Loss of Preexisting Immunological Memory Among Human Immunodeficiency Virus-Infected Women Despite Immune Reconstitution With Antiretroviral Therapy

Abstract

Background: It is unclear whether human immunodeficiency virus (HIV) infection results in permanent loss of T-cell memory or if it affects preexisting antibodies to childhood vaccinations or infections.

Methods: We conducted a matched cohort study involving 50 pairs of HIV-infected and HIV-uninfected women. Total memory T-cell responses were measured after anti-CD3 or vaccinia virus (VV) stimulation to measure T cells elicited after childhood smallpox vaccination. VV-specific antibodies were measured by means of enzyme-linked immunosorbent assay (ELISA).

Results: There was no difference between HIV-infected and HIV-uninfected study participants in terms of CD4+ T-cell responses after anti-CD3 stimulation (P = .19) although HIV-infected participants had significantly higher CD8+ T-cell responses (P = .03). In contrast, there was a significant loss in VV-specific CD4+ T-cell memory among HIV-infected participants (P = .04) whereas antiviral CD8+ T-cell memory remained intact (P > .99). VV-specific antibodies were maintained indefinitely among HIV-uninfected participants (half-life, infinity; 95% confidence interval, 309 years to infinity) but declined rapidly among HIV-infected participants (half-life; 39 years; 24-108 years; P = .001).

Conclusions: Despite antiretroviral therapy-associated improvement in CD4+ T-cell counts (nadir, <200/μL; >350/μL after antiretroviral therapy), antigen-specific CD4+ T-cell memory to vaccinations or infections that occurred before HIV infection did not recover after immune reconstitution, and a previously unrealized decline in preexisting antibody responses was observed.

Keywords: ART; HIV; antiretroviral therapy; immunological memory; smallpox; vaccination.

Figure 1.

Cytokine production by CD4⁺ and CD8⁺ T cells after polyclonal anti-CD3 stimulation. A, B, Frequency of functional memory CD4⁺ (A) and CD8⁺ (B) T cells from human immunodeficiency virus (HIV)–infected and HIV-uninfected participants that respond directly to anti-CD3 stimulation by simultaneously producing 2 antiviral cytokines, interferon (IFN) γ and tumor necrosis factor (TNF) α, as determined by intracellular cytokine staining and flow cytometry. The mean frequency of responsive T cells is plotted, with error bars representing 95% confidence intervals. C, D, Proportions of anti-CD3-responsive CD4⁺ (C) and CD8⁺ (D) T cells that produce both IFN-γ and TNF-α (IFN-γ ⁺TNF-α ⁺) or that produce only IFN-γ (IFN-γ ⁺TNF-α ⁻) or only TNF-α (IFN-γ ⁻TNF-α ⁺) after direct ex vivo stimulation with anti-CD3. All values are background subtracted (medium alone), and P values were determined by means of Wilcoxon signed rank test.

Figure 2.

Quantitation of vaccinia virus (VV)–specific CD4⁺ and CD8⁺ T-cell memory. A, B, The quantitation of VV-specific CD4⁺ T cells (A) and the percentage of human immunodeficiency virus (HIV)–infected and HIV-uninfected participants with detectable VV-specific CD4⁺ memory T cells (B) were determined after direct ex vivo stimulation with VV. C, D, The frequency of VV-specific CD8⁺ T-cell responses (C) and the percentage of HIV-infected and HIV-uninfected participants with detectable VV-specific CD8⁺ T cells (D) were determined after stimulation with VV in the same assays. A frequency of ≥20 virus-specific interferon γ ⁺ tumor necrosis factor α ⁺ T cells per million T cells is considered a positive antiviral T-cell response. P values were determined using the exact McNemar test. Abbreviation: LOD; limit of detection.

Figure 3.

Longitudinal analysis of vaccinia virus (VV)–specific antibody responses. A, Longitudinal antibody responses of individual human immunodeficiency virus (HIV)–infected participants (red or yellow lines) and HIV-uninfected participants (blue lines) as a function of age. The dashed line indicates the limit of detection (LOD; 200 enzyme-linked immunosorbent assay [ELISA] units) and values below the LOD are considered equivocal and excluded from analysis. B, Estimated half-life of VV-specific antibody responses based on the individual slopes of each longitudinal antibody response. These values were calculated using the least squares method to show the overall distribution of VV-specific antibody decay rates (percentage change in antibody levels). The mean estimated antibody half-life of each group is shown with error bars representing 95% confidence intervals, and statistical comparisons between groups were determined using a longitudinal mixed-effects model. A mean of 9 serum samples per HIV-infected participant and a mean of 9 serum samples per HIV-uninfected participant were examined over a median period of 17.4 to 17.8 years of time for HIV-infected and HIV-uninfected participants, respectively. Two HIV-infected participants became VV seronegative so quickly that there were not ≥3 data points above the LOD (the minimum for accurate half-life determinations); therefore, their data is presented here graphically but was excluded from the overall group antibody half-life estimation and statistical comparisons. The HIV-infected individuals with the most rapid loss of virus-specific antibodies are shown as yellow lines (A) or yellow-filled symbols (B).