Introduction Where are we with HIV today? What are the current therapies? What are the challenges? Prospects for future treatmentReferencesRead more
Human immunodeficiency virus (HIV), the viral agent that causes acquired immunodeficiency syndrome (AIDS), is a devastating and lethal disease that has caused widespread suffering worldwide for nearly half a century. We still don’t have a cure for this disease. Although those infected can expect to continue treatment throughout their lives, in recent times, there have been advances in therapeutics.
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Where are we with HIV today?
The human immunodeficiency virus (HIV) is the etiological agent that leads to acquired immunodeficiency syndrome (AIDS). Lifelong treatment is required, and there is currently no cure. The HIV virus cannot work alone, so it not only sets up a home with the host cell, but also takes advantage of it by exploiting its resources.
To accomplish this feat, the virus must hijack the host’s cellular machinery to avoid detection by the immune system. HIV integrates its genome into host chromosomal DNA. The provirus can then lie dormant within the host cell, where it persists throughout the life of the infected cell. This latent virus can operate silently inside the cell; its method of replication makes it completely undetectable to the human immune system.
HIV DNA is detected in CD4+ T cells in blood and lymphoid tissue in almost all cases of HIV infection. Individuals with natural resistance to HIV who maintain a viral load <50 copies/ml without any therapeutic intervention are known as “elite” controllers. Those that exhibit remarkable resistance are called "exceptional" drivers. Naturally, these individuals have been the focus of intense research for many years because of the clues they offer to find a cure. And hope for such a cure was presented by a case study involving an infected patient -- widely known as the 'Berlin patient' -- who underwent a bone marrow transplant courtesy of 'a donor who was naturally resistant to the virus.
What are the current therapies?
The introduction of daily combination antiretroviral therapy (cART) led to a significant decrease in AIDS-related morbidity and mortality. However, one mechanism for the persistence of HIV today is the proliferation of cells that were infected before the introduction of ART. In addition, CART therapy comes with a number of problems, including premature aging, drug fatigue, toxicity, and inflammatory effects. These side effects exacerbate the incidence of other diseases, such as cardiovascular disease and chronic obstructive pulmonary disease (COPD).
To block HIV-1 before it has a chance to integrate with host chromosomal DNA, scientists have targeted key proteins involved in the replication cycle: reverse transcriptase (RT), integrase (IN) and protease. These enzymes are crucial in the development of current antiretroviral drugs.
A recent advance in treatment that has shown promise has been the arrival of integrase inhibitors. The process by which the virus integrates its genome into the host chromosomal DNA is controlled by an enzyme called integrase. This protein is highly conserved in the Retroviridae family. This means that the targeting of the integrase leads to the prevention of replication.
Related: HIV-1 vs. HIV-2: What’s the Difference?
What are the challenges?
Knowledge gaps remain in the HIV campaign. The challenges of long-acting antiviral therapy involve resistance and understudied populations. The development of drug-resistant mutations has been a barrier to achieving a cure for HIV. Meanwhile, problems with adherence to cART regimens involve adverse drug reactions and limited access to therapy.
For patients on cART, medications that limit the side effects of therapy, as well as the frequency of dosing, may improve the adherence rate. Emerging approaches to long-acting antiviral therapies are expected to provide new and simpler options for HIV prevention and treatment, thus providing hope for many patients in the future.
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Prospects for future treatment
A complete cure for HIV would lead to both remission and eradication. The problems of resistant mutations represent an ongoing challenge for scientists in the fight against HIV and complicate treatment regimens that must be continuously updated.
Targeting integrase has been considered one of the most promising approaches to combat HIV infection. This protein is very unique. Inhibitors formulated to inhibit integrase are long-acting and have shown exceptional promise in their ability to block HIV integration and replication. Meanwhile, another technique that holds promise is the in vivo delivery of gene-editing tools to target the virus or enhance the immune system or protect cells from infection.
There are opportunities for collaborative effort and cross-fertilization of concepts from cancer research, for example, using studies conducted on immune resistance in the field. The same is true of research into the 2019 coronavirus disease (COVID-19), whereby greater knowledge of the mechanisms involved in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral infection could help better understanding of HIV.
A final consideration is that currently most research into a cure for the virus has been conducted in high-income countries. Here the incidence of infection rates is much lower and tends to be mainly problematic in the area of the male homosexual population. With this in mind, we must be aware that HIV strains are genetically and biologically diverse and vary by sex, ethnicity and geographic location.
References
- Cobb, D., et al. (2020) Long-acting approaches to antiretroviral drug delivery for HIV prevention and treatment: a review of recent research. Expert opinion on drug delivery. Doi: 10.1080/17425247.2020.1783233.
- Deeks, S., et al. (2021) Research Priorities for an HIV Cure: Global Science Strategy of the International AIDS Society. Nat Med. Doi: 10.1038/s41591-021-01590-5.
- Rana, A. et al. (2020) Advances in long-acting agents for the treatment of HIV infection. drugs Doi: 10.1007/s40265-020-01284-1.
- Trivedi, J., et al. (2020) Recent advances in the development of integrase inhibitors for the treatment of HIV. Curr HIV/AIDS. Doi: 10.1007/s11904-019-00480-3.