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  • Writer's pictureAarathi Manchikalapudi

The Conundrum of HIV Treatment

Updated: May 29

Many of us are aware of the HIV/AIDS (Human Immunodeficiency Virus/Acquired Immunodeficiency Syndrome) epidemic that tore through the world in the 1980s, but are unaware of the progress made in HIV research and subsequent benefits to human disease treatment that science has brought about.

 

At the time of its emergence, HIV was a complete mystery to the world, with little understanding of its transmission nor its means for impairing the health of infected individuals. Over the past four decades, however, our understanding has grown exponentially. HIV is a retrovirus, a type of virus that inserts its RNA into the genome of an infected individual, which severely deteriorates the immune system and results in AIDS. HIV is transmitted through the blood and bodily fluids, after which it can bind to CD4 cells, a type of T-lymphocyte or “helper” T-cell that is responsible for triggering immune responses. CD4 is a protein expressed on the outside of those cells.


Within a CD4 cell, the RNA genome of HIV is converted to DNA through a process called reverse transcription, and can then be integrated into the host cell genome. HIV uses an enzyme called reverse transcriptase to accomplish this. Once integrated into the genome, the transcript is replicated and leaves the cell through a process known as exocytosis to infect other cells. Cycling of this process eventually kills many helper T-cells.


More recent research also suggests that the presence of reverse transcripts and HIV proteins produced once integrated can cause inflammation within the cell, which prompts it to activate the "programmed cell death pathway," known in technical terms as caspase-1-mediated pyroptosis. The inflammation then perpetuates an immune response that results in more T-cells going to the site of inflammation, upon which byproducts of pyroptosis (death) of the original cell can then cause an inflammatory reaction in surrounding T-cells. This causes these cells to die, too, as a result of pyroptosis, illustrating why HIV infection manifests as the reduction of CD4 cells. Left untreated, the loss of these helper T-cells will lead to AIDS. The T-cells essentially kill themselves more through pryoptosis than HIV does through infection. Infected individuals become severely immunocompromised and extremely susceptible to a plethora of other diseases, making AIDS extremely fatal without intervention.


However, treatments such as antiretroviral therapy (in this case, medications called "protease inhibitors" that help stop the replication process) now exist to manage disease progression, and the mechanism of reverse transcription has become an increasingly promising field of research.

 

Moreover, inactivated versions of HIV have been able to be synthesized by means of chemicals like beta-propiolactone, binary ethylenimine, and formaldehyde in efforts of vaccine synthesis, but have also been found useful in other ways. Many forms of gene therapy, including gene modification through the famous CRISPR-Cas9 complex, have been effective in vitro, but lack a suitable vector for use in multicellular organisms. HIV’s unique capacity to penetrate our mucous and cellular membranes along with its ability to reverse transcribe and integrate makes it the optimal vector for gene therapy. More specifically, it seems to be ideal for transgene delivery in stem cells, due to its ability to infect non-dividing cells. This might seem far-fetched, but there are several instances in which these beneficial traits of HIV have led to successful treatment. .

 

In a related example of advancements derived from HIV research, retro-vector immunotherapy has been developed to treat certain types of leukemia, such as chronic lymphocytic leukemia, in which the T-cells of patients are transduced by an HIV vector that integrates a chimeric antigen receptor (CAR) that specifies for leukemic B-cell antigens, into the patient's own T-leukocytes. In essence, the patient’s own T-cells are modified with a transgene that causes them to attack their own leukemic B-cells. There was longitudinal presence of these CAR-positive T-cells in this study, indicating regular replication cycles of the cells post-modification, allowing for long term targeting of leukemic B-cells.

 

Due to the mechanism by which HIV acts, it has thus far been most useful in treating diseases of the blood, but research continues to search for new ways to manipulate HIV and other retroviruses so that they might serve as vectors in gene therapy treatment. Like any treatment, there exists the potential for harmful side effects. Since retroviral vectors like HIV modify the host genome, they have the capacity to activate protooncogenes (those genes which could predispose someone to cancer). However, thus far that problem has not arisen in T-lymphocytes, and “self-inactivating” forms of these vectors have even been created in order to avoid such oncogenic events, serving as an extra layer of protection from potential issues.

 

So here is the conundrum: can the human immunodeficiency virus, once a complete mystery, and an incurable threat to human health, now be enlisted as an aid to combat other illnesses which plague that same society? The answer, hopefully with further research, will prove to be a resounding, “yes!”


Aarathi Manchikalapudi is a 1st Year student at the University of Virginia. She hopes to major in biochemistry and is currently involved in tissue engineering research.

 

Sources:

 

Berkhout, B. (2013). HIV, leukemia, and New Horizons in Molecular Therapy. Journal of the Formosan Medical Association, 112(8), 441–444. https://doi.org/10.1016/j.jfma.2013.01.009


Gonçalves, J., Moreira, E., Sequeira, I. J., Rodrigues, A. S., Rueff, J., & Brás, A. (2016). Integration of HIV in the human genome: Which sites are preferential? A genetic and statistical assessment. International Journal of Genomics, 2016, 1–6. https://doi.org/10.1155/2016/2168590


Khan Academy. (n.d.). How HIV infects US: CD4 (T-helper) lymphocyte infection (video).



Kurian, K. M. (2000). Retroviral vectors. Molecular Pathology, 53(4), 173–176. https://doi.org/10.1136/mp.53.4.173


MM;, P. K. (n.d.). Use of HIV as a gene transfer vector. Acta biochimica Polonica. https://pubmed.ncbi.nlm.nih.gov/19936329/


Rios, A., Poteet, E. C., Siwak, E. B., Anderson, D. W., & Yao, Q. C. (2015). HIV inactivation. AIDS, 29(1), 129–131. https://doi.org/10.1097/qad.0000000000000522


Yale Medicine. (2022, September 24). Human immunodeficiency virus (HIV). Yale Medicine. https://www.yalemedicine.org/conditions/human-immunodeficiency-virus-hiv

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