· Of the 25 children in the trial, 11 (44%) continued to suppress HIV in the absence of antiretroviral drugs.
Roger M. Smith, Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health. An early trial by Roger L. Shapiro's team in HIV-infected children showed that broad-spectrum neutralizing antibodies (bNAb) could provide an alternative to standard antiretroviral therapy (ART) to control HIV-1 replication and may have immunotherapeutic effects on the HIV-1 reservoir. The paper was published online in Science Translational Medicine on July 5, local time.
"This is a very clear proof of concept and we are able to use broad-spectrum neutralizing antibodies as an alternative therapy." Study leader Shapiro said.
The medical full name of AIDS is "acquired immunodeficiency syndrome", which is caused by the human infection with the human immunodeficiency virus, known as the human immunodeficiency virus (HIV). HIV mainly attacks CD4+ T lymphocytes in the human immune system, destroys the human immune system, causes various opportunistic infections and tumors, and even eventually leads to death.
Factors that produce broad-spectrum neutralizing antibodies.
Broad-spectrum neutralizing antibodies are produced by the human body in the process of fighting the virus, which can identify areas where the surface of the HIV-1 strain is not easy to change, so as to capture a variety of strains, inhibit virus replication in patients, and effectively reduce the level of HIV-1 virus in the human body. However, according to the Chinese Center for Disease Control and Prevention, only 10%-15% of people can produce neutralizing antibodies after infection with HIV-1 virus, of which only 2%-5% have broad-spectrum neutralizing antibodies.
In recent years, there have been many attempts to use neutralizing antibodies to treat HIV. In October 2022, Laura Waters, president of the British Association for Sexual Health and HIV, and others published a review in the journal Clinical Infectious Diseases, noting that some antibody therapies have been shown to delay viral rebound without antiretroviral therapy. But none of them can stop it completely.
HIV continued to be suppressed in 44% of children
For the study, Shapiro's team recruited 25 children who started small molecule antiretroviral therapy (ART) within 7 days of birth for at least 96 weeks and received a combination of two broad-spectrum HIV-1 neutralizing antibodies, VRC01LS and 10-1074.
They gave intravenous doses to children participating in the trial every 4 weeks, stopped after 8 weeks, and then these children continued to take antiretroviral drugs for 24 weeks. Of the 25 children, 11 (44%) continued to suppress HIV in the absence of antiretroviral drugs.
Shapiro's team then conducted genomic tests to measure the amount of HIV in children's blood samples. They found that these children had a lower viral load in their DNA and a smaller reservoir of viruses in immune cells (a group of immune cells in people infected with HIV that are infected with HIV but do not actively produce new HIV, and that they may become active again and make more HIV). This means that HIV-infected children treated with neutralizing antibodies are more likely to lead healthy lives, and the findings are similar to those conducted in adults with HIV.
Shapiro's team notes that their study was small and therefore may not be representative of other HIV-infected children. On the other hand, children already on antiretroviral therapy also have lower viral banks. "It's hard to measure the impact of [neutralizing antibodies] on the viral reservoir to a greater extent." Shapiro said.
Shapiro told industry media STAT that his research team is currently recruiting all HIV-infected children to participate in long-term trials to deeply analyze viral reservoir cells and immune responses.
In recent years, there have been many studies that have tried to use neutralizing antibodies to treat people with HIV, but their focus has been on infected adults. From this perspective, "this experiment is significant. Ann Chahroudi, an associate professor of pediatrics at Emory University's School of Medicine, said.
According to a report by the United Nations Children's Fund (UNICEF), an estimated 110 000 children and adolescents (aged 0-19 years) died globally from HIV-related conditions in 2021; At the same time, there are 310,000 new HIV-infected people in this age group.
HIV-infected children must take antiretroviral drugs daily for months, but administering medicines is complex for a number of reasons, such as paediatric formulations that may be in short supply, caregivers of children often struggle to prepare and administer medicines effectively, and families face financial burdens such as the cost of transportation to dispense medicines in hospitals and comply with follow-up visits.
UNICEF also reports that the proportion of infected children aged 0-4 who do not receive antiretroviral treatment has been increasing over the past seven years (2014-2021), reaching 72% in 2021.
There are still many hurdles to overcome in the treatment of HIV with neutralizing antibodies
In October 2022, Laura Waters, president of the British Association for Sexual Health and HIV, and others wrote a review in the journal Clinical Infectious Diseases arguing that the appropriate combination of antibodies lacks clarity, requires resistance testing, and poor permeability to anatomical reservoirs. Together, these result in broadly neutralizing antibodies being less practical than antiretroviral therapy.
According to the article, antibodies 3BNC117, 10-1074, VRC01 and PTG121 showed the highest ability to suppress HIV in the absence of antiretrovirals. However, as monotherapy (using one antibody at a time), several past studies have shown that the duration of viral suppression is relatively short, about 3-10 weeks, depending on the antibody tested and the number of doses given. In addition, when the viral load rebounds, the virus almost always develops resistance to the antibodies tested. Therefore, Waters et al. believe that combination therapies consisting of multiple broad-spectrum neutralizing antibodies have the highest prospect.
The combination of 3BNC117 and 10-1074 is the most widely tested mixture. In one test, 3 out of 4 people who responded to treatment did not produce sustained viral "clearance" (undetectable virus), and everyone involved in the study developed some level of resistance to one of these two antibodies.
In April 2022, a paper published in Nature reported a phase clinical trial of the HIV broad-spectrum neutralizing antibody combination GS-5423/GS-28721b, GS-5423/GS-2872 is also a combination of 3BNC117 and 10-1074, which was developed by Michel Nussenzweig, a pioneer in immunology at Rockefeller University, and was later developed by Gilead Sciences，GILD. US) in the pocket.
The study was divided into two treatment groups, and in the first treatment arm, 17 HIV-infected people received 7 doses of GS-5423/GS-28721b dual antibody after stopping antiretrovirals, and 13 of them achieved up to 20 weeks of virologic suppression. In the second treatment group, 6 HIV-infected patients received 7 doses of biantiviral therapy during antiretroviral therapy, stopping antiretroviral therapy at the same time, 5 patients experienced viral rebound 1-2 months after both treatment was stopped, and 1 patient required antiretroviral therapy at all times. After one year, 2 of all patients treated with 7 doses of biantibodies remained virologically suppressed.
Waters et al. said in the aforementioned article that some antibody therapies have been shown to delay viral rebound without antiretroviral therapy, but none can completely stop it. The article also points out that some studies have shown that broad-spectrum neutralizing antibodies do not significantly reduce the latent viral reservoir, which is necessary to truly eradicate HIV from the body. They suggest that a combination of broad-spectrum neutralizing antibodies and antiretroviral therapy could be used to provide a long-acting therapy.
Another limiting factor is cost. While neutralizing antibodies have been used to treat diseases including COVID-19, they are expensive to manufacture, leaving many people without access to new treatments. Waters et al. argue that broad-spectrum neutralizing antibodies are unlikely to be used as first-line treatment for HIV without removing barriers to resistance screening and maintaining long-term viral suppression.
But Shapiro is hopeful. "Research has to start somewhere, and we're just beginning to understand what's possible in biology, even though it seems like an expensive, logistically challenging strategy."
Resources:
1. https://news.un.org/zh/story/2022/11/1112822
2. https://pubmed.ncbi.nlm.nih.gov/36303321/
3. https://www.statnews.com/2023/07/05/first-pediatric-study-to-test-neutralizing-antibodies-against-hiv-shows-promise/