Neutralizing antibodies associated with viremia control in a subset of individuals after treatment of acute human immunodeficiency virus type 1 infection

Abstract

Immediate treatment of acute human immunodeficiency virus type 1 (HIV-1) infection has been associated with subsequent control of viremia in a subset of patients after therapy cessation, but the immune responses contributing to control have not been fully defined. Here we examined neutralizing antibodies as a correlate of viremia control following treatment interruption in HIV-1-infected individuals in whom highly active antiretriviral therapy (HAART) was initiated during early seroconversion and who remained on therapy for 1 to 3 years. Immediately following treatment interruption, neutralizing antibodies were undetectable with T-cell-line adapted strains and the autologous primary HIV-1 isolate in seven of nine subjects. Env- and Gag-specific antibodies as measured by enzyme-linked immunosorbent assay were also low or undetectable at this time. Despite this apparent poor maturation of the virus-specific B-cell response during HAART, autologous neutralizing antibodies emerged rapidly and correlated with a spontaneous downregulation in rebound viremia following treatment interruption in three subjects. Control of rebound viremia was seen in other subjects in the absence of detectable neutralizing antibodies. The results indicate that virus-specific B-cell priming occurs despite the early institution of HAART, allowing rapid secondary neutralizing-antibody production following treatment interruption in a subset of individuals. Since early HAART limits viral diversification, we hypothesize that potent neutralizing-antibody responses to autologous virus are able to mature and that in some persons these responses contribute to the control of plasma viremia after treatment cessation.

FIG. 1

Cases where autologous neutralizing-antibody levels correlated with viremia control following treatment interruption. The HIV-1 RNA level in plasma was measured at closely spaced intervals, usually every 3 to 7 days, during the periods of treatment and treatment interruption. Neutralizing-antibody levels were measured at various intervals while the subjects remained off therapy. Intervals when the subjects were on therapy are shaded. Plasma HIV-1 RNA levels (copies per milliliter) are shown as open circles, where a value of 5,000 is indicated by a horizontal dashed line. Titers of neutralizing antibodies are shown as solid circles (autologous virus), solid squares (HIV-1_MN), and solid triangles (HIV-1_IIIB). Titers of neutralizing antibodies that were below the limit of detection (<1:4 for autologous viruses and <1:20 for HIV-1_MN and HIV-1_IIIB) were assigned a value of 2. It should be noted that neutralization assays were performed with all viruses for each plasma sample, such that negative values at early time points overlap in the figure.

FIG. 2

Cases where autologous neutralizing-antibody levels did not correlate with viremia control following treatment interruption. Plasma RNA and neutralizing-antibody levels were assessed at intervals described in the legend to Fig. 1. Symbols are as in Fig. 1.

FIG. 3

ELISA reactivity over time in subjects receiving HAART. Plasma samples were assessed at multiple time points for reactivity to MN_gp120 and IIIB_p24. Intervals when subjects were on therapy are shaded. Anti-Env antibodies are shown as solid circles; anti-Gag antibodies are shown as open circles.

FIG. 4

Proposed model for a secondary neutralizing-antibody response following treatment interruption in a subset of study subjects.