The presence of anti-Tat antibodies in HIV-infected individuals is associated with containment of CD4+ T-cell decay and viral load, and with delay of disease progression: results of a 3-year cohort study

Abstract

Background: Tat is a key HIV-1 virulence factor, which plays pivotal roles in virus gene expression, replication, transmission and disease progression. After release, extracellular Tat accumulates in tissues and exerts effects on both the virus and the immune system, promoting immune activation and virus spreading while disabling the host immune defense. In particular, Tat binds Env spikes on virus particles forming a virus entry complex, which favors infection of dendritic cells and efficient transmission to T cells via RGD-binding integrins. Tat also shields the CCR5-binding sites of Env rendering ineffective virus neutralization by anti-Env antibodies (Abs). This is reversed by the anti-Tat Abs present in natural infection or induced by vaccination.

Findings: Here we present the results of a cohort study, showing that the presence of anti-Tat Abs in asymptomatic and treatment-naïve HIV-infected subjects is associated with containment of CD4+ T-cell loss and viral load and with a delay of disease progression. In fact, no subjects with high anti-Tat Ab titers initiated antiretroviral therapy during the three years of follow-up. In contrast, no significant effects were seen for anti-Env and anti-Gag Abs. The increase of anti-Env Ab titers was associated with a reduced risk of starting therapy only in the presence of anti-Tat Abs, suggesting an effect of combined anti-Tat and anti-Env Abs on the Tat/Env virus entry complex and on virus neutralization.

Conclusions: Anti-Tat immunity may help delay HIV disease progression, thus, targeting Tat may offer a novel therapeutic intervention to postpone antiretroviral treatment or to increase its efficacy.

Figures

Figure 1

Kaplan-Meier curves, CD4+ T-cell number and viral load stratified by anti-Tat Abs. (A) Cumulative probability to remain naïve to therapy according to the presence (n = 20) or absence (n = 41) of anti-Tat Abs, and (B) for subjects with high titers of anti-Tat Abs (n = 11) versus subjects with low/no anti-Tat Abs (n = 50). (C) Baseline values and changes from baseline values of CD4+ T-cell counts and (D) viral load levels at years 1, 2 and 3, according to the presence or absence of anti-Tat Abs, respectively, in subjects naïve to therapy (anti-Tat Ab-positive n = 16 year 1, n = 10 year 2, n = 10 year 3; anti-Tat Ab-negative n = 32 year 1, n = 17 year 2, n = 9 year 3). A longitudinal analysis for data arising from repeated measures, adjusted for baseline values, was applied, using the generalized estimating equations method, where the measurements were assumed to be multivariate normal. Data are presented as mean values with standard error.

Figure 2

Changes over time of CD4+ T-cell number and viral load by anti-Tat Abs in individuals naïve to therapy. (A) CD4+ T-cell counts and (B) viral load in subjects who remained naive to therapy were analyzed over time, according to the presence or absence of anti-Tat Abs, by applying a random-effect regression model. The decrease from baseline of CD4+ T cells/μl was -1.1 (95% CI -3.7; 1.5) per month in the anti-Tat Ab-positive subjects and -5.9 (95% CI -8.7; -3.1, p < 0.0001) per month in the anti-Tat Ab-negative individuals, respectively. The difference between the coefficients of regression was statistically significant (p = 0.0060). Similarly, the increase of viral load was 0.003 log10 copies/ml (95% CI -0.004; 0.010) per month in anti-Tat Ab-positive patients and 0.015 (95% CI 0.009; 0.022, p < 0.0001) per month in anti-Tat Ab-negative subjects, respectively. The difference between the slopes was statistically significant (p = 0.0105). All longitudinal samples from 48 individuals were included in the analysis.