by Jennifer Ma

Graphic design by Anne Catalina McGrath

The human immunodeficiency virus (HIV) epidemic swept through the world in the 1980s and 1990s. By the time it reached its peak in 1995, the World Health Organization (WHO) estimated that at least 15 million people had been infected. Without medical management, HIV will target an individual’s white blood cells and accumulate in viral reservoirs, gradually weakening the immune system.¹ After approximately 7-8 years, this weakened state typically develops into acquired immunodeficiency syndrome (AIDS), leaving the individual susceptible to potentially fatal diseases, including pneumonia, tuberculosis or other opportunistic infections with a 50% mortality over two subsequent years.¹ This was this context that motivated Dr. Mario Ostrowski, who was training in internal medicine at the time, to pursue HIV research.

“Previously healthy people were suddenly developing multiple opportunistic infections at once,” he said. “It was quite devastating.” 

Following the completion of his research training with Dr. Anthony Fauci, he is now a Professor of Medicine, Immunology, and Laboratory Medicine and Pathobiology at the University of Toronto, and an infectious diseases consultant at St. Michael’s Hospital, where he studies the immunopathogenesis of HIV. Significant advancements in treatment, primarily due to anti-retroviral therapy (ART), can reduce the viral load to undetectable levels, meaning HIV rarely progresses to AIDS if managed properly. However, ART is not able to eradicate the virus entirely, meaning the accumulated viral reservoirs have the potential to activate and progress the disease resulting in an increased incidence of chronic conditions like cardiovascular disease; bone, liver, kidney disease and advanced aging. Dr. Ostrowski’s research is therefore focused on understanding how the immune system interacts with HIV, with the goal of developing a therapeutic vaccine or cure. Lifetime costs of daily antiretroviral treatment is over a million dollars per person living with HIV.

The COVID-19 pandemic is one such example, as individuals with HIV generally face more severe symptoms and a higher risk of mortality following infection due to immune suppression.² It was therefore unclear whether these individuals could mount a sufficient neutralizing response to the vaccines, even on ART. Additionally, people do not respond uniformly to ART, with the CD4⁺ T cell count of so-called non-responders remaining suppressed, indicating that the immune system has not completely recovered, despite the virus stopping its replication. A recent study from Dr. Ostrowski’s lab enrolled older HIV patients on treatment, most of whom received a mRNA COVID-19 vaccine. They observed “quite poor neutralizing antibody response[s] with the vaccine” following the standard two doses compared to controls. A third dose did improve the antibody response, suggesting a third dose may be necessary for HIV patients. As well, mRNA vaccines can be immune activating, which has the potential to reactivate HIV or increase viral reservoirs. However, Dr. Ostrowski’s team only found increases in these reservoirs among patients with low levels of virus circulating in blood while on treatment, with no detrimental clinical effect. The meaning of this finding is still unclear.

Additionally, Dr. Ostrowski has been working with Providence Therapeutics, a Canadian company specializing on mRNA vaccines, on the pre-clinical development of their mRNA vaccines. He is also interested in optimizing current COVID-19 mRNA vaccines by exploring a vaccine delivered mucosally or orally, as opposed to intramuscularly.

“[mRNA injected into muscle] mostly makes Immunoglobulin G (IgG),” he explained. “But Immunoglobulin A (IgA) is more potent for mucosally-transmitted viruses, so [delivering a vaccine] mucosally might offer better protection through IgA.” There is indeed great promise in mRNA vaccine technology, which can potentially be applied to develop novel therapeutic options for currently tough-to-treat diseases, such as HIV. 

One of the key reasons the effort to develop an HIV therapeutic vaccine or cure has been so difficult is the sheer diversity. Since HIV mutates so quickly, every patient’s specific virus has slight genetic differences, making them uniquely difficult to target in a vaccine. HIV is also able to “hide” from the immune system, as it contains a protein called Nef, which can both enhance viral replication and reduce the ability for the immune system to recognize and destroy infected cells. Dr. Ostrowski’s work is therefore aimed at understanding the immunological mechanisms of control to try to reproduce these effects in others by harnessing a patient’s own immune system.

One strategy is simply blocking the pathway that allows HIV to hide. Dr. Ostrowski is collaborating with medicinal chemists to develop new compounds that can block Nef, as downregulating its activity would help the immune system target infected cells, and therefore reduce HIV reservoirs. 

Another strategy is to assist a patient’s immune system and directing them to target HIV-infected cells. Dr. Ostrowski emphasized that current therapeutic vaccination efforts “[do not] seem to be that effective, so we’re thinking to use personalized ways.” He is collaborating with Moderna to apply mRNA vaccine technology to HIV. Their strategy borrows from the cancer vaccine field, as cancer is also able to “hide” from the immune system, preventing the tumour from being destroyed. Personalized cancer mRNA vaccines therefore aim to identify the cancer in an individual, and modify the proteins on cancer cells so their immune system recognizes it as foreign, destroying them.³ Similarly, Dr. Ostrowski’s strategy involves “studying patients’ immune response against the virus, characterizing their virus’ sequence, and identifying the parts of the virus where the immune response does not work [in order to] expand the cytotoxic killer T cell response.” Currently, he is studying virus samples from patients to see if they can first reproduce these findings in vitro. They are using these samples to redirect a patient’s own cells to target new epitopes, regions that can bind antibodies and elicit an immune response, from their own unique virus, as well as examining antigens that may be expressed on latently infected cells. 

“Can we make people like long-term non-progressors?” Dr. Ostrowski asked. “It is a test of concept since nobody knows how to get rid of the virus entirely.” Realistically, he imagines a multi-pronged approach using a combination of techniques, including a Nef inhibitor and mRNA therapeutic vaccine alongside ART, may prove most effective. The large stigma from the peak of the HIV/AIDS epidemic also still lingers, despite the major treatment advances that have been made, and serves as a source of motivation for Dr. Ostrowski to pursue research looking for a cure.

“The virus usually stops growing [following treatment],” he emphasized. “The CD4⁺ T cell count can be reconstituted back to normal, and [a patient] will likely not develop AIDS. The life expectancy is slowly approaching that of someone without HIV, but [because of the stigma,] most people would rather have a condition like diabetes, [where treatment involves] more burden on the patient, constant monitoring, and will not prevent all the complications.”

In borrowing techniques from both the COVID-19 and the cancer vaccine field, Dr. Ostrowski’s work highlights the multidisciplinary scope involved in the effort to develop an HIV therapeutic vaccine. Though major strides in HIV therapy have already been made, perhaps these are the strategies that will help cure it completely.  

References

1. Norris S, Nixon A, Murray W. AIDS: Medical and Scientific Aspects. Government of Canada Publications [Internet]. 2001 Dec 18 [cited 2023 Sep 9];95(5E). Available from: https://publications.gc.ca/Pilot/LoPBdP/CIR/935-e.htm
2. Matveev VA, Mihelic EZ, Benko E, et al. Immunogenicity of COVID-19 vaccines and their effect on the HIV reservoir in older people with HIV [Internet]. bioRxiv; 2023 [cited 2023 Sep 11]. p. 2023.06.14.544834. Available from: https://www.biorxiv.org/content/10.1101/2023.06.14.544834v1
3. Sample I. Vaccines to treat cancer possible by 2030, say BioNTech founders. The Guardian [Internet]. 2022 Oct 16 [cited 2023 Sep 8]; Available from: https://www.theguardian.com/society/2022/oct/16/vaccines-to-treat-cancer-possible-by-2030-say-biontech-founders