Characterization of HIV-1 subtype C envelope glycoproteins from perinatally infected children with different courses of disease.

Hong Zhang,Xiang He,Ruth M Ruprecht,Federico Hoffmann,Jun He,Charles D Mitchell,John T West,Guillermo Orti,Charles Wood,Chipepo Kankasa

doi:10.1186/1742-4690-3-73

Abstract

BackgroundThe causal mechanisms of differential disease progression in HIV-1 infected children remain poorly defined, and much of the accumulated knowledge comes from studies of subtype B infected individuals. The applicability of such findings to other subtypes, such as subtype C, remains to be substantiated. In this study, we longitudinally characterized the evolution of the Env V1–V5 region from seven subtype C HIV-1 perinatally infected children with different clinical outcomes. We investigated the possible influence of viral genotype and humoral immune response on disease progression in infants.ResultsGenetic analyses revealed that rapid progressors (infants that died in the first year of life) received and maintained a genetically homogeneous viral population throughout the disease course. In contrast, slow progressors (infants that remained clinically asymptomatic for up to four years) also exhibited low levels variation initially, but attained higher levels of diversity over time. Genetic assessment of variation, as indicated by dN/dS, showed that particular regions of Env undergo selective changes. Nevertheless, the magnitude and distribution of these changes did not segregate slow and rapid progressors. Longitudinal trends in Env V1–V5 length and the number of potential N-glycosylation sites varied among patients but also failed to discriminate between fast and slow progressors. Viral isolates from rapid progressors and slow progressors displayed no significant growth properties differences in vitro. The neutralizing activity in maternal and infant baseline plasma also varied in its effectiveness against the initial virus from the infants but did not differentiate rapid from slow progressors. Quantification of the neutralization susceptibility of the initial infant viral isolates to maternal baseline plasma indicated that both sensitive and resistant viruses were transmitted, irrespective of disease course. We showed that humoral immunity, whether passively acquired or developed de novo in the infected children, varied but was not predictive of disease progression.ConclusionOur data suggest that neither genetic variation in env, or initial maternal neutralizing activity, or the level of passively acquired neutralizing antibody, or the level of the de novo neutralization response appear to be linked to differences in disease progression in subtype C HIV-1 infected children.

Highlights

The causal mechanisms of differential disease progression in human immunodeficiency virus type 1 (HIV-1) infected children remain poorly defined, and much of the accumulated knowledge comes from studies of subtype B infected individuals
Characteristics of seven HIV-1 infected children The subjects analyzed in this study were part of a mother/ infant cohort followed for HIV-1 infection
There are reports that higher dN/dS ratios are linked with longterm survival [20,55]; we found that the highest dN/dS value was estimated for envelopes from a rapid progressor child at the final timepoint prior to death (Table 1, 8-month sample from infant 1449)

Summary

Introduction

The causal mechanisms of differential disease progression in HIV-1 infected children remain poorly defined, and much of the accumulated knowledge comes from studies of subtype B infected individuals. The survival time for HIV-1 infected children is shorter, on average, than that of infected adults [21], and could be explained by a number of factors including: immaturity of their immune system [21], failure to acquire passive immunity from the mother, timing of transmission [2,22,23] or maternal HIV-1 RNA levels [24,25] Other factors, such as viral replication rate, syncytium-induction, CD4+ T-cell depletion, and thymic infection have been shown to associate with early onset of pediatric AIDS [25,26,27,28]. Humoral immunity has been suggested to play a role in the disease for both adults and children, but the function of neutralizing antibody responses in delaying disease progression or preventing HIV-1 infection, especially in children, has not been fully established [5,19,20,31,32,33]

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