HIV/AIDS Immunity and Paths to a Potential Cure

By: Srinivas Sowmiyanarayanan

Human immunodeficiency virus (HIV) affects over 38 million people worldwide and has resulted in the death of approximately 40.1 million people since the beginning of the epidemic (World Health Organization, 2022). Prior to the development of treatments for HIV, the disease had a poor prognosis. This caused patients to develop terminal acquired immunodeficiency syndrome (AIDS) over time. With the advent of antiretroviral therapy (ART), many patients can lead regular lifestyles while preventing transmission to others (Centers for Disease Control and Prevention, 2022). However, it is important to note that ART is not a cure and needs to be continually taken to have therapeutic effects. HIV is difficult to cure because the virus “integrates into the genome of CD4+ T cells that then transition into resting memory cells, creating a persistent viral reservoir” (Kazer et al., 2020). Viral reservoirs occur when “HIV lies dormant inside a small number of cells in the body” (National Institute of Allergy and Infectious Diseases, 2018). Although there is no true cure, there are instances where individuals who were once HIV positive are now considered “cured” of the disease, such as the Berlin Patient and the London Patient. Examining how this type of “cure” has occurred allows us to evaluate its practicality and its implications for future research into HIV treatments.

HIV primarily infects white blood cells such as macrophages and CD4 T-cells by “bind[ing] to the primary cellular receptor CD4 and then to a cellular coreceptor” (Wilen et al., 2012). Once this occurs, the viral envelope can fuse with the cell membrane and release its contents. All HIV variants that infect humans utilize the CCR5 and/or CXCR4 receptors, depending on which variant of HIV is responsible for the infection (Wilen et al., 2012).

Figure 1: The HIV particle uses both the CD4 receptor and a coreceptor to bind and fuse with CD4 T-cells.

Some people have a genetic mutation that causes them to have fewer or completely lack CCR5 receptors, called the CCR5∆32 mutation. This mutation can create varying levels of immunity to HIV, depending on the extent to which CCR5 receptors are missing from their cells. It is important to note that this immunity pertains to the HIV variant that uses the CCR5 coreceptor (Samson et al., 1996). Those homozygous for this mutation have greater immunity than those heterozygous for the mutation since heterozygous individuals will still express the CCR5 gene to some extent, thus allowing some HIV to infect cells (Samson et al., 1996).

Figure 2: This figure highlights the difference between CD4 T-cells that contain or are deficient in CCR5 coreceptors and how that affects the HIV virus particle’s ability to enter the host cell.

The CCR5∆32 mutation played a role in the notable cases of individuals cured of HIV, including the Berlin Patient and the London Patient. The Berlin Patient, who had acute myeloid leukemia, received a hematopoietic stem cell transfusion (HSCT) in 2007 because he did not respond to chemotherapy. The donor was homozygous for the CCR5∆32 mutation, meaning that their CD4 T-cells did not contain the CCR5 coreceptor (Yukl et al., 2013). Similarly, the London Patient also received HSCT in 2019 from a homozygous CCR5∆32 donor to treat Hodgkin's lymphoma instead (Gupta et al., 2019). The transfused cells begin attacking and replacing both patients' original cells in order to kill the existing cancer cells. As a side effect, they also destroyed infected cells in the process and prevented the new cells from being infected because of the immunity conferred by the CCR5∆32 mutation.

The process by which the donor cells attack the host cells is known as graft versus host disease (GvHD) and could play a role in fighting HIV infection in the host beyond simply preventing new infections (Kuritzkes, 2016). Unfortunately, HSCT is not a simple procedure and its associated GvHD can be debilitating, preventing it from being a viable cure (Bailon et al., 2020). In addition, there are many other logistical difficulties, such as finding donors with matching or very similar human leukocyte antigen (HLA) profiles, which is what allows immune cells to differentiate between the body’s own cells and foreign cells.

Although the CCR5∆32 mutation and HSCT cannot be used as cures, the mechanisms that underlie both could potentially be useful to find new treatments.

Maraviroc, an entry inhibitor that is used to treat HIV, works by blocking the HIV particle from binding with CCR5 (Woollard & Kanmogne). Bailon et al. (2020) discuss “Kick-and-Kill'' strategies which use an immune response to attack cells with HIV by reactivating them from a latent state. This method is similar to the GvHD mechanism that is thought to play a role in the HIV cures found in the Berlin and London Patients, the only difference being that the body’s own immune cells would be responsible for killing the infected cells, rather than a host’s immune cells. Ultimately, a complete cure may not offer a significant quality-of-life improvement over existing ART which allows many patients to live without worry of passing HIV onto their partners or children.

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Images

Wilen, C. B., Tilton, J. C., & Doms, R. W. (2012). HIV: Cell binding and entry. Cold Spring Harbor Perspectives in Medicine, 2(8), 2. https://doi.org/10.1101/cshperspect.a006866

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