In 2022, 1.3 million people across the globe were newly diagnosed with human immunodeficiency virus (HIV) infection. HIV infects and kills cells of the body’s immune system, particularly a type of white blood cell called CD4 T cells. If left untreated, HIV infection progresses to a spectrum of conditions known as AIDS (acquired immunodeficiency syndrome), where patients become extremely vulnerable to other infections and cancers which are usually kept at bay by an intact immune system. There is currently no cure for HIV; however, it can be successfully prevented. Drugs originally designed to treat patients living with HIV, known as antiretroviral therapy (ART), are now being prescribed to populations with high incidence rates to prevent HIV acquistion. Used in this way, these drugs are known as pre-exposure prophylaxis (PrEP). “PrEP has revolutionized HIV prevention, giving many people a great tool for HIV prevention all over the world,” says Dr. Maria Lemos, a member of the HIV Vaccine Trials Network (HVTN) and an equal-contributing author with Dr. Yunda Huang on a recent paper in Nature Communications studying the effect of combining PrEP with an anti-HIV antibody, a new type of HIV prevention.
Antibodies form part of the body’s normal immune response to viral infection, protecting against re-infection in the future by binding to viruses and preventing them from infecting our cells. There are currently multiple anti-HIV antibodies under assessment in clinical trials. VRC01, the antibody assessed in Dr. Lemos and Dr. Huang’s study, was originally isolated from a person living with HIV for more than 15 years whose immune system was able to keep HIV at bay without taking any medicine. VRC01 is an example of a rare antibody that can recognize many different HIV strains, a broadly-neutralizing antibody or bNAb, and in principle could be used to protect against infections from many different HIV strains. A combined regimen of PrEP and bNAb could be even more effective at preventing HIV infection if the two treatment modalities worked together. If 1+1=2. “We decided to look for differences between PrEP and non-PrEP users because many HVTN trials are testing prophylactic antibodies and recruit people who take or do not take these medications. Others have previously characterized the side effects of PrEP for prevention of HIV, and intestinal issues early after uptake had been described,” says Dr. Lemos. Previous studies assessing VRC01’s efficacy have not considered the effect of using PrEP, which could affect the way VRC01 is processed and cleared from the body. Furthermore, there have been multiple reports of interactions between antibodies and small molecule drugs in clinical trials for rheumatoid arthritis, cancer, and heart disease. “Our work demonstrates VRC01 is cleared ~15% faster from the blood serum in men who take PrEP, and that this is associated with increased intestinal permeability,” says Dr. Lemos. In other words, 1+1=1.85 in serum, sort of. “Additional studies will be needed to find out whether 1+1 <, = or > 2 in tissues, where the first battle against HIV often takes place” says Dr. Huang, also a member of the HVTN and the corresponding author of the paper. While uncommon, PrEP usage can affect the liver and kidneys; however, the team observed no association between VRC01 clearance and liver and kidney function, nor markers of inflammation.
“Our findings raise lots of questions. What are the asymptomatic changes to the intestinal permeability associated with PrEP? We are starting to evaluate this question assessing changes to the epithelium of male PrEP and non-PrEP users in collaboration with Dr Florian Hladik (University of Washington) who has investigated this issue. We plan to look at biopsies of trial participants before starting PrEP and after months of PrEP use. We are also interested in looking at whether this permeability issue and enhanced VRC01 clearance also occurs in females,” says Dr. Lemos. Given that PrEP has been licensed in several countries as an HIV prevention tool, future antibody clinical trials for HIV prevention or other diseases may include PrEP users. Therefore, understanding how PrEP affects clearance of antibodies is important to ensure optimal dosing for those undergoing treatments for cancer and autoimmune diseases.
The spotlighted research was funded by the National Institute of Allergy and Infectious Diseases (NIAID).
Fred Hutch/University of Washington/Seattle Children's Cancer Consortium members Larry Corey, Juliana McElrath and Peter Gilbert contributed to this work.
Huang Y, Zhang L, Karuna S, Andrew P, Juraska M, Weiner JA, Angier H, Morgan E, Azzam Y, Swann E, Edupuganti S, Mgodi NM, Ackerman ME, Donnell D, Gama L, Anderson PL, Koup RA, Hural J, Cohen MS, Corey L, McElrath MJ, Gilbert PB, Lemos MP (2023) nature communications 4(1):7813.