In this blog post, we’ll explore how AIDS treatments are developed and their limitations, based on the mechanism of HIV.
This year marks exactly 21 years since AZT (azidothymidine), the first treatment for AIDS (Acquired Immunodeficiency Syndrome), was developed. Since then, more than 20 treatments have emerged, shifting the perception of AIDS from a fatal, incurable disease to a chronic infectious disease where, while a cure remains impossible, symptoms can be kept at bay for long periods or their onset delayed—much like diabetes. However, even with the development of these treatments, approximately 36.7 million people worldwide are still suffering from AIDS, and in certain African countries, more than 20% of the population is infected, making AIDS a serious social problem. How are these AIDS treatments, which address such a vast problem, developed? The answer lies in the mechanism of action of HIV, the virus that causes AIDS.
HIV is primarily transmitted through contaminated needles, blood transfusions from infected donors, and sexual contact with an infected person. Once HIV enters the human body, it first infects helper T cells (cells that activate and direct other immune cells) and macrophages (cells that ingest antigens or recognize and present them to induce an immune response). Upon infection, the viral envelope fuses with the target cell’s membrane, releasing HIV’s RNA into the cytoplasm.
Since HIV contains only RNA as its genetic material, it uses its own reverse transcriptase to synthesize DNA using the RNA as a template. This reverse transcription process is the opposite of normal transcription (i.e., the process of synthesizing RNA using DNA as a template). The HIV-derived DNA produced by reverse transcription moves into the nucleus and is then inserted into the target cell’s DNA using an enzyme called integrase. Subsequently, as the target cell’s transcriptional activity proceeds, the HIV genes are transcribed along with it. The proteins required by HIV are synthesized from the transcribed mRNA, processed, and then new viral particles are produced. Once the number of viral particles reaches a certain level, the target cell’s plasma membrane is damaged, the cell is destroyed, and the infection spreads to other cells.
Various types of antiretroviral drugs have been developed to target this HIV replication process. First, there is T-20 (Enfuvirtide), a drug that inhibits the fusion of the cell membrane and the viral envelope during the early stages of HIV entry into the cell. Enfuvirtide interferes with the process by which the surface glycoproteins gp120 and gp41 bind to proteins on the target cell when HIV invades it. This drug can be effective even in cases of resistance to existing medications, but it is very expensive (over $25,000 per year) and can cause skin reactions such as eosinophilia or, rarely, pneumonia.
Second, nucleoside reverse transcriptase inhibitors (NRTIs) are a class of drugs that are incorporated into the reverse transcription process in place of normal nucleotides, thereby halting reverse transcription. Drugs in this class include AZT; once inside the cell, they are activated into the 5′-triphosphate form, which interferes with the action of the HIV reverse transcriptase, preventing the reverse transcription process from proceeding. While these drugs have demonstrated clear benefits such as viral suppression and increased lymphocyte counts, they can cause side effects such as bone marrow toxicity and anemia. Furthermore, since resistance to the drug develops when used alone for more than one year, it is essential to administer them in combination with other drugs.
Third, non-nucleoside reverse transcriptase inhibitors (NNRTIs) are drugs that bind directly to the reverse transcriptase enzyme and inhibit its activity by altering the enzyme’s three-dimensional structure. Efavirenz and rilpivirine belong to this class; while they exhibit relatively low toxicity, resistance can develop within 6 to 12 weeks of use, necessitating combination with other drugs. Side effects such as skin rashes have also been reported.
Recently, combination therapy—the simultaneous use of drugs with different mechanisms of action—has become the standard of care. Typically, a three-drug regimen is used, consisting of two drugs from the NRTI class combined with one drug from a different class, such as an NNRTI or a protease inhibitor. Using drugs that target different mechanisms simultaneously prevents the development of drug-specific resistance, which would reduce treatment efficacy, and allows for more effective overall suppression of HIV replication.
Nevertheless, the reason AIDS remains incurable lies in the HIV reverse transcription process. During reverse transcription, there is no mechanism to correct erroneous insertions, as there is during DNA replication, resulting in a very high error rate. For example, in the process of synthesizing DNA using an RNA template, there is a high probability that bases such as cytosine (C) and uracil (U) will be confused and inserted incorrectly; furthermore, correction mechanisms available in DNA replication, such as template marks or methylation, do not apply to reverse transcription. Consequently, reverse transcription rapidly generates various mutations, allowing variants resistant to specific drugs to emerge almost instantly. For this reason, it is difficult to achieve complete control with just one or two drugs, and the development of curative treatments is being delayed.
Consequently, a wide variety of AIDS treatments have been developed, and these are used in combination to alleviate symptoms and delay the progression of the disease. Although research to increase the likelihood of a cure is actively underway, the high mutation rate resulting from the reverse transcription process remains a major obstacle. Nevertheless, given that various treatments have already emerged and therapeutic efficacy has greatly improved, there remains hope that more effective cures will be developed in the future.
