidemic cannot be ended without “the needs of people living with and affected by HIV, and the determinants of health and vulnerability, being addressed.”– UNAIDS[9]
Read more here about HIV/AIDS and the UN Sustainable Development Goals.
Read more about World AIDS Day 2020 here.
More about Dr Thandeka Moyo
GCRF START Postdoctoral Research Fellow, Dr Thandeka Moyo, holds a BSc with distinctions in Biochemistry and Microbiology and a BSc (Hons) in Biochemistry from Rhodes University. She went on to obtain a MSc (Med) and PhD in Clinical Science and Immunology from the University of Cape Town where she looked at the mechanisms used by various HIV strains to gain resistance to broadly neutralizing antibody responses. Based at South Africa’s National Institute for Communicable Diseases and affiliated to the University of the Witwatersrand, Thandeka’s postdoctoral research involves understanding the structure and function of HIV neutralizing antibodies by X-ray crystallography. More recently she has added SARS-CoV-2 to her research focus, developing serological assays to measure humoral responses to infection and vaccination.
More about Prof. Penny Moore
GCRF START Co-I, Prof. Penny Moore, is a Reader and DST/NRF South African Research Chair of Virus-Host Dynamics at the University of the Witwatersrand and the National Institute for Communicable Diseases. She holds a joint appointment as Honorary Senior Scientist in Virus-Host Dynamics at the Centre for the AIDS Programme of Research in South Africa (CAPRISA), University of KwaZulu-Natal. Moore co-directs a team of more than 15 scientists and 10 graduate students, with the team’s research focused predominantly on HIV neutralizing antibodies and their interplay with the evolving virus.
©Diamond Light Source
Footnotes
[1] https://www.unaids.org/en/resources/fact-sheet accessed November 2020
[2] RERKS-NGARM, S., PITISUTTITHUM, P., NITAYAPHAN, S., KAEWKUNGWAL, J., CHIU, J., PARIS, R., PREMSRI, N., NAMWAT, C., DE SOUZA, M. & ADAMS, E. 2009. Vaccination with ALVAC and AIDSVAX to prevent HIV-1 infection in Thailand. New England Journal of Medicine, 361, 2209-2220; doi: 10.1056/NEJMoa0908492.
[3] The structure was solved by Dr Thandeka Moyo from the NICD, South Africa, and Taylor Sicard and Dr Jean-Philippe Julien from the University of Toronto, Canada.
[4] http://aidsinfo.unaids.org/ accessed November 2020.
[5] The donor was identified by Prof. Penny Moore in research that commenced in 2005.
[6] GORMAN, J., CHUANG, G.-Y., LAI, Y.-T., SHEN, C.-H., BOYINGTON, J. C., DRUZ, A., GENG, H., LOUDER, M. K., MCKEE, K. & RAWI, R. 2020. Structure of Super-Potent Antibody CAP256-VRC26. 25 in Complex with HIV-1 Envelope Reveals a Combined Mode of Trimer-Apex Recognition. Cell Reports, 31, 107488, https://www.cell.com/cell-reports/pdf/S2211-1247(20)30366-1.pdf.
[7] SCARFF, C. A., FULLER, M. J., THOMPSON, R. F. & IADANZA, M. G. 2018. Variations on negative stain electron microscopy methods: tools for tackling challenging systems. JoVE (Journal of Visualized Experiments), e57199. https://www.jove.com/t/57199/variations-on-negative-stain-electron-microscopy-methods-tools-for.
[8] WIBMER, C. K., GORMAN, J., OZOROWSKI, G., BHIMAN, J. N., SHEWARD, D. J., ELLIOTT, D. H., ROUELLE, J., SMIRA, A., JOYCE, M. G., NDABAMBI, N., DRUZ, A., ASOKAN, M., BURTON, D. R., CONNORS, M., ABDOOL KARIM, S. S., MASCOLA, J. R., ROBINSON, J. E., WARD, A. B., WILLIAMSON, C., KWONG, P. D., MORRIS, L. & MOORE, P. L. 2017. Structure and Recognition of a Novel HIV-1 gp120-gp41 Interface Antibody that Caused MPER Exposure through Viral Escape. PLoS Pathog, 13, e1006074. https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1006074.
[9] https://www.unaids.org/en/AIDS_SDGs accessed November 2020.