HIV-1 antigen-specific and -nonspecific B cell responses are sensitive to combination antiretroviral therapy

Abstract

We studied how combination antiviral therapy affects B cell abnormalities associated with HIV-1 infection, namely elevated circulating immunoglobulin (Ig)G antibody-secreting cell (ASC) frequencies and hypergammaglobulinemia. Within a few weeks of starting antiviral therapy, there is a marked decline in IgG-ASC frequency in both acutely and chronically infected people, whereas the hypergammaglobulinemia often present during chronic infection is more gradually resolved. These reductions are sustained while HIV-1 replication is suppressed. HIV-1 antigen-specific B cell responses are also affected by therapy, manifested by a rapid decline in circulating gp120-specific ASCs. Anti-gp120 titers slowly decrease in chronically infected individuals and usually fail to mature in acutely infected individuals who were promptly treated with antiretroviral therapy. Long-term nonprogressors have high titer antibody responses to HIV-1 antigens, but no detectable gp120-specific IgG-ASC, and normal (or subnormal) levels of total circulating IgG-ASC. Overall, we conclude that HIV-1 infection drives B cell hyperactivity, and that this polyclonal activation is rapidly responsive to decreases in viral replication caused by combination antiviral therapy.

Figure 1

Baseline ASC frequencies and spontaneous IgG secretion in cohort 1. ASC frequencies were determined in freshly isolated PBMCs from uninfected individuals (n = 6) and from three groups of individuals who had been infected with HIV-1 for varying lengths of time. All study subjects were drug naive at the time of assay except for one individual whose baseline value could only be determined after 1 wk of therapy (indicated by asterisk). ELISPOT plates were coated with either (a) anti–human IgG Fc to detect IgG-ASCs or (b) anti–human IgM Fc to detect IgM-ASCs. (c) Spontaneous IgG secretion after 8 d of culture was also measured by ELISA for the same individuals. Bars represent the median values for each group.

Figure 2

Correlation between the number of IgG-ASCs and plasma viral load. The 18 drug-naive HIV-1–infected individuals from cohort 1 were studied as in Fig. 1. Viral load was determined using the bDNA assay and IgG-ASC frequencies were determined by ELISPOT.

Figure 3

Longitudinal analysis of the effects of antiretroviral therapy on IgG-ASC frequency. Four acutely infected and six chronically infected individuals from cohort 1 were studied. Baseline data were not available from subjects no. 909 and no. 896, so the first data points are from wk 1 and 3 after therapy was initiated, respectively.

Figure 4

Effects of antiretroviral therapy on IgG-ASC frequencies and viral load. Longitudinal IgG-ASC and viral load data for (a) four acutely and (b) six chronically infected individuals from cohort 1. Antiviral therapy was initiated on day 0. Baseline ASC data were not available from subjects no. 909 and no. 896, so the first data points are from wk 1 and 3 after therapy was initiated, respectively. The half-lives of IgG-ASCs are indicated on the figures for nine of the individuals. Note that, unlike in Fig. 3, the IgG-ASC frequencies are plotted on different scales for each individual, in order to depict the rates of change of ASC frequency with maximum clarity.

Figure 4

Effects of antiretroviral therapy on IgG-ASC frequencies and viral load. Longitudinal IgG-ASC and viral load data for (a) four acutely and (b) six chronically infected individuals from cohort 1. Antiviral therapy was initiated on day 0. Baseline ASC data were not available from subjects no. 909 and no. 896, so the first data points are from wk 1 and 3 after therapy was initiated, respectively. The half-lives of IgG-ASCs are indicated on the figures for nine of the individuals. Note that, unlike in Fig. 3, the IgG-ASC frequencies are plotted on different scales for each individual, in order to depict the rates of change of ASC frequency with maximum clarity.

Figure 5

Effects of antiretroviral therapy on HIV-1–specific antibody titer and ASC frequency. Depicted are plasma anti-gp120 (•) and anti-p24 (▴) midpoint antibody titers and gp120- (○) and p24-specific (▵) ASC frequencies, in (a) four acutely infected and (b) six chronically infected individuals from cohort 1. Antiviral therapy was initiated on day 0. The first data point for subject no. 909 is from 1 wk after therapy began. Fresh PBMCs were not available from individual no. 896 on day 0 for ASC frequency determination.

Figure 5

Effects of antiretroviral therapy on HIV-1–specific antibody titer and ASC frequency. Depicted are plasma anti-gp120 (•) and anti-p24 (▴) midpoint antibody titers and gp120- (○) and p24-specific (▵) ASC frequencies, in (a) four acutely infected and (b) six chronically infected individuals from cohort 1. Antiviral therapy was initiated on day 0. The first data point for subject no. 909 is from 1 wk after therapy began. Fresh PBMCs were not available from individual no. 896 on day 0 for ASC frequency determination.

Figure 6

Relationship between circulating IgG-ASC frequencies and plasma antibody titers. (a) Baseline IgG-ASC frequencies are compared with plasma IgG concentrations; (b) circulating anti-gp120 IgG-ASC frequencies are compared with anti-gp120 antibody titers; for 18 members of cohort 1, including 4 acutely (▴) and 11 chronically (•) infected individuals and 3 LTNPs (○). See text for information on asterisked individual.

Figure 7

Effect of combination antiviral therapy on plasma IgG concentration and specific antibody titers in cohort 2. Four chronically infected individuals were treated for ∼1 yr. Plasma anti-gp120 titers (•), anti-p24 titers (▴), and total plasma IgG concentrations (+) are shown. Estimated half-lives for the decay in excess total IgG, anti-gp120, and anti-p24 and for each individual were, respectively: no. 1007, 12, 7, and 9 wk; no. 1004, 9 and 15 wk; no. 1010, 4, 21, and 9 wk; no. 1013, 6, 16 and not applicable (no anti-p24 titer).