Early highly active antiretroviral therapy for acute HIV-1 infection preserves immune function of CD8+ and CD4+ T lymphocytes

Abstract

Highly active antiretroviral therapy (HAART) has been advocated for the management of primary HIV-1 infection without clear understanding of its immunological effects. Here, we demonstrate that early use of HAART during primary infection preserves HIV-specific CD8(+) T cells physically and functionally while HIV-specific T cell help is sustained. We also show that even transient administration of HAART at seroconversion can preserve HIV-specific immunity. In contrast, delayed initiation of HAART is associated with a progressive loss of HIV-specific CD8(+) T cells and absent HIV-specific T cell help. These results imply that HIV-specific T help is damaged during primary HIV-1 infection. Early drug treatment, which preserves this immunity, also preserves HIV-specific CD8(+) T cells. These results have implications for understanding the early pathogenesis of HIV-1 infection and suggest that acute HIV infection should be treated aggressively and as early as possible.

Figure 1

CTL activity of SC2, SC10, and SC12 soon after infection. Chromium release assays were performed with bulk-cultured PBL of SC2 at 22 DFOSx (A), SC10 at 36 DFOSx (B), and SC12 at 30 DFOSx (C). HLA B8-expressing target cells (B-LCL) were labeled with the indicated HLA B8-binding peptides, and bulk-cultured PBL were used at an effector to target ratio of 60:1 in B, and as indicated in A and C. Spontaneous release was below 20%.

Figure 2

The immune response during and after HIV infection. Thawed, uncultured PBL of SC2 (A), SC9 (B), SC19 (C), SC10 (D), SC12 (E), SC15 (F), SC11 (G), and SC18 (H) were studied. For viral load (●), data points on the baseline were below the limit of detection of the assay (<400 copies per ml). PBL were stained with tetramers specific for the HLA B8-restricted epitope FLK (□). Median values are shown and expressed as percentage of total CD8⁺ T cells. Initiation and duration of HAART is indicated by the black bar on top of the upper panel. IFN-γ-ELISPOT analysis is shown in the lower panels and the time of analysis is indicated by the arrows pointing to the time axis (x axis). Specific IFN-γ release indicated the number of spots induced by peptide stimulation (peptides are indicated at the x axis of the ELISPOT panels) divided by the number of spots observed without antigen stimulation. In each patient, 9–20 peptides were used to screen CD8⁺ T cell responses in each sample, but only those peptides that stimulated a response at some point in the study are shown. Consistently negative responses are not plotted.

Figure 3

HIV-specific CD4⁺ T cell responsiveness. CD8-depleted PBL of SC2 (A), SC19 (B), SC10 (C), SC12 (D), SC18 (E), and SC11 (F) were stimulated with the indicated HIV-derived antigens, and specific IFN-γ secretion is shown as the number of spots induced by antigen stimulation (antigens are indicated at the x axis of the ELISPOT panels) divided by the number of spots observed without peptide stimulation. Values in parentheses indicate the months following onset of symptoms when cells were sampled and the assay performed.