As the medical community and those it serves welcomed in a new year, it brought with it the hope of scientific advancements that will alter the course of certain disease states. These advancements include the use of stem cells to treat to treat macular degeneration, novel microscopic techniques to capture images of the brain, the continued observed effectiveness of the experimental Ebola vaccine, and countless other interventions aimed at creating a healthier global society. Included in these optimisms for 2019 is the possibility for novel treatment options and a possible cure for one of the world’s leading causes of death, HIV. The stories of Timothy Brown – the only individual ever to be cured of HIV, the Mississippi baby and Clark Hawley – both having an extended period of time with undetectable HIV viral load with an interruption of Antiretroviral Therapy (ART), and the Boston patients/Mayo Clinic patient – all three having undetectable HIV viral loads for an extended period of time after a stem cell transplant, have brought much sanguinity to health care professionals and patients alike. However, these exciting results have been unable to be replicated in the majority of the population suffering from HIV and remain unique in their respective occurrences. Although ART has been vital to the HIV community in terms of longevity and quality life, there are still certain populations that are seeking other mechanisms to treat this infectious disease – and, of course, always coveting the idea of a cure. The following is a brief glimpse at the vast pipeline that awaits 2019 and the anticipations of the global healthcare community.
- The AIDS Clinical Trial Group (ACTG) is currently exploring the option of combining vorinostat, a HDAC inhibitor along with tamoxifen, which is an FDA approved medication the treatment of breast cancer for postmenopausal women. Utilizing this approach is thought to prevent the reactivation of HIV in CD4+ cells that are latent in addition to increasing the latency-reversal effect of vorinostat through tamoxifen.
- Researchers from the USA, France, Germany, Italy, Spain, Switzerland, and the UK are collaborating for a trial testing the combination of two HIV vaccine candidates alongside a monoclonal antibody called vedolizumab. This method of treatment is thought to target a certain protein in the body, α4β7 integrin, that plays a role in transmission of HIV into CD4+ cells. In a macaque model, this combination has shown the control of SIV (HIV but in simians) after discontinuing ART.
- At the University of Minnesota, researchers are testing infusions of natural killer (NK) cells with the administration of cytokine interleukin-2 (IL-2). The researchers are hoping to add to the evidence of NK cells being able to exhaust HIV reservoirs and to control virus replication.
- In a version of the “kick & kill” method of curing HIV, researchers in Oxford and Barcelona are using a medication to active the latent HIV reservoir while boosting the immune response 1000 times stronger than the usual to rid the body of the virus. Preliminary results showed that 5/15 patients had undetectable viral loads for seven months without ART.
- Immunocore, a company founded in Oxford with heavy investment by Bill Gates, has designed T cell receptors that seek out and bind with the HIV virus. These receptors then instruct immune T cells to eliminate any HIV-infected cells, even when the levels happen to be extremely low. Since levels can be rather low in the reservoir of HIV virus that exists in an infected individual, this is a promising lead to completely remove this retrovirus from the body. This immunotherapy has shown to be effective in human tissue samples, but no results being tested in humans have been released.
- In France, a company known as InnaVirVax has established a vaccine, VAC-3S, that allows the body to stimulate a production of antibodies against the HIV protein 3S. This, in turn, causes T cells to attack the virus. This is considered a novel approach because it encourages the immune system to recover while equipping it with the tools to continue fighting off the virus. VAC-3S has completed Phase 2a trials, and is partnered with a DNA-based vaccine from FIT Biotech, a Finnish company, that both parties believe can lead to a functional cure.
- In a recently initiated trial, IMPAACT 2008, held in the USA, Botswana, Brazil, and Zimbabwe, a broadly neutralizing antibody termed VRC01 is being investigated for its effectiveness in infants with HIV who are also started on ART within 12 weeks of birth. Although the study aims at establishing the safety profile for VRC01, it is also observing the difference in the HIV reservoir compared with only ART.
Novel Antiretroviral Agents
- The manufacturer, ABIVAX, believes it has developed a compound that may help the immune system recognize cells infected with HIV by allowing an increased presentation of HIV antigens on the cell’s service. This would lead to an augmented immune response to abolish these infected cells. This compound has been labelled ABX464 and targets the HIV protein Rev, which is responsible for the transcription of HIV RNA. Reductions of measured HIV DNA have been reported from 25% to 50% in eight of the fifteen patients participating in the study; however, no delay in viral load rebound was found when compared with placebo.
- Gilead has created a novel mechanism of targeting the HIV virus through the capsid inhibitors class. Capsids are involved in protecting HIV RNA and related proteins, and capsids also breaks down to release the viral contents into CD4 cells which enable reverse transcription to take place. The novel agent by Gilead, GS-CA1, blocks both the assembly and disassembly of capsids that create non-infectious and defective viruses.
- Chimeric antigen receptor (CAR) T therapy has been re-initiated in the first cure related clinical trial of this approach in people living with HIV who are on ART. CAR T cell therapy involves the modification of an individual’s T cells that can target antigens of interest. The specific cells modified by the initiative in China, called VC-CAR-T cells, have been modified to target HIV gp120. These modified cells were able to induce the destruction of HIV-infected cells, including latently infected cells exposed to latency-reversing agents, in the laboratory setting.
- With the knowledge of knowing that about 1% of the world’s population is immune to HIV due to a genetic mutation on the gene that encodes for CCR5, US-based Sangamo has begun to edit DNA to introduce the aforementioned mutation. The CCR5 protein is attached to the surface of CD4 cells that allows HIV to enter and infect the cell; with the mutation, it would be impossible for HIV to enter cells. This company extracts patient’s CD4 cells in order to use zinc finger nucleases to edit patient’s DNA to make them resistant to HIV.
- Although a highly controversial topic amid the recent publication of the use of CRISPER in twin daughters in China, scientists believe that this tool can lead to a cure for HIV as it is believed to be a much easier, faster, and effective approach than other gene-editing methods. However, the majority of the global health community is in agreement that years of laboratory research and ethical standards need to be established before human trials are properly started.
With the HIV virus adapting and mutating to evade treatments almost as rapidly as the world is producing novel approaches to treating this infectious disease, the drive for continued research and testing should be relentless. These aforementioned examples of novel treatments and possible cures display the creative and diverse thought processes the medical community has put forth to tackle one of the most stigmatized diseases on this earth. However, the ethics behind these trials need to be sound and forthcoming for all of humanity. The trials that occur need to ensure an assortment of demographics including individuals from both developed and developing nations – a subtle form of medical colonialism has no place in the global health community. In addition, trials that enroll patients who willingly accept the benefits and risks associated with the experimental therapy have the moral obligation to supply lifetime treatment if it happens to be effective. The researchers and medical professionals who monitor these participants need to take extreme caution in ART interruptions/discontinuations and certify that the patients realize what complications could transpire due to them. Finally, and most importantly, the interventions that show promise of novel ways to approach HIV or even a cure have to be accessible, affordable, and available to all humans who suffer from HIV. The health inequalities that plague this fragile planet have already been clearly highlighted in this ailment throughout history; the global health community is in debt to humanity for a cure for all when discovered.
With the global health community’s commitment, the future of the HIV virus continues to transition from infectious disease to chronic disease. While the step that will advance the chronic disease to a cure is still thought to be unknown, the excitement behind the aforementioned gene editing therapy is substantial. The ability to safely, effectively and ethically modify human cells to prevent the entry of the virus into the immune system is certainly the most promising option recently and possibly from this disease’s initial appearance; although, health care professionals haven’t quite figured out how to combine these aspects yet. A cure or even functional cure may be years away, but the global health community needs to continue to accompany those inflicted by this chronic infectious disease to meet the hopes and expectations of alleviating the burdens of HIV.