Herpesvirus infections may affect the size of the HIV reservoir in ART-treated children

From the Lehman lab, Human Biology Division, and the Department of Global Health at the University of Washington

Antiretroviral therapy (ART) for HIV-infected individuals effectively suppresses viral replication, restoring immune functions, and preventing life-threatening HIV-related opportunistic infections. However, during the early stages of infection, the HIV genome integrates into long-lived cellular reservoirs that persist during ART and can cause viral rebound if treatment ceases. Thus, although ART dramatically improves HIV-infected individuals’ quality of life, it is not a curative treatment and requires life-long adherence to be effective.

Understanding the dynamics of the HIV reservoir has become a priority in HIV cure research because it likely holds the key in developing novel strategies for its elimination. Researchers in the Lehman lab at the Human Biology Division study longitudinal HIV reservoir dynamics in a cohort of ART-treated Kenyan infants and children. Using this unique specimen repository, the researchers studied the relationship between reservoir size and coinfection with common herpesviruses to determine if targeting these infections may be a potential intervention to reduce the HIV reservoir in children. The group recently published the results of this study in the Journal for Infectious Diseases.

Herpesviruses cytomegalovirus (CMV) and Epstein-Barr virus (EBV) infections are commonly acquired in infants during primary HIV infection (PHI). Researchers in the Lehman lab and collaborators at the University of Washington (UW) evaluated longitudinal plasma samples for HIV, CMV, and EBV replication from early-treated, HIV RNA-suppressed infants participating in a study in Nairobi, Kenya called the Optimizing Pediatric HAART (OPH Study), and assessed associations with HIV DNA levels –a proxy for HIV reservoir size– after 24 months of ART.

The investigators first determined associations between several HIV variables, including HIV RNA area-under-the-curve (AUC), derived from longitudinal HIV RNA viral loads. As expected, higher HIV RNA AUC was associated with higher HIV DNA levels. Early acquisition of CMV and EBV was associated with higher HIV DNA levels, independently of HIV RNA AUC, suggesting that differences in HIV RNA containment did not drive the association. For EBV, the association with HIV DNA levels was sensitive to EBV acquisition timing: the association was found only in children that acquired EBV before six months of age. “These data suggest that these common herpesvirus coinfections may impact HIV reservoir level, and could be novel targets for interventions,” says Dr. Jennifer A. Slyker, first author in the study and an associate professor in Global Health and Epidemiology at UW.

Dr. Slyker adds, “Our results suggest that uncontrolled viral shedding of these common herpesviruses in HIV co-infected children may lead to a higher number of HIV latently infected cells that persist during antiretroviral treatment and are the major barrier to an HIV cure.” The authors discussed that, since both CMV and EBV infections elicit T cell activation and proliferation, coinfection with these viruses during PHI could either expand the pool of HIV target cells or stimulate HIV-infected T cells to proliferate. In summary, this work showed that early CMV and EBV infections could impact the size of the HIV reservoir in children, suggesting that controlling EBV and CMV infections could be a novel target to limit reservoir formation.

Slyker JA, Guthrie B, Pankau M, Tapia K, Wamalwa D, Benki-Nugent S, Ngugi E, Huang ML, Njuguna I, Langat A, John-Stewart G, & Lehman D. (2020). Cytomegalovirus and Epstein-Barr virus viremia are associated with HIV DNA levels in the reservoir of Kenyan infants on antiretroviral therapy. The Journal of infectious diseases, jiaa640. Advance online publication. https://doi.org/10.1093/infdis/jiaa640

This work was supported by grants from the National Institutes of Health, the UW Center for AIDS Research (CFAR), and the UW Global Center for Integrated Health of Women, Adolescents, and Children.