HIV reservoir decay rates defined for children receiving ART

Can HIV cure be achieved in children? Children with HIV face a lifetime of antiretroviral therapy (ART) to suppress HIV replication. While this is one outlook, an HIV cure in children would re-write this future—one without receiving routine ART to maintain remission. The possibility of ART-free HIV remission, although temporary, was demonstrated by a ‘Mississippi baby’ who was confirmed to have HIV and treated very early to reduce the HIV reservoir (i.e. HIV that remains dormant or hidden in cells despite no additional virus production). Following treatment, the ‘Mississippi baby’ remained in ART-free remission for just under 2 years before detectable levels of virus were found in the blood, an indicator of active, virus-producing infection. While remission was temporary, this case provided hope that understanding how to achieve smaller HIV reservoirs may help achieve HIV cure in children. To advance this understanding, research spearheaded by Dr. Daniel Reeves, a Principal Staff Scientist in the Vaccine and Infectious Disease Division at Fred Hutchinson Cancer Center and an Affiliate Assistant Professor in Global Health at the University of Washington, provides new insights into the rate of HIV reservoir decay in children living with HIV and receiving ART. This work was published recently in PLoS Pathogens.

On the road to pediatric HIV cure, the researchers sought to better understand how HIV persists in children during ART. This endeavor required a strong community of HIV researchers, which exists in Seattle, to form a “large collaboration between clinical studies, basic immunology, human biology and genetic sequencing, and mathematical modeling,” shared Dr. Reeves. To begin, the study cohort was managed by Dr. Grace John Stewart, Dr. Jenn Slyker, Dalton Wamalwa and others at both the University of Washington and the University of Nairobi. The cohort used in this study was a key strength since it was a “cohort of children with HIV that has been followed since birth for up to 12 years (and longer now!),” commented Dr. Reeves. “These children are from Nairobi Kenya, acquired HIV at birth, and are a mix of ages and genders and subtypes of HIV they acquired.” The events and data available from this group represent real-life care for children living with HIV. Data from planned and unplanned treatment interruptions was kept and used to help inform how unavoidable treatment interruptions affect HIV persistence.

To quantify HIV persistence that occurs despite ART adherence, the researchers measured the abundance of HIV reservoirs. HIV can be measured in the blood during an active infection (i.e. HIV RNA), yet during ART, this is largely suppressed. To measure dormant HIV, another method of quantifying HIV reservoirs (i.e. HIV DNA) was used. Dr. Reeves shared, “The study uses a powerful new assay developed by the Lehman lab [including Dr. Dara Lehman (Fred Hutch), Morgan Litchford, Carolyn Fish and others] that enables quantification of the long-term HIV reservoir in these children across the broad spectrum of subtypes.” Importantly, this method distinguishes between intact and defective HIV DNA. Intact HIV DNA can reactivate to produce virus, but defective HIV DNA cannot and can be excluded from the clinically relevant HIV reservoir measurement. Additionally, “the study applies modern T cell sequencing approaches that can contrast how HIV persists via how healthy cells persist in the same children,” explained Dr. Reeves. This work was contributed by the Cohn lab.

These analyses provided two complex datasets that with mathematical modeling performed by Dr. Reeves and his group, provided novel insights into HIV persistence in children. Dr. Reeves explained, “All these data together make a few key contributions: 1) a comprehensive assessment of the pediatric HIV reservoir in globally representative populations, which shows intact HIV reservoirs clear faster than total HIV DNA and 2) that treatment interruptions transiently raise HIV DNA but do not affect long-term reservoir clearance if treatment is reinitiated.”
 

Now that we better understand the rate at which HIV reservoirs decay in children living with HIV and receiving ART, Dr. Reeves shares their next line of unresolved questions: “Why do certain children appear to have very low reservoirs at the initiation of therapy? Do treatment interruptions affect those children more strongly? Are there specific CD4+ T [immune] cells that tend to harbor HIV DNA in children with HIV?” These questions continue to probe the research area where HIV biology, immunology and mathematical modeling intersect to understand how to achieve HIV cure for children. “We are seeking funding to perform viral sequencing to determine whether treatment interruptions have any implications for drug resistance and possibly estimate infection timing,” shared Dr. Reeves. The researchers are particularly enthusiastic about one hypothesis: that children with smaller HIV reservoirs acquired HIV in utero instead of during birth. Detangling how to maintain low HIV reservoirs would bring us one step closer to achieving pediatric HIV cure.

The spotlighted research was funded by the National Institutes of Health and the University of Washington/Fred Hutch Center for AIDS Research.

Reeves DB, Litchford M, Fish CS, Farrell-Sherman A, Poindexter M, Ahmed N, Cassidy NAJ, Neary J, Wamalwa D, Langat A, Chebet D, Moraa H, Antar AAR, Slyker J, Benki-Nugent S, Cohn LB, Schiffer JT, Overbaugh J, John-Stewart G, Lehman DA. 2025. Intact HIV DNA decays in children with and without complete viral load suppression. PLoS Pathog. 21(4):e1013003.