CD8+ T-cell-mediated suppression of HIV replication in the first year of life: association with lower viral load and favorable early survival.

OBJECTIVE AND DESIGN: To study the role and development of non-cytotoxic CD8+ T-cell-mediated suppression of HIV replication in early perinatal HIV infection in a prospective study of vertically infected infants. CD8 T-cell-mediated HIV suppression was measured several times during the first year of life and correlated with viral load, cytotoxic T-cell (CTL) activity, in vitro antibody production (IVAP) and clinical outcome. METHODS: CD8+ T-cell-mediated HIV suppression was measured by comparing the amount of p24 antigen produced by endogenously infected lymphocytes with cultures of the same number of autologous CD4+ T cells from which CD8+ cells were removed immunomagnetically. CD8 viral suppressive activity (VSA) was defined as a > or = 50% reduction in p24 antigen in the cultures containing CD8+ cells. RESULTS: CD8+ T-cell-mediated HIV VSA was detected in 11/16 infants in the first year of life, including six/nine infants studied before 6 months and as early as 3 weeks of age. Infants who demonstrated CD8 VSA had a lower early peak and 6-month 'setpoint' plasma HIV RNA concentration than infants who lacked CD8 VSA [1.51 versus 4.94 and 0.094 versus 0.639 x 10(6) copies/ml, respectively, and higher CD4 percentage at 1 year of age. Survival of infants lacking CD8 VSA (four/six were rapid progressors) was shorter than for infants who demonstrated CD8 VSA (none out of 10 were rapid progressors). CD8 VSA was present before CTL and before or at the same time as IVAP in two of two and 11 of 14 infants studied, respectively. CONCLUSIONS: CD8+ T-cell-mediated VSA can be demonstrated in a large proportion of HIV-infected infants early in the course of infection. This non-cytolytic HIV-suppressive immune response appears to play an important protective role in the early control of perinatal HIV infection at a time when other immune responses are either absent or deficient.

Effects of antiviral therapy on the production of anti-human immunodeficiency virus-specific immunoglobulin in infants and children.

The effect of zidovudine therapy on human immunodeficiency virus (HIV)-specific antibody production was studied in 64 HIV-1-infected infants and children > 6 months old. HIV-specific in vitro antibody production (IVAP) was measured in cultures of peripheral blood mononuclear cells (PBMC). IVAP decreased in 85% of children after zidovudine was initiated (mean decline, 1 log within 2 months). Effects were seen as early as 1 week after starting zidovudine. No change in IVAP was seen in children not treated. In comparison, plasma core (p24) antigen levels declined and CD4+ lymphocytes increased in only 42% and 52%, respectively, of treated subjects. Thus, the production of antibody to HIV-1 decreases rapidly after the initiation of antiretroviral therapy. This response to therapy may provide a simple and sensitive method of monitoring antiretroviral therapy.

A novel detection assay for the early diagnosis of HIV-1 infected infants.

This investigation compares the results of a new method of diagnosing HIV-1 infection in infants < 6 months of age with currently employed techniques including cocultivation, the polymerase chain reaction (PCR), serum p24 antigen, and in vitro antibody production (IVAP) measurements. The new method, called in vitro antigen (IVAG), measures p24 antigen released into culture supernatants of peripheral blood mononuclear cells that are incubated with Epstein-Barr virus (EBV). No activated donor lymphocytes or interleukin 2 (IL-2) are added to the culture. Using this technique, HIV-1 infection was detected in 15 of 17 HIV-1-infected infants < 2 months of age, including 3 of 7 infants tested at birth, and 15 of 15 HIV-1-infected infants between 2 and 6 months of age. None of 83 determinations of 15 uninfected infants were positive. These results were found to be comparable to results obtained by the traditional cocultivation technique and the polymerase chain reaction. Because of its simplicity and reduced cost, this sensitive and specific assay could be a valuable addition to the current methods of diagnosis of HIV-1 infection in young infants.

Ontogeny of anti-human immunodeficiency virus (HIV) antibody production in HIV-1-infected infants.

The early serologic response of infants to infection with human immunodeficiency virus type 1 (HIV-1) is normally obscured by the presence of transplacentally acquired maternal HIV antibody. By measuring HIV antibody produced in vitro by lymphocytes isolated from peripheral blood of infants and children of HIV-1-infected mothers, we have been able to study the natural acquisition of humoral immunity to perinatal HIV-1 infection. One hundred ninety-seven infants of HIV-1-infected women were studied prospectively and longitudinally from birth. In the neonatal period, infected infants produced only small amounts of HIV-specific IgG antibodies to a restricted number of antigens. The amount of immunoglobulin to HIV-1 and the number of HIV-1 antigens recognized increased with age. After 6 months of life 85% of infected infants made detectable antibody to two or more viral proteins. Antibody to gp160 appeared first and was the most frequently found at all ages, followed by antibody to the envelope proteins gp120 and gp41. The amount of HIV antibody produced correlated positively with the percentage of CD4+ T lymphocytes in peripheral blood. This assay provides a method of studying the immunogenicity of vaccines against HIV-1 in HIV-1-infected infants and of assessing the effect of early therapeutic interventions on the humoral response to HIV-1.