A longitudinal assessment of autologous neutralizing antibodies in children perinatally infected with human immunodeficiency virus type 1

Abstract

The evolution of autologous neutralizing antibodies to sequential human immunodeficiency virus type 1 (HIV-1) isolates was studied in a population of 16 children who were perinatally infected with human immunodeficiency virus type 1. The cohort included seven children with rapid disease progression (RP) and nine who had nonrapid disease progression (NRP). Four of the NRP after 6 months of age harbored viruses that could be neutralized by antibodies found in autologous contemporaneous plasma (titers up to 1:640) while the majority of longitudinally collected viruses from five NRP were resistant to neutralization with contemporaneous plasma. Because of their shorter survival, only five of the RP had studies after 6 months of age; three of the five had neutralizing antibodies to contemporaneous virus isolates and the highest titers were 1:20. The highest titers in RP (up to 1:160) occurred in specimens obtained prior to 6 months of age but these were most likely of maternal origin. Most isolates that were not neutralized by contemporaneous plasma could be neutralized using noncontemporaneous plasma obtained months to years after the virus isolates. These autologous noncontemporaneous neutralizing antibodies persisted for years, had titers that were higher to viruses isolated at younger ages, and were generally more potent in children with NRP than RP. Demonstration of neutralizing antibodies to viruses previously resistant to neutralization by contemporaneous plasma suggests a continuous evolution of virus variants in vivo that are able to escape the effect of neutralizing antibodies.

Neutralizing antibody responses drive the evolution of human immunodeficiency virus type 1 envelope during recent HIV infection

“…Because of the similar rates of mounting of neutralizing antibody responses and viral escape from these responses, the titers of neutralizing antibody remain low and constant for matched plasma and virus samples, an example of ''Red Queen'' evolutionary dynamics (65). Viral loads remain relatively constant throughout the period of escape, consistent with mathematical models (42) and data from HIV-infected children (36) and HIV-infected hu-PBL-SCID mice (66). Hence, neutralizing antibody responses exert ''soft'' selection pressure (67), by affecting the relative fitness of different strains present in the viral quasispecies.…”

“…Evolution of escape to cellular immune responses may also play a role in driving the rapid divergence of env, although cellular responses may be stronger and͞or more common to other genes such as gag, nef, and tat, especially during recent HIV infection (30)(31)(32). In contrast, selection by neutralizing antibody responses has been shown to result in rapid, continuous in vivo evolution of viral escape at the phenotypic level (33)(34)(35)(36), and therefore may contribute to the rapid evolution of HIV-1 envelope.…”

Breadth of Neutralizing Antibody Response to Human Immunodeficiency Virus Type 1 Is Affected by Factors Early in Infection but Does Not Influence Disease Progression

“…Our results from a longitudinal study of a seroincident cohort strengthen prior evidence that NAbs do not contribute significantly to the control of HIV-1 infection (8,12,33). A possible explanation for the lack of association between a broad NAb response and an improved clinical outcome is that antigenic stimulation, although important for the generation of a broad NAb response, may actually impair other immune responses.…”

Comparison of Heterologous Neutralizing Antibody Responses of Human Immunodeficiency Virus Type 1 (HIV-1)- and HIV-2-Infected Senegalese Patients: Distinct Patterns of Breadth and Magnitude Distinguish HIV-1 and HIV-2 Infections

“…Additionally, some studies suggest that potent heterologous neutralizing antibody responses contribute to the control of HIV-1 in patients classified as long-term nonprogressors (12,13,33,38), although other studies have failed to replicate these findings (7,10,21,26). Most individuals recently infected with HIV-1 mount a vigorous neutralizing antibody response directed against autologous virus; however, antibody escape often emerges during early infection (3,5,18,34,42,51). By contrast, neutralizing antibody responses to heterologous primary isolates or to laboratory strains have been shown to be negligible or nonexistent during the first year or two of HIV-1 infection (1,32,34,42).…”