The Quest to Cure HIV Through International Interdisciplinary Collaboration
MARCH 05, 2018
Julie Overbaugh, PhDJulie M. Overbaugh, PhD, endowed chair for Graduate Education at the Fred Hutchinson Cancer Research Center, was presented with the honor of delivering the opening lecture for the 25th Conference on Retroviruses and Opportunistic Infections (CROI).
Each year, the opening session lecture, delivered in the name of Bernard Fields, PhD, a highly esteemed microbiologist and virologist, is presented by a basic scientist recognized for contributions to the fields of virology as well as viral pathogenesis.
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.
“If all goes well,” shared Overbaugh, “what I hope you’ll take away from this lecture is the potential of interdisciplinary international collaborations to inform prevention research.”
Overbaugh shared data and examples of the trial informed studies of interdisciplinary viral and immunological consequences of HIV infection in mother-infant transmission, and some of the work conducted in the field utilizing this reagents in unexpected ways to help advance vaccine studies.
The work 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, Overbaugh said, the World Health Organization (WHO) still recommended 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 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.
Overbaugh joined the research team to provide support with viral assays because at that time, these were the strongest tests to detect infection and 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. Overbaugh shared that by 24 months of life, 40% of infants in the breastfeeding arm were infected. Investigators found that much of the transmission occurred within the first week of life.
The data informed researchers how to best approach prevention methods in order to block and prevent HIV transmission through breastmilk — especially with an estimated risk of transmission at 16%.
In addition to having an increased risk of acquiring HIV early on in life, the investigators found 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.
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.
If an infant is HIV-negative at birth and exposed through breastfeeding, the infant is then exposed in the face of pre-existing HIV-specific antibodies from the mother — a situation that is envisioned to occur when a vaccine is developed that elicits these types of antibodies.
Researchers then question: Are HIV-specific passive antibodies contributing to protection?
According to 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. 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 Overbaugh.
When NAbs were examined in the same way there was no difference between infants who acquired HIV and infants who remained uninfected.
After citing more studies that examined both antibodies, Overbaugh shared that overall, lab-based collaborative studies leveraged samples and data included in the Nairobi trial, revealing distinct nature of the infant immune response, identifying 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,” 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.”
According to Overbaugh, 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.
“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.”
Overbaugh closed out her lecture by addressing young up-and-comers in the field encouraging 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 of curing HIV.
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