Linking Susceptibility to Infectious Diseases to Immune System Abnormalities among HIV-Exposed Uninfected Infants

Abstract

HIV-exposed uninfected (HEU) infants experience increased overall mortality from infectious causes when compared to HIV-unexposed uninfected (HU) infants. This is the case in both the resource-rich and resource-limited settings. Here, we explore the concept that specific types of infectious diseases that are more common among HEU infants could provide clues as to the potential underlying immunological abnormalities. The most commonly reported infections in HEU vs. HU infants are caused by encapsulated bacteria, suggesting the existence of a less effective humoral (antibody, complement) immune response. Decreased transplacental transfer of protective maternal antibodies has consistently been observed among HEU newborns, suggesting that this may indeed be one of the key drivers of their susceptibility to infections with encapsulated bacteria. Reassuringly, HEU humoral response to vaccination appears to be well conserved. While there appears to be an increase in overall incidence of acute viral infections, no specific pattern of acute viral infections has emerged; and although there is evidence of increased chronic viral infection from perinatal transmission of hepatitis C and cytomegalovirus, no data exist to suggest an increase in adverse outcomes. Thus, no firm conclusions about antiviral effector mechanisms can be drawn. However, the most unusual of reported infections among the HEU have been opportunistic infections, suggesting the possibility of underlying defects in CD4 helper T cells and overall immune regulatory function. This may relate to the observation that the immunological profile of HEUs indicates a more activated T cell profile as well as a more inflammatory innate immune response. However, both of these observations appear transient, marked in early infancy, but no longer evident later in life. The causes of these early-life changes in immune profiles are likely multifactorial and may be related to in utero exposure to HIV, but also to increased environmental exposure to pathogens from sicker household contacts, in utero and postnatal antiretroviral drug exposure, and, in certain circumstances, differences in mode of feeding. The relative importance of each of these factors will be important to delineate in an attempt to identify those HEU at highest risk of adverse outcomes for targeted interventions.

Immunobiological aspects of vaccines in pregnancy: Maternal perspective

“…Studies from low and high income countries reported decreased transfer of maternal IgG in children born to HIV-infected mothers across multiple vaccine and pathogen-specific antigens [119,126,127]. This is particularly significant given the increased infectious morbidity and mortality observed in HIV-exposed uninfected as compared to HIV-unexposed infants [120,128]. This notion is supported by a recent study conducted in Belgium, showing an association between reduced transfer of maternal antibodies, as well as immune activation in the newborn, and risk of hospitalization for infection during the first months of life in HIV-exposed uninfected infants [127].…”

Opportunistic Infections

“…Although bacterial infections may be common to all children, the spectra of disease presentations are different and may be more severe in the HIV infected child. More current published data suggest that the HIV exposed uninfected infant has a different immunologic profile from the unexposed infant and hence predisposed to bacterial infections with encapsulated organisms [6].…”

Tuberculosis and HIV—An Update on the “Cursed Duet” in Children

“…exposure in utero (39). Therefore, we consider the term "latent" a misnomer as it implies inactivity rather than preclinical disease with a strong likelihood of progression to disease.…”