Transient CD4-Cell-Depletion Therapy for HIV/AIDS Cure
Human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) remains a significant global public health challenge, with approximately 38 million people living with HIV by the end of 2019. Despite advancements in treatment, there is still no routine cure for HIV/AIDS. Current therapies, such as combined antiretroviral therapy (cART), effectively control HIV replication but fail to eradicate the HIV reservoir, which is the primary barrier to a cure. The HIV reservoir, defined as resting CD4+ cells harboring replication-competent HIV, is established within 2 to 3 days of primary infection. These reservoirs persist in long-lived memory CD4+ cells, making them resistant to cART and leading to viral rebound upon treatment interruption.
The only acknowledged HIV cure case is the “Berlin patient,” who received a bone marrow transplant from a donor with a CCR5-tropic-HIV-resistant homozygous CCR5 Δ32 mutation. This treatment, combined with the use of anti-T cell antibodies and cyclophosphamide, cleared all T cells, including the HIV reservoir. Similarly, the “London patient” underwent a comparable procedure and has shown no HIV rebound after stopping cART. However, bone marrow or stem cell transplantation is not a feasible option for all HIV patients, especially given the effectiveness of current cART.
The success of the Berlin patient has shifted scientific focus towards the CCR5 Δ32 mutation. Researchers have successfully converted wild-type CCR5 to homozygous CCR5 Δ32 in lymphocytes using CRISPR-Cas9 gene-editing technology, providing autologous homozygous CCR5 Δ32 cells. However, this approach does not eliminate wild-type CCR5+ CD4+ cells, which continue to support HIV replication, thus failing to cure HIV/AIDS. The pre-transplant treatment in the Berlin patient, which included anti-T cell antibodies and cyclophosphamide, played a crucial role in clearing the HIV reservoir.
This observation led to the hypothesis of “transient CD4-cell-depletion therapy (TCDT)” as a potential method to eradicate the HIV reservoir. The proposed TCDT involves several steps: First, HIV/AIDS patients are treated with cART until their plasma viral load is undetectable. Patients are maintained in good health, with antibiotics administered if necessary. Second, patients receive a specific anti-human CD4 monoclonal antibody to deplete all CD4+ cells, including T cells, macrophages, and dendritic cells, regardless of their HIV status. This step aims to eradicate the HIV reservoir, with treatment continuing until peripheral blood CD4+ cells are nearly zero. During this period, cART is maintained. Third, TCDT is stopped, and patients are monitored for several weeks until CD4+ cells recover to normal levels, with cART continued. Finally, cART is discontinued, and patients are observed for HIV rebound.
TCDT transiently depletes CD4+ cells in HIV-infected patients, targeting both HIV-infected and uninfected cells. The therapy aims to clear HIV reservoirs in peripheral blood, lymph nodes, brain, bone marrow, and gut-associated lymphoid tissues. Although TCDT has not been tested in HIV/AIDS patients, a phase II clinical trial using the anti-CD4 monoclonal antibody zanolimumab in T cell lymphoma therapy demonstrated its safety and tolerability in humans.
The primary risk of TCDT is temporary immunodeficiency, leading to potential opportunistic infections. Preparations such as placing patients in sterile environments and administering antibiotics and antiviral agents can mitigate these risks. The immunodeficiency caused by TCDT is transient and recoverable. Evidence from clinical trials and cART treatment in late-stage AIDS patients confirms that CD4+ cells can recover after depletion, as the stem cells producing CD4+ cells remain intact.
In cases where CD4+ cells do not reach zero after TCDT, a significant reduction in the HIV latent reservoir may still allow for a cure, as the residual virus and infected cells could be cleared by the patient’s immune system. While TCDT may not cure all HIV/AIDS patients, even a 30% success rate would represent substantial progress. Concerns about the induction of autoantibodies by anti-CD4 antibodies are unfounded, as no such cases were reported in previous human trials.
HIV’s accessory protein Nef downregulates CD4 and major histocompatibility complex molecules, potentially allowing CD4- HIV-infected cells to evade TCDT. However, cART can inhibit Nef production by preventing viral replication, making it a crucial component of TCDT. Newly generated CD4+ cells remain susceptible to HIV, and TCDT is not suitable for late-stage AIDS patients with already low CD4+ counts.
The loss of immune memory in CD4+ T cells post-TCDT may render previous vaccines ineffective. However, patients can be re-vaccinated after recovery to stimulate immune responses. TCDT’s advantage lies in its ability to clear resting CD4+ T cells and monocytes/macrophages of the HIV reservoir in various tissues. The therapy is transient, tolerable, and recoverable, and a significant reduction in the HIV reservoir size could lead to a cure.
In 2018, the FDA approved the anti-CD4 monoclonal antibody ibalizumab (Trogarzo) for HIV treatment, which prevents HIV binding to CD4 receptors but does not deplete CD4+ cells. There is no evidence that ibalizumab can cure HIV/AIDS. Other studies on CD4+ cell depletion focus on observing cell function rather than eradicating the HIV reservoir, distinguishing them from TCDT.
The COVID-19 pandemic highlighted the importance of eliminating the virus to prevent outbreaks. Similarly, HIV/AIDS cannot be cured if HIV and HIV-producing cells persist. TCDT offers a theoretical pathway to cure HIV/AIDS by clearing the latent reservoir. However, TCDT remains a hypothesis and must undergo animal testing and clinical trials before application in HIV patients.
doi.org/10.1097/CM9.0000000000001654
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