Breadth of neutralizing antibody response to human immunodeficiency virus type 1 is affected by factors early in infection but does not influence disease progression

Abstract

The determinants of a broad neutralizing antibody (NAb) response and its effect on human immunodeficiency virus type 1 (HIV-1) disease progression are not well defined, partly because most prior studies of a broad NAb response were cross-sectional. We examined correlates of NAb response breadth among 70 HIV-infected, antiretroviral-naïve Kenyan women from a longitudinal seroincident cohort. NAb response breadth was measured 5 years after infection against five subtype A viruses and one subtype B virus. Greater NAb response breadth was associated with a higher viral load set point and greater HIV-1 env diversity early in infection. However, greater NAb response breadth was not associated with a delayed time to a CD4(+) T-cell count of <200, antiretroviral therapy, or death. Thus, a broad NAb response results from a high level of antigenic stimulation early in infection, which likely accounts for prior observations that greater NAb response breadth is associated with a higher viral load later in infection.

FIG. 1.

Summary of the IC₅₀s and NAb response breadth scores of 70 plasma samples. The first column indicates the subject identifier of each plasma sample, and the next three columns indicate the env V1 to V5 subtype (available for 53/70 women), the set point viral load (available for 64 women), and the viral load at ∼5 ypi, when the NAb response breadth was measured. Data not available are indicated by a period. Each subsequent column shows the results with one panel virus (indicated at the top of the column). Results are the average of three experiments in which each plasma-virus pair was tested in duplicate. In the case of Q769 and Q259, two closely related viruses from the same individual were used in one (Q769.h5, Q259.d217) and two (Q769.b9, Q259.d226) of the three experiments. The IC₅₀ for each plasma-virus pair is the reciprocal dilution of plasma that led to a 50% reduction in infectivity, averaged across the three experiments. IC₅₀s are shown in gray scale to represent increasing neutralization sensitivity, with white for values of <100, light gray for values of >101 and <1,000, and dark gray for values of >1,001. Plasma-virus pairs in which 50% neutralization was not detected at the highest plasma dilution (1:50) are indicated by a pair of dashes. The NAb response breadth score for each plasma sample was calculated as follows. For each experiment, the median IC₅₀ for each virus (across all 70 plasma samples) was determined. Plasma samples were assigned a score of 1 for every virus against which their IC₅₀ was greater than the median IC₅₀, and the score was summed across all six viruses. The NAb response breadth scores that are shown here (and which were used for analysis) were calculated by taking the average response breadth score across the three independent experiments; they were not calculated from the average IC₅₀s shown.

FIG. 2.

Associations between NAb response breadth and viral load. In each plot, the NAb response breadth score is indicated on the y axis and the contemporaneous (∼5 ypi) viral load (a) or viral load set point (b) is indicated on the x axis. Each point represents one individual. The results of Spearman correlation analysis are shown above the plots.

FIG. 3.

Model of NAb response breadth in natural infection. Solid arrows indicate associations detected in this study, while dashed arrows indicate associations found in prior studies of the same cohort, and the crossed-out arrow indicates no association. Factors that contribute to greater NAb response breadth include the viral load set point and early env diversity, which have been found to be associated with one another in a prior study (31). Although NAb response breadth is associated with the chronic infection viral load in a univariate analysis, this is attributable to the viral load set point (no arrow depicted), and NAb response breadth does not affect disease progression.