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Human immunodeficiency virus (HIV) is a retrovirus that infects cells of the human immune system, destroying or damaging its function. There is no symptom at the beginning of HIV infection, but as the infection progresses, the immune system begins to weaken. The final stage of infection is the acquired immunodeficiency syndrome, AIDS.

 

According to WHO official data (updated in July 2018), nearly 37 million people worldwide are infected with HIV; in 2017, 940,000 people died of HIV-related illnesses.

 

HIV-infected people may develop AIDS after 10-15 years, and antiretroviral drugs can further delay the process.

 

Although the emergence of antiretroviral drugs has dramatically changed the status of AIDS treatment since the 1990s, such diseases remain a major threat to global public health. AIDS is still incurable, patients must take medication for life, and the development of AIDS vaccines has been defeated. Scientists have been hoping to find new treatments for AIDS, and immunotherapy is the direction that many teams are working hard.

 

To survive and replicate, HIV usually infects CD4+ T lymphocytes, a white blood cell that activates the body’s defenses against infection. During antiretroviral therapy, HIV persists in latently infected CD4+ T cells. Studies have shown that immune checkpoint molecules, including PD-1, are preferentially expressed on the surface of persistently infected CD4+ T lymphocytes.

In the field of cancer, PD-1 has become a very popular target, and PD-1 antibodies have been shown to treat a variety of cancers. So, how does PD-1 affect the latent infection of HIV and the maintenance of the HIV virus pool?

Using CD4+ T cells from HIV-infected individuals, Canadian scientist Rémi Fromentin et al. found that PD-1 involvement not only inhibits HIV production at the transcriptional level, but also inhibits T cell receptor-induced HIV reactivation in latently infected cells.

 

Based on these findings, the researchers further confirmed that the PD-1 antibody Keytruda combined with the latent reversal agent bryostatin (grassin, a complex 26-membered macrolide marine natural product with significant anti-cancer, anti-HIV , the treatment of a variety of biological activities such as Alzheimer’s disease) increased the production of HIV.

 

The authors believe that these results suggest that treatment of HIV-infected individuals receiving antiretroviral therapy with immunological checkpoint inhibitors such as PD-1 antibodies may help to disrupt the latency of HIV. The above results were published in the February issue of Nature Communications.

Seeing this study, I can’t help but think of a paper published in Annals of Oncology in December 2017. A French research team observed that patients with lung cancer who were infected with HIV were treated with the PD-1 antibody Opdivo. The reservoirs of cells that were “hidden” by HIV in the body and evaded antiretroviral therapy were greatly weakened.

 

The patients reported in the study were diagnosed HIV-positive in 1995 and were diagnosed with non-small cell lung cancer in May 2015. Since December 2016, the patient has been treated with Opdivo and is administered every 2 weeks.

 

When the researchers first injected Opdivo into the patient, HIV could not be detected in the blood sample. As the treatment continues, the level of HIV detected in the blood sample gradually increases, reaching its highest level by day 45, and then begins to decline again. At the 120th day of treatment, the cell pool of “hidden” HIV showed a dramatic and sustained decline. This was associated with a significant increase in CD8+ T cell activity on days 30 to 120 of treatment.

If HIV carriers stop taking antiretroviral drugs, the virus hidden in dormant cells will quickly “force” and infect more cells.

It is reported that this is the first study to prove that targeting PD-1 can eliminate HIV latent infected cells in humans. However, it should be noted that although the patient did not have side effects, the researchers were still cautious about their results.

 

Professor Jean-Philippe Spano, who led the study, explained: “There is three reasons for this caution. First, this is the first case of a sharp decline in the HIV depot. We also published details of another case. However, there is no decline in the HIV repositories in this case. Second, we must assess the potential toxicity of these drugs to HIV-infected patients. Finally, we need to find markers that can predict the response to treatment, so as to achieve precise treatment. This has been particularly important in cases where one responder and one non-responder have been observed.”

 

Fabrice André, editor-in-chief of Annals of Oncology, gave a high rating to the study. He believes that although it is only a single case study, it is indeed an exciting result. Because, at present, although daily drug treatment can keep the virus in the blood of HIV carriers at a low level, there is still no way to eliminate HIV-infected cells that are dormant in humans. The findings of Professor Spano and others have produced the hypothesis that drugs that let hidden viruses disappear may cure AIDS patients.

In fact, in addition to PD-1 antibodies, another representative of cancer immunotherapy, CAR-T therapy, is also expected to contribute to the fight against AIDS.

In a paper published in PLOS Pathogens at the end of 2017, scientists designed a hematopoietic stem cell (HSPCs) carrying the chimeric antigen receptor (CAR) gene. This particular gene allows HSPCs to detect and destroy HIV-infected cells.

How does CAR-T therapy, which has made important breakthroughs in the treatment of blood cancer, fight HIV?

 

It turns out that HIV-infected cells require a molecule called CD4. Based on this, the researchers designed a CAR molecule to block the key interaction between HIV and the CD4 molecules on the surface of infected cells, allowing T cells derived from HSPCs to “kill” HIV-infected cells. When CD4 on the CAR molecule binds to HIV, other regions of the molecule signal the T cells that carry it, making it active and killing cells infected with HIV.

In the test animals, the engineered hematopoietic stem cells maintained stable production of CAR-expressing cells for more than two years without any side effects. In addition, these cells are widely distributed in lymphoid tissues and the gastrointestinal tract, which are the main sites where HIV replicates and persists in infected individuals. More importantly, these CD4-expressing CAR-T cells have demonstrated efficacy in attacking and killing HIV-infected cells.

 

The authors believe that the results of the study indicate that HSPC-derived CAR-T cells have long-term retention and immune surveillance capabilities. This study demonstrates for the first time the safety and feasibility of HSPC-based CAR therapy in preclinical models of large animals.

The researchers hope that this treatment will reduce the dependence of infected individuals on antiviral drugs, reduce the cost of treatment, and at the same time bring the possibility of “completely eradicating HIV from its hiding place.”

In summary, these three papers convey a positive signal of using immunotherapy to fight HIV infection. So, can PD-1 antibodies and CAR-T therapy really create miracles in the AIDS field? Look forward to having further clinical data to give an answer as soon as possible.

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