Antibody therapy offers promising lead for sustained HIV control

BY NOAH BEATTIE-MOSS

HIV/AIDS is a global pandemic, and has remained at the forefront of American consciousness since the 1980s, when hundreds of thousands of people, predominantly young gay men, passed away from the disease. Today, over 36 million people live with the disease worldwide, with over 1.2 million patients in the United States alone. It can be managed with continuous antiretroviral therapy, but there is still no known cure or vaccine. Recent research published in the journal Science, however, suggests the potential for a new combination therapy that may act as a functional cure.

Human immunodeficiency virus is categorized as a retrovirus, meaning it has an RNA genome enclosed by a protein capsid and a lipid envelope derived from the cell membrane of the host. Molecules on the HIV particle bind to receptors on the surface of T helper cells, especially CD4+ T cells, which play an essential role in the proper functioning of the immune system. Once inside a host cell, the viral RNA is converted into DNA, transported into the nucleus, and integrated into the cellular genome. This viral DNA is called a provirus, and is transcribed by the cell to produce new virus particles.

image-cycle-1-noah-beattie-moss
HIV-infected T cell, captured by a scanning electron microscope.

Antiretroviral therapy (ART) can target several different steps in this viral life cycle, such as blocking membrane fusion of HIV with the cell, or inhibiting reverse transcriptase, the enzyme which transcribes the viral RNA into DNA. But it has downsides: ART requires continuous daily medication, and viral loads regenerate if therapy is stopped, so it is not a cure. Long-term ART also has side effects such as toxicity, inflammation, and an elevated risk of aging-related diseases such as liver dysfunction and osteoporosis. In addition, access to medication poses a problem: in 2010, the average lifetime cost of treating HIV in the US was approximately $380,000, and distribution of ART medication in developing countries is extremely limited.

Research led by Dr. Aftab Ansari of the Emory University School of Medicine, published on October 14, 2016, investigated the effect of ART alongside an antibody targeting α4β7, a receptor on the surface of CD4+ cells which enables them to traffic into gastrointestinal tissues. During a typical infection, depletion of CD4+ cells in these tissues causes gut epithelial damage and allows the formation of persistent viral reservoirs, leading to general immune dysfunction. It was hypothesized that by blocking entry of CD4+ cells into this area, the immune system would remain strong enough to control the infection.

The investigation was conducted on macaques, using SIV, the simian analogue of HIV. Eighteen monkeys were infected with the virus and were started on a daily ART regimen after five weeks. Starting at week nine, eleven of the animals were treated with the α4β7 antibody, while the other seven received a nonspecific antibody as a control. ART was terminated for both groups at 18 weeks, and antibody treatment was terminated at 32 weeks.

The results were dramatic: macaques which received the α4β7 antibody had an absent or minimal viral load after ART was ceased, while the control group rebounded to high viral levels. Control over viral levels persisted through the end of the study, at week 90.

This indicates that α4β7-directed therapy not only stopped temporary entrance of HIV-infected T cells into gastrointestinal tissue, reducing tissue damage, but also allowed the immune system to subsequently control infection after therapy was discontinued.

The precise mechanism by which this operates is yet unknown, but the combination of α4β7-directed antibodies with ART seems to have functionally cured SIV infection in the macaques, granted this is not a complete cure, because the viral genome is still present in the host. The human equivalent for the α4β7 antibody is already an FDA-approved drug called vedolizumab, currently used to treat Chron’s disease and ulcerative colitis. A clinical trial was begun in May 2016 to see if vedolizumab is safe for AIDS patients, and whether it allows the immune system to control HIV infection after ART is discontinued. The study is expected to be completed in 2020.

A great deal of work remains to be done to understand the molecular implications of this treatment, but the results of the clinical trial are eagerly awaited. Long-term immune control over infection promises to be a groundbreaking step forward in our ability to treat AIDS and could effectively eliminate the need for recurring medication. This would solve a major distribution challenge for developing countries, and could herald a new era in humanity’s relationship with this virus.

Image source: https://www.flickr.com/photos/54591706@N02/6813384933

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