The identification of a way to single out those HIV+ infants at highest risk for the rapid and aggressive development of AIDS means that doctors may now target these babies for early, powerful therapies, report Emory University researchers in this week's New England Journal of Medicine.
Infants who test positive for HIV can generally be divided into two groups: those in whom AIDS symptoms develop quickly and aggressively -- within the first one to two years of life -- and those in whom symptoms may not appear for a number of years. Until now, doctors have not known conclusively how to predict which HIV+ infants will fall into which category.
Thymus dysfunction was common to the majority of HIV+ infants whose AIDS symptoms progressed rapidly, reports Athena P. Kourtis, M.D., Ph.D., fellow; Andre J. Nahmias, M.D., M.P.H., director, Division of Infectious Diseases, Epidemiology and Immunology, Department of Pediatrics, Emory University School of Medicine; and their colleagues, in their study of 232 infants below six months of age. While the thymus organ, located in the chest, becomes virtually nonfunctional in older age, it serves the important function in children of producing T lymphocyte immune cells. In particular, it produces the CD4+ helper T cells that are depleted by the AIDS virus. It also produces CD8+ cytotoxic T cells. Both types of cells are involved in resistance to HIV, as well as to many other microorganisms.
The researchers postulated that certain strains of the AIDS virus not only deplete mature CD4+ and CD8+ T cells in infants, but also inhibit production of these cells by damaging the thymus. Thus, certain infants would exhibit particularly low levels of CD4+ and CD8+ T cells -- and would develop AIDS symptoms sooner. This tendency to delete both types of T cells is in contrast to what occurs in most other HIV-infected children or adults; usually when the number of CD4+ T cells decreases, the number of CD8+ T cells increases.
An important part of the study was the team's comparison of infants with acquired immune deficiency from HIV to infants with a type of congenital immune deficiency known as the DiGeorge syndrome. Children with DiGeorge syndrome have thymic defects and characteristically low CD4+ and CD8+ T cell counts, as well as low CD5+ B cells. These B cells comprise the majority of immunoglobulin-producing B lymphocytes during gestation and infancy.
The team did indeed find that the number of CD4+ T cells in the 17 HIV-infected infants they characterized with a thymic-defect profile averaged 536 cells per mm3 compared with 2,139 cells per mm3 in 42 HIV-infected infants without the profile and with 3,142 cells per mm3 in 168 control infants who were exposed to, though not infected with, HIV. The team found a similar distribution of CD8+ T cells among the three patient groups: 512 cells per mm3 among the HIV-infected infants with thymus defect profiles compared to 1,214 cells per mm3 among the HIV-infected without the profile and 1,191 cells per mm3 among HIV-exposed controls.
The researchers estimate this subgroup of HIV-infected infants represents about 15 percent of all HIV-infected children. They found that 82 percent of infants in the thymic-defect group would develop AIDS before their first birthday and 38 percent would die; 96 percent would develop AIDS before their second birthday and two-thirds would die. This compares with 34 percent of infants in the no-thymic-defect group developing AIDS by two years and 3 percent dying. The researchers also report that infants in the thymic-defect group were more likely to show abnormalities not only in their cell-mediated immunity but also in their immunoglobulin and antibody production (humoral immunity).
"In this study, we have identified a subpopulation of HIV-infected infants with an immunophenotype resembling that of patients with the DiGeorge syndrome," the authors report. "Our findings suggest that the pathogenesis of disease in this group of infants may involve HIV-induced dysfunction of the thymus...
"Thus, the bimodal pattern of progression in pediatric AIDS may largely be explained by differences in the potential of (certain) HIV strains (with particular affinity to the thymus and which can cross the placenta during gestation) to cause early thymic disruption... "In addition to their pathogenetic importance, our findings have clinical implications that include the need for prompt identification of patients in whom AIDS progresses early and who have the thymic-defect profile," the authors report.
High-risk infants may be identified currently by blood test measurements of the joint distribution of their CD4+ and CD8+ T cells counts, as well as by obtaining CD5+ B cell counts, as early after birth as possible. Newer tests being developed by the Emory group involving the virus may provide other, even earlier, methods of identification.
"The recent recommendations (made by the U.S. Centers for Disease Control and Prevention) for early prophylaxis against P. carinii pneumonia in all HIV-exposed children may prove particularly beneficial in children under the age of six months," the authors conclude. "Therapeutic approaches will need to be more aggressive among these infants, with earlier use of antiviral agents and perhaps even immune reconstitution with thymic transplantation (currently being explored by the Emory group)."
Other Emory authors of the study included Christian Ibegbu, Ph.D.; Francis K. Lee, Ph.D.; Mary K. Sawyer, M.D.; and Steven Nesheim, M.D., all of the Division of Infectious Diseases, Epidemiology and Immunology of Emory's Department of Pediatrics, and W. Scott Clark, Ph.D., of Emory's Rollins School of Public Health.
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