International interdisciplinary collaboration will bring us that much closer to a cure for HIV.
In the opening session of the 25th Conference on Retroviruses and Opportunistic Infections (CROI), Julie M. Overbaugh, PhD, Endowed Chair for Graduate Education at the Fred Hutchinson Cancer Research Center was bestowed the honor of delivering a lecture in the name of Bernard Fields, PhD, a highly esteemed microbiologist and virologist. Each year, the lecture is presented by a basic scientist recognized for their contributions to the fields of virology as well as viral pathogenesis.
Dr. Overbaugh’s presentation highlighted the work accomplished in the Nairobi Breastfeeding clinical trial, the subsequent research that was inspired by it, and the power of international, interdisciplinary collaboration.
She shared data and examples of how the trial informed studies of interdisciplinary viral and immunological consequences of HIV infection in mother-infant transmission, as well as some of the work that has been done in the field using this reagent in unexpected ways to help advance vaccine studies. “If all goes well,” shared Dr. Overbaugh, “what I hope you’ll take away from this lecture is the potential of interdisciplinary international collaborations to inform prevention research.”
It all began with a randomized clinical trial conducted from November 1992 to July 1998 in antenatal clinics located throughout Nairobi, Kenya. At the time that this trial was initiated, Dr. Overbaugh said, the World Health Organization was still recommending breastfeeding in HIV-positive women.
“It was known that breastmilk could transmit HIV, but the risk of HIV infection was not clear,” Dr. Overbaugh explained, “And of course, at this time, antiretrovirals were not yet available for prevention of mother-to-child transmission.”
Investigators on the trial sought to compare infant HIV infection between 2 arms: infants who were breastfed and infants who were formula-fed. They wanted to understand the frequency and timing of breastmilk transmission from a mother to her infant. To this end, a total of 425 women were enrolled in the study, along with their infants; there was a median follow-up period of 24 months.
Dr. Overbaugh joined the research team to provide support with viral assays because at that time, these were the strongest tests to detect infection; quantitative assays capable of detecting different viral subtypes were not yet available.
The results of the trial revealed that breastfeeding nearly doubled the risk of infant infection. “Almost 40% of infants were infected in the breastfeeding arm by 24 months of life,” shared Dr. Overbaugh. Furthermore, the investigators found that much of the transmission occurred early, within the first week of life. “This was important because it would inform how we would approach prevention methods to try to block and prevent HIV transmission through breast milk,” she explained. The estimated risk of breastmilk transmission was 16%.
In addition to having an increased risk of acquiring HIV early on in life, the investigators found that infants are also at higher risk of mortality if they do acquire the virus. Furthermore, infants infected earlier in life also had a higher viral load compared with those infected later in life.
The Nairobi trial inspired several subsequent studies, such as 1 study that looked at clinical and viral correlates of infant HIV infection risk and showed that prematurity, genital ulcers, breast disease, and breastmilk exposure were all correlated with infant risk. Another subsequent study found that transmitting mothers had higher levels of cell-associated HIV in their breast milk compared with non-transmitting mothers, implicating cell-associated virus in transmission.
Dr. Overbaugh stressed that studying mother-to-child transmission of HIV offers researchers an opportunity to study passive antibodies and how they impact infection because the mother transfers HIV-specific antibodies to their infant in utero, achieving their highest levels at birth. “In the case of an infant who is HIV-negative at birth and exposed through breastfeeding, the infant is exposed in the face of pre-existing HIV-specific antibodies from the mother,” she explained. “This is a situation that is much like what we envision will happen when we develop a vaccine that elicits these types of antibodies.”
All this begs the question: Are HIV-specific passive antibodies contributing to protection?
That’s what researchers want to find out.
According to Dr. Overbaugh, the 2 types of antibodies of particular interest are neutralizing antibodies (NAbs) and antibody-dependent cellular cytotoxicity (ADCC) antibodies. Studies from the Nairobi trial were used to examine the role of passive ADCC and NAb activity in infant outcome, she said. For example, 1 study enrolled infants who were uninfected at birth but subsequently exposed to HIV. The investigators found that 21 out of 72 infants acquired HIV, but 51 remained uninfected. Infants who remained uninfected had a higher level of passively-acquired ADCC antibodies; however, this finding was not found to be statistically significant.
“I think this actually points to the need for more studies of this type to try to define the role of ADCC antibodies given that the direction of this difference suggests that they could be protective,” emphasized Dr. Overbaugh.
When NAbs were examined in the same way, she added, there was no difference between infants who acquired HIV and infants who remained uninfected.
After citing more studies that examined both antibodies, Dr. Overbaugh shared that overall, lab-based collaborative studies leveraged samples and data included in the Nairobi trial and “revealed the unique nature of the infant immune response and identified ADCC antibodies as a correlate of protection in infants.”
Results yielded in the Nairobi trial also led to unexpected findings in subsequent studies. For example, 1 study looked at an envelope variant representing a transmitted virus from an infant from the Nairobi trial; the variant was dubbed BG505. “This infant-derived Env variant has informed our understanding of the structure and immunogenicity of HIV Env,” Dr. Overbaugh said. “Because the Env trimer mediates entry into the cell and is the target of NAb, the structure of Env holds the key to designing biological approaches to prevent HIV infection.”
The substantial impact of the Nairobi breastfeeding trial and subsequent research underscore the immense potential of international interdisciplinary research in the realm of HIV prevention, according to Dr. Overbaugh. “The trial revealed risk and correlates of breastmilk transmission as was its original intent. But the data and samples from the trial were instrumental in revealing unique aspects of infant immune response,” she said. “It has been very exciting to see how the field has converged on a virus from an infant in the trial, an unexpected outcome when the trial was first designed, and that this BG505 trimer is advancing vaccine research at a rapid pace.”
Closing out her lecture by addressing young up-and-comers in the field, Dr. Overbaugh encouraged them to look for the opportunities that exist to be a part of meaningful collaborative study that could not only impact the trajectory of their careers, but also broaden research in positive ways, bringing everyone that much closer to the ultimate end goal: to cure HIV.