An Introduction to HIV and AIDS: Understanding Risks and Prevention
Acquired immunodeficiency syndrome (AIDS) is a significant global health concern caused by human immunodeficiency virus type 1 (HIV-1) infection (Figure 1). The virus was initially identified in the early 1980s by the USA's Center for Disease Control and Prevention (CDC, 1982). HIV-1, a retrovirus, harbours genes encoding various viral and antisense proteins (Liu et al., 2019).
Besides the more widely recognised HIV-1, there is another variant of the virus known as HIV-2. While HIV-1 is prevalent globally and responsible for most HIV infections, HIV-2 has a more limited distribution and is primarily found in some areas of West Africa. Although both types belong to the same family of retroviruses and share similarities in their mechanisms of infection, there are notable distinctions between them (Visseaux et al., 2019).
HIV-2, like HIV-1, attacks the immune system, leading to immunodeficiency and the potential development of AIDS. However, studies suggest that individuals infected with HIV-2 tend to experience a slower progression from initial infection to the onset of AIDS. This delayed progression is thought to be, in part, due to differences in the genetic makeup of HIV-2 and its interactions with the immune system (Guyader et al., 1987). HIV-2 is defined by a low transmission rate, which explains why it is less prevalent on a global scale. Nonetheless, HIV-2 has shown resistance to some antiretroviral drugs that are effective against HIV-1. This resistance can complicate treatment regimens for individuals infected with HIV-2. It is important to note that diagnostic tests for HIV-2 differ from those for HIV-1, requiring specific testing to accurately distinguish between the two types (Visseaux et al., 2019).
The focus of this article centres on HIV-1, the more widespread variant; however, the existence and unique characteristics of HIV-2 should be acknowledged. While HIV-1 remains the predominant concern in the global fight against HIV/AIDS, understanding the distinctions between these two variants underscores the complexity of the virus and the continuous actions to combat its impact.
What you Need to Know about HIV/AIDS
The conjoined phrase 'HIV/AIDS' is widely used to capture the interrelation between HIV and AIDS. It emphasises the connection between the virus that weakens the immune system and the advanced stage of the disease characterised by severe immune deficiency and susceptibility to infections. Utilising 'HIV/AIDS' underscores the broader impact of the condition on various aspects of health and society and highlights the need for both prevention and treatment efforts.
Viral Structure and Mechanism of Action
The HIV-1 particle is composed of various components. It has a covering made from the outer layer of the cell it attacks, and this covering has special spikes known as viral envelope glycoprotein spikes. Beneath this covering and attached to it, there is a round protein shell called the matrix protein. This matrix protein offers structural reinforcement to the virus and arranges the elements within the virus particle. In the middle, there is a densely packed, cone-shaped part formed by a protein called the capsid protein. This essential core houses two identical copies of the viral RNA and necessary proteins for viral replication, including reverse transcriptase, integrase, and protease (Adamson & Freed, 2007). HIV-1 exhibits an affinity for cells that possess the CD4 receptor on their outer surfaces (Rojas-Celis et al., 2019). As a result, it can target and infect a range of cell types, namely T lymphocytes (García et al., 2020), monocytes/macrophages (Veenhuis et al., 2021), dendritic cells (Han et al., 2022), and microglia (Bai et al., 2023).
The HIV-1 pathogen engages host cells by establishing interaction between its envelope glycoprotein and the CD4 receptor localised on the extracellular surface of the host cell membrane. That way, it interacts with co-receptors such as CCR5 or CXCR4. These interplays allow the virus to enter the cell. Once inside, the viral RNA changes into double-stranded DNA through reverse transcription, allowing the DNA to integrate into the host cell chromosome, creating a provirus. This provirus serves as a blueprint for the transcription of viral RNAs, encoding a spectrum of proteins ranging from structural entities to enzymes and regulatory factors (Sadowski & Hashemi, 2019). Once integrated, the provirus chooses one option out of three, depending on the nature of the host cell: latency, controlled replication, or aggressive proliferation leading to host cell damage, which enables the virus to avoid both the immune system and antiviral treatments (Rojas-Celis et al., 2019).
The virus's preference for primary CD4+ T cells compromises the immune system, rendering individuals vulnerable to diverse infections and certain types of cancers. Moreover, HIV-1 can also infect cells in the central nervous system, leading to neurological complications (Zhang et al., 2022).
Treatment
Pharmacology has significantly transformed the landscape of HIV management, playing a pivotal role in controlling the virus and improving the quality of life for individuals living with HIV/AIDS. While not the sole approach, pharmacology is one of the most widely adopted strategies in combating HIV/AIDS due to its proven efficacy in suppressing viral replication and delaying disease progression.
Combined Antiretroviral Therapy
The treatment of HIV-1/AIDS heavily relies on pharmacology, which involves using medications to target different stages of the virus's life cycle. In the mid-1990s, a significant shift occurred in the battle against AIDS. Breakthroughs emerged through the development of inhibitors targeting crucial enzymes of HIV-1 replication—specifically, the viral reverse transcriptase and protease. The joint administration of these inhibitors gave rise to the cornerstone approach in the battle against AIDS - combined antiretroviral therapy (cART). The development of this strategy marked a pivotal moment, substantially prolonging the lives of people living with HIV (PLWH) (Egger et al., 2002). As mortality rapidly fell, what was once an abhorrent death sentence was transformed into a manageable chronic condition (Rojas-Celis et al., 2019).
Current guidelines recommend the commencement of cART for all HIV-positive individuals, regardless of previous health conditions, symptoms, viral load, or CD4+ cell count (Saag et al., 2018). Primary cART regimens today comprise a trio of antiretroviral drugs, often conveniently combined into a single pill for once-daily oral administration (Gulick & Flexner, 2018). This approach has proven highly effective, achieving virological suppression in over 80% of HIV-infected patients in both controlled clinical trials and real-world clinical settings, bringing their life expectancy to levels comparable to their healthy counterparts (Samji et al., 2013). However, it is important to acknowledge that instances of resistance to all available antiretroviral medications have been documented (Wainberg et al., 2011).
Classes of ART Drugs
Antiretroviral drugs used to treat HIV/AIDS fall into seven distinct classes, each with a unique mechanism of action targeting various stages of the virus's life cycle. Nucleoside Reverse Transcriptase Inhibitors (NRTIs) hinder viral replication by incorporating themselves into the viral DNA chain, leading to premature termination. Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) bind to the reverse transcriptase enzyme, disrupting its function and preventing the synthesis of viral DNA. Protease Inhibitors (PIs) obstruct the protease enzyme, which is essential for maturing infectious viral particles. Fusion Inhibitors stop the virus from merging with host cells by targeting the viral proteins that facilitate this attachment. CCR5 Antagonists hinder viral entry by blocking the CCR5 co-receptor used by the virus to infect specific cells. Post-Attachment Inhibitors work after viral attachment, preventing further infection steps. Integrase Strand Transfer Inhibitors (INSTIs) disrupt the integrase enzyme's action, preventing viral DNA from integrating into the host cell's DNA. Combined, this range of drug classes effectively suppresses viral replication, reduces the viral load, and enhances the quality of life for PLWH (Blevins et al., 2020; Li et al., 2022; Mohamed et al., 2022; Scarsi et al., 2020).
Adhering to antiretroviral therapy schedules holds immense significance in achieving favourable outcomes for PLWH. Consistently following prescribed medication routines is pivotal for attaining and sustaining viral suppression—an objective that involves reducing HIV levels in the body to undetectable levels. Effective viral suppression improves the overall health and well-being of HIV-positive individuals and substantially diminishes the likelihood of transmitting the virus to others. Equally vital is the role of strict adherence in thwarting the development of drug resistance, a phenomenon wherein the virus mutates to counteract the effects of medication. Inadequate compliance leaves room for viral replication, enabling drug-resistant strains to emerge, potentially jeopardising the effectiveness of current and future treatment options. Hence the importance of self-discipline and a high sense of responsibility (Cao et al., 2020; Ware et al., 2020).
Challenges
Although cART effectively decreases the viral load and lessens the occurrence of opportunistic infections, it does not eliminate the virus within latent reservoirs (Guo & Buch, 2019), which refer to infected cells in which the virus remains hidden or dormant within the body. These reservoirs are primarily found in CD4+ T cells and macrophages (García et al., 2020). The virus within these reservoirs is not replicating, and the immune system or antiretroviral drugs do not target it. This hidden virus can awaken and start replicating if the person stops taking their medication or if conditions change within the body. For that reason, the complete eradication of the virus is extremely challenging, as these latent reservoirs can lead to viral rebound and disease progression if not effectively managed (Chen et al., 2022). Targeting latent copies of HIV involves various strategies to eliminate or control the virus within hidden reservoirs. "Shock and kill" is a common approach, where latency-reversing agents awaken the dormant virus, making it vulnerable to immune and drug attacks (Sadowski & Hashemi, 2019). On the contrary, the "block and lock" method focuses on maintaining the virus in the dormant state to prevent reactivation (Vansant et al., 2020). New technologies like gene editing using CRISPR/Cas9 are explored to directly modify viral DNA in reservoir cells (Atkins et al., 2021).
The increased lifespan of PLWH has brought to light a growing prevalence of neurocognitive dysfunction linked to HIV-1 infection. The introduction of cART, alongside the life-expectancy increase, revealed indications of declining brain function, motor skills, and changes in behaviour and mood—hallmarks of HIV-associated neurocognitive disorder (HAND). HAND is categorised into three severity levels: asymptomatic neurocognitive impairment, mild neurocognitive disorder, and HIV-associated dementia (Antinori et al., 2007). The impact of HIV-1 on the central nervous system (CNS) varies across infection stages. In the early stage, viral infection or immune-mediated processes contribute to neurological issues. In the intermediate stage, complications arise from immune system actions and metabolic effects of antiretroviral drugs. In the late stage, neurological problems emerge due to a combination of prior factors along with opportunistic infections or tumours (Rojas-Celis et al., 2019). The entry of HIV-1 into the CNS typically occurs during the initial weeks of infection (Valcour et al., 2012).
Adverse Effects
Whilst cART has undoubtedly revolutionised the treatment of HIV/AIDS, like any medical intervention, it is not without potential risks and side effects. A range of adverse effects can arise from using antiretroviral drugs in the form of short-term nuisances or long-term health consequences (Figure 7.). Common side effects include gastrointestinal discomfort, manifesting as nausea, vomiting, and diarrhoea, which can disrupt daily life and compromise commitment to the treatment regimen (Basile et al., 2021). Persistent fatigue and headaches are also reported, further affecting individuals' overall quality of life on cART (Dai et al., 2020). Additionally, metabolic changes represent a notable concern, with some antiretroviral drugs contributing to lipodystrophy —a condition characterised by abnormal fat distribution— as well as elevated cholesterol levels and insulin resistance, heightening the risk of cardiovascular diseases and metabolic disorders (Tshamala et al., 2019). Certain antiretroviral drugs can cause decreased bone density and potentially escalate the likelihood of fractures and osteoporosis (Biver, 2022). Kidney and liver function may be compromised by specific medications, necessitating consistent monitoring of these vital organs (Fortuny et al., 2015). The occurrence of immune reconstitution inflammatory syndrome poses another challenge, where the improved immune response upon cART initiation can paradoxically lead to exacerbated inflammation and deterioration of pre-existing conditions (Thapa & Shrestha, 2023). The first generation of ART drugs significantly impacted metabolism. Newer drugs show milder effects, likely due to lower HIV severity or varied toxicities. The INSTI class is considered metabolic-friendly, although recent concerns have emerged about its effects on adiposity and glucose metabolism (Lagathu et al., 2019). As aforementioned, the development of drug-resistant strains of HIV remains a significant concern, primarily driven by inconsistent adherence to medication regimens.
Moreover, a subset of antiretroviral drugs may induce abnormal lipid profiles, heightening the risk of cardiovascular complications (Fortuny et al., 2015). In rare instances, the accumulation of lactic acid in the blood, known as lactic acidosis, can arise as a severe consequence of specific medications, presenting symptoms like abdominal pain and nausea (Smith et al., 2019). While cART's benefits in viral suppression and immune enhancement are undisputably significant, the comprehensive understanding and management of potential side effects are vital for providing holistic care to individuals undergoing treatment.
Pre-exposure Prophylaxis
While strides have been made in HIV care and treatment, addressing the challenge of preventing new HIV infections persists, as both a vaccine and a definitive cure for HIV remain elusive. One particularly productive strategy in preventing HIV transmission is pre-exposure prophylaxis (PrEP) (Figure 8.). Over a decade has passed since the initial evidence showcased the efficacy of daily oral HIV PrEP. This regimen is nearly 100% effective in individuals who adhere to it (Rutstein et al., 2020). This method involves people who are not infected but have a high risk of contracting the virus (Bavinton & Grulich, 2021). Those individuals are encouraged to take a daily pill containing two HIV antiretroviral drugs, specifically tenofovir (TFV) and emtricitabine, before potential exposure to HIV (Tran et al., 2020). Concerning TFV, in addition to the well-established tenofovir disoproxil fumarate, a newer TFV prodrug named tenofovir alafenamide has been developed. This prodrug offers reduced adverse effects on kidney function and bone mineral density (Aloy et al., 2016). The efficacy of daily oral TFV/emtricitabine in preventing HIV infections has been demonstrated in high-risk populations. Health authorities like the Centers for Disease Control and Prevention have recommended prioritising PrEP for specific groups like injection drug users, men intimate with other men, and serodiscordant heterosexual couples (United Nations, 2016).
Conclusions
This article comprehensively explores HIV-1 and AIDS, delving into their structure, mechanisms, treatments, challenges, and prevention strategies. Pharmacology, particularly combined antiretroviral therapy, has transformed HIV management, extending lives and shifting the narrative from despair to manageability. While challenges like latent reservoirs and potential side effects persist, the evolution of treatment guidelines and the promising approach of pre-exposure prophylaxis offers hope in the ongoing fight against HIV/AIDS. The tireless efforts of the scientific community will undoubtedly enlarge the pool of possible treatments and bring new avenues for even more effective HIV/AIDS control.
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