Antiretroviral therapy initiated during acute infection in women with HIV-1 clade C reduces anti-Tat antibody production and lowers CD8+ T cell activation

Abstract

Introduction: The HIV-1 Tat protein is essential for virus replication and spread and is therefore a potential target for anti-HIV therapy. Anti-Tat antibodies have been shown to slow HIV disease progression and improve antiretroviral therapy (ART) efficacy. Long-term ART results in partial reconstitution of the immune system in people living with HIV-1 (PLWH) who start treatment in the chronic phase of infection, but the impact of ART initiation in the acute phase of infection is less studied. In this study, we investigate the effect of initiating ART in acute phase infection on the production of anti-Tat antibodies and on T-cell activation.

Methods: Anti-Tat IgA, IgG, and IgM titres were evaluated longitudinally by enzyme-linked immunosorbent assay in plasma samples collected from 34 women who started ART immediately following the detection of acute HIV-1 infection. Total HIV-1 DNA measurements were performed by droplet digital PCR from total peripheral blood mononuclear cells at 1-year post ART initiation. T-cell activation was assessed longitudinally by analysis of the expression of HLA-DR and CD38 on CD4+ and CD8+ T-cells using flow cytometry. We also explored the association between anti-Tat antibody titres and CD4+ T-cell counts.

Results: The data showed that anti-Tat IgG and IgM titres had decreased significantly after 12 months of treatment (p=0.0001) with no correlation between anti-Tat IgA, IgG or IgM and CD4+ T-cell counts (r= -0.09 to 0.2, p>0.05). There was no correlation between anti-Tat antibody levels and total HIV-1 DNA levels at ART initiation (r= 0.2143, p= 0. 6191) or after 12 months post-ART (r= -0. 2857, p= 0, 5008). There was a significant decrease in CD8+ T-cell activation between the baseline (day 1 on ART) and 12 months post-ART (p=0.0129).

Discussion and conclusion: These findings suggest early initiation of ART reduces the production of anti-Tat antibodies and reduces CD8+ T-cell activation. Further studies on the impact of early ART on antiviral immune responses are needed and may shed light on mechanisms of optimal immune reconstitution and reservoir control in PLWH.

Keywords: ART; ELISA - enzyme-linked immunosorbent assay; HIV-1 Tat; Tat antibodies; early treated HIV.

Figure 1

There were 34 acute treated participants analyzed, with samples collected on the day of ART initiation (day 1) and at 3 and 12 months post-ART. The controls were HIV-1 chronically infected ART naïve participants (n=10) and HIV-1 uninfected participants (n=10). Samples were obtained once for the latter 2 groups. The various assays performed at each timepoint are shown by the orange (anti-Tat antibodies), green (total HIV-1 DNA) and purple arrows (markers of T-cell activation).

Figure 2

Longitudinal analyses of anti-Tat antibody isotypes in PLWH who initiated ART during acute infection, with HIV-1 negative and chronically infected ART-naïve samples as negative and positive controls respectively. Antibody isotypes compared were (A) IgA, (B) IgG and (C) IgM. Y-axes represent anti-Tat antibody titers, and X-axes represent different post-ART time points. Highlighted in yellow are HIV-1 uninfected negative controls, followed by acute treated participants at day 1 (blue), 3 months (red) and 12 months (green) post-ART and chronically infected ART-naïve participants (purple). The straight line within the data points represents the median value. Statistical comparisons were made using the Mann-Whitney test. * represent the significant p value.

Figure 3

T-cell activation frequencies in HIV-1 uninfected controls and in participants who initiated ART in acute HIV-1 infection. (A) The percentages of CD4+ T-cells expressing CD38 and HLA-DR and (B) The percentages of CD8+ T-cells expressing CD38 and HLA-DR. The T-cell activation frequencies are shown on the Y-axes, while the treatment duration is shown by X-axes. Shapes highlighted in blue, red, green and black represent HIV-1 negative, day 1, 3 months and 12 months of infection, respectively. Statistical comparisons were performed using the Mann-Whitney test.