Unveiling the Progress and Challenges in the Fight Against HIV
HIV is an ongoing public health issue, but progress may be pushing us toward a potential cure and more effective treatments.
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It is estimated by the World Health Organization (WHO) that by the end of 2022, 39 million people were living with human immunodeficiency virus (HIV), and in that year alone, 630,000 people had died from HIV-related causes and 1.3 million people had acquired the disease.
With the assistance of 11 UN cosponsors, UNAIDS is hoping to end the HIV and AIDS epidemic by 2030.
This article will explore the difficulties faced in attempting to treat HIV, an innovative prevention strategy and the possibility of a cure.
Challenges in HIV management
HIV is a retrovirus and can integrate its genetic material into host genomes, making it difficult to treat, and currently lacking a cure. If left untreated, HIV can lead to acquired immunodeficiency syndrome (AIDS).
What is AIDS?
AIDS is a disease that occurs when the immune system is damaged by HIV. When treated, HIV is prevented from progressing, so many people with HIV do not develop AIDS.
A person with HIV is considered to have AIDS either when the number of CD4 (a type of white blood cell) cells drops below 200 cells per cubic millimeter (A healthy person has anywhere from 500 to 1,600 cells per cubic millimeter) or if they develop one or more opportunistic infections.
Without treatment, people with AIDS typically survive around 3 years.
Even though treatment can help to effectively manage the condition, some immune cells go into a dormant state but still contain viral DNA and can reemerge once treatment ceases.
“HIV can establish latent reservoirs within our body. What this means is that they can hide within cells in our body and lay dormant for a long period of time (e.g., months or years). Once they become active, they can immediately replicate and infect other immune cells,” said Dr. Emmanuel Ho, a professor at the University of Waterloo. “HIV is able to alter its genetic makeup to avoid our immune system or develop resistance against anti-HIV drugs. HIV can also infect and kill immune cells in our body. As a result, these immune cells will no longer be able to participate in the fight against HIV.”
Combined antiretroviral therapy (cART) is currently the only treatment for HIV. cART uses a mix of different antiviral drugs to stop HIV replicating.
“cART targets the virus at several key stages of its infection and replication cycle. By doing so, cART reduces the amount of virus in the body to undetectable levels, thereby protecting and preserving these cells and the host's immune system,” said Dr. Jamie Mann, senior lecturer in vaccinology and immunotherapy at the University of Bristol. “When HIV infects T cells, on rare occasions, rather than the virus replicating and killing the host cell, the virus becomes dormant. In this dormant state, the virus is not susceptible to cART and can exist for a very long time.”
Although cART is the main treatment for those living with HIV, this therapy cannot eradicate the latent reservoirs developed by the virus, so the treatment must be ongoing to be effective. While necessary, long-term use of cART is associated with toxicity and drug resistance.
There is also a global disparity in access to treatments:
- Approximately 10 million people living with HIV still do not have access to antiretroviral therapy. According to the 2023 UNAIDS report, only 43% of children living with HIV have access to life-saving medicine.
- Over 25 million people living with HIV at the end of 2022 were in Africa. Gender inequalities continue to make an impact on the HIV/AIDS response, particularly in sub-Saharan Africa. In 2022, women in the region accounted for 63% of new infections. Worldwide, this figure was 46%.
- Adolescent girls and young women in sub-Saharan Africa are at a higher risk of infection than other groups, in part due to violence, stigma, discrimination and harmful laws and practices. Other factors impacting the odds of infection include unstable housing, lower levels of education, poverty and food insecurity.
- Across the globe, HIV prevalence was 14 times higher among transgender people, 11 times higher among men who have sex with men, 7 times higher among people who inject drugs and 4 times higher among sex workers in 2022 when compared with adults in the general population.
“Stigma, discrimination, healthcare access and treatment adherence issues will all contribute to different populations facing distinct challenges when attempting to cure HIV,” said Mann.
Protecting against sexual transmission of HIV
Dr. Emmanuel Ho leads a research group focused on developing and characterizing innovative drug delivery strategies, including nanomedicines, medical devices and biomaterials, for the treatment and prevention of HIV/AIDS, among other diseases. Ho recently developed a novel nanomedicine loaded with genetic material called small interfering RNAs (siRNAs) to fight HIV.
siRNAs are non-coding double-stranded RNA molecules, typically used to silence a gene of interest. These RNA interference tools are useful in the study of gene function and can even be utilized for the treatment of diseases such as cancer.
“siRNAs will play an important role in the development of novel HIV therapeutics. If we can identify a ‘target’ (e.g., gene) in our body that promotes or enhances HIV infection, as long as we know the genetic sequence of the target, we can easily design siRNAs to bind and knockdown the expression of that target,” said Ho.
The nanomedicine is intended to reduce the expression of CCR5 – a gene that encodes a protein expressed by T cells and macrophages, known to be an important co-receptor for HIV to enter host cells - to prevent HIV from attaching to and entering host cells. “This gene plays a role in the HIV infection process. By reducing the expression of CCR5, we hope to reduce HIV infection,” explained Ho.
By releasing a second siRNA to reduce the expression of Nef, a protein produced by HIV to inhibit autophagy, the nanomedicine can reactivate autophagy to eliminate the HIV still present in the cells. As Ho explained, “If, unfortunately, HIV is still able to infect immune cells within the body, we hope that our nanoparticles can reactivate autophagy.”
When administered directly into the vagina, naked siRNAs have difficulties in achieving efficient mucosal uptake due to their rapid degradation. To get around these issues, Ho’s team encapsulated the siRNA in PEG-PLGA polymer nanoparticles.
The nanomedicine was developed to be delivered intravaginally to protect against sexual transmission of HIV. However, intravaginal delivery can come with challenges. “In order to deliver nanoparticles to the submucosal layer where immune cells are located, it will first have to move across a layer of cervicovaginal mucus, which can trap the nanoparticles. Afterwards, it will have to penetrate across an epithelial layer. Finally, it is important to have the nanoparticles enter the appropriate cells,” explained Ho.
The team plans to optimize the nanoparticle system to attempt to achieve 100% protection against infection.
Looking ahead: Is a cure on the horizon?
While infection with HIV is treatable, there is no cure available. Dr. Jamie Mann is interested in addressing this issue with the development of novel therapeutic and prophylactic vaccines against HIV.
“The global distribution of HIV subtypes varies, with certain subtypes being more prevalent in specific regions. This variation presents unique challenges for an HIV cure, as transmission, disease progression and responses to treatments differ. Ultimately, the cost and complexity of the treatment must be such that it is easily accessible for all who require it,” said Mann.
Mann recently co-led an international study to demonstrate the ability of a new therapeutic to cure HIV. The therapeutic, an HIV-virus-like particle (HLP), can reactivate the virus when dormant, rendering it susceptible to cART and the immune system.
Using blood samples from 32 participants living with chronic HIV, who were on stable cART for a median of 13 years, the team found that HLP was able to specifically target just the immune cells containing latent HIV reservoir and purge these cells of their HIV. “Our data shows that divergent strains of HIV are also susceptible to the same HLP treatment, suggesting that the HLP could have global applications as a therapy,” said Mann.
HLP are engineered to resemble HIV and lack a viral genome, making them incapable of causing an infection or replicating. These particles can be administered by intramuscular injection. The study shows that the HLP reverses latency irrespective of the subtype of the individual’s infection.
Mann and the team plan on transitioning this work from the lab to clinical trials. “These trials will allow us to rigorously evaluate the effectiveness of our strategy in a controlled setting and hopefully bring us another step closer to making a cure a reality.”
Research is driving the development of new treatments and could introduce a cure for HIV, but ending this epidemic will be a global effort, requiring improved access to preventatives, therapeutics and education for at-risk groups.
