Human immunodeficiency virus (HIV) infections are lifelong, potentially life-threatening infections that weaken an individual’s immune system, rendering them susceptible to severe secondary infections. The virus is primarily transmitted through exposure to infected bodily fluids, most commonly via sexual contact or intravenous drug use. Although there is no cure for HIV, current treatments have extended the lifespan for people living with HIV. These treatments, collectively known as antiretroviral therapy (ART), preserve the immune system in patients and decrease their HIV burden by targeting different stages of the viral lifecycle and preventing HIV replication. ART is a major step forward in HIV management, but they cannot cure the infection entirely. Because a cure has been so elusive, doctors and researchers have instead focused their efforts into looking for ways to prevent HIV infection in the first place.
Pre-exposure prophylaxis (PrEP) is one particularly effective method to prevent HIV infections. Like ART medications, PrEP interrupts HIV at different stages in the viral life cycle. Unlike ART, PrEP is taken before someone contracts an active HIV infection. PrEP gives the body machinery to fight HIV and eliminate the virus before it establishes infection. PrEP has had an astounding level of success. PrEP is 99% effective at preventing sexually transmitted HIV infections, and ~74% effective at preventing infections from IV drug use. While these are amazing outcomes, they depend on a patient’s strict adherence to the daily medication regimen. In the USA, new regimens now include long-acting injectables that provide protection for 2 or 6 months, but these drugs are not available in regions of the world with high HIV prevalence.
Daily PrEP is the standard of care in many low- and middle-income countries, but it can become a hurdle when countries have an inconsistent supply of pills for the people who need them or if these medications are too expensive to take regularly. PrEP also faces other hurdles. Some people do not want to face the stigma a person whose sexual behaviors require HIV prevention strategies. Others have difficulty discussing and negotiating HIV prevention with their sexual partners and would like to use prevention tools that are only known to them and their health practitioners, such as long-lasting injectables.
These access and stigma issues led researchers to develop new ways to prevent HIV infection in the form of antibody-mediated prevention (AMP). AMP involves the infusion of antibodies targeting HIV into a healthy person. If the person is exposed to HIV after receiving AMP, the antibodies bind to the HIV virus, neutralize it, and prevent its entry into cells. Though they are still early in development, AMP is a promising prevention tool. Two efficacy studies demonstrated protection against some HIV strains, but higher concentrations of potent antibodies are needed to block most current viruses. Because infused antibodies are given intravenously, confidentially at a clinic, require no medication to take home, and remain in a person’s body for 2-3 weeks, they could be an effective way to avoid the stigma and daily task of taking PrEP pills.
Much is still unknown about how long and where the antibodies persist in the body. To effectively protect patients from sexually transmitted HIV, the AMP antibodies must stay in tissues like the rectum and genitals that are likely to be exposed to the virus. To ensure this is happening effectively, Drs. Maria Lemos and Rena Astronomo, co-first authors of the study, alongside Dr. Julie McElrath in the Vaccine and Infectious Disease Division conducted a phase 1 clinical trial to track down exactly where the antibodies were persisting in healthy patients that received AMP. The team demonstrated that in humans the infused antibody reaches key sites of HIV transmission such as the blood, the rectum, the vagina, the cervix and semen. This suggests that the AMP strategy can block the virus at early stages of transmission, before the virus can hide and establish residence inside of cells.
The team demonstrated that in rectal and female genital tract tissue, high amounts of antibody reach inner layers of tissue, where many HIV target cells reside. However, the distribution of both antibodies within the outer cell layers of tissue was inconsistent, suggesting these areas might not be as well protected by AMP.
Two different types of HIV-binding antibodies were compared in the study. One antibody was left unmodified, and the other was modified with LS, a modification that allows the antibody to be recycled back into the body to extend the interval between AMP doses to months. When the group measured the concentration of each antibody in different parts of the trial participants’ bodies, they were encouraged to find that the modified antibody persisted for a year in tissues, whereas the unmodified antibody disappeared in 6-8 weeks. Thus, this LS modification can increase dosing intervals and antibody concentrations at key sites of exposure. Newer and more potent antibodies in the AMP development pipeline will incorporate LS to ensure that effective, high levels of antibody are maintained for longer.
This work was supported by the National Institute of Health, the National Institute of Allergy and Infectious Disease, the Experimental Histopathology and Cell Imaging Shared Resource of the Fred Hutch/University of Washington Cancer Consortium.
Fred Hutch/UW/Seattle Children’s Cancer Consortium members Dr. Juliana McElrath contributed to this work.
Lemos MP, Astronomo RD, Huang Y, Narpala S, Prabhakaran M, Mann P, Paez CA, Lu Y, Mize GJ, Glantz H, Westerberg K, Colegrove H, Smythe KS, Lin M, Pierce RH, Hutter J, Frank I, Mascola JR, McDermott AB, Bekker L, McElrath MJ. 2024, Enhanced and sustained biodistribution of HIV-1 neutralizing antibody VRC01LS in human genital and rectal mucosa. Nat Commun. 15(10332).
Kelsey Woodruff is a PhD candidate in the Termini Lab at Fred Hutch Cancer Center. She studies how acute myeloid leukemia cells remodel the sugars on their membranes to reprogram cancer cell signaling. Originally from Indiana, she holds a bachelor's degree in Biochemistry from Ball State University. Outside of lab, you can find her crocheting and enjoying the Seattle summers.
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