Anti-Tat Immunity in HIV-1 Infection: Effects of Naturally Occurring and Vaccine-Induced Antibodies Against Tat on the Course of the Disease

Aurelio Cafaro, Antonella Tripiciano, Orietta Picconi, Cecilia Sgadari, Sonia Moretti, Stefano Buttò, Paolo Monini, Barbara Ensoli, Aurelio Cafaro, Antonella Tripiciano, Orietta Picconi, Cecilia Sgadari, Sonia Moretti, Stefano Buttò, Paolo Monini, Barbara Ensoli

Abstract

HIV-1 Tat is an essential protein in the virus life cycle, which is required for virus gene expression and replication. Most Tat that is produced during infection is released extracellularly and it plays a key role in HIV pathogenesis, including residual disease upon combination antiretroviral therapy (cART). Here, we review epidemiological and experimental evidence showing that antibodies against HIV-1 Tat, infrequently occurring in natural infection, play a protective role against disease progression, and that vaccine targeting Tat can intensify cART. In fact, Tat vaccination of subjects on suppressive cART in Italy and South Africa promoted immune restoration, including CD4+ T-cell increase in low immunological responders, and a reduction of proviral DNA even after six years of cART, when both CD4+ T-cell gain and DNA decay have reached a plateau. Of note, DNA decay was predicted by the neutralization of Tat-mediated entry of Env into dendritic cells by anti-Tat antibodies, which were cross-clade binding and neutralizing. Anti-Tat cellular immunity also contributed to the DNA decay. Based on these data, we propose the Tat therapeutic vaccine as a pathogenesis-driven intervention that effectively intensifies cART and it may lead to a functional cure, providing new perspectives and opportunities also for prevention and virus eradication strategies.

Keywords: HIV reservoir; HIV-1 Tat; HIV-1 Tat therapeutic vaccine; HIV-1 vaccine development; anti-Tat antibodies; cART intensification; crossclade antibodies; functional cure; natural vs. vaccine-induced antibody response; perspective for clinical implications.

Conflict of interest statement

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Figures

Figure 1
Figure 1
Functional domains of HIV-1 Tat (HXB2). Amino acid numbering according to the IIIB/Lai sequence. Tat can be divided into six domains: a proline-rich acidic N-terminus (aa 1–21), a cysteine-rich region (aa 22–37), a hydrophobic core region (aa 38–48), an arginine-rich basic domain (aa 49–57), a glutamin-rich region (aa 60–76) and a C-terminal domain containing the RGD sequence, recognized by RGD-binding integrins. Shown is the 86 aa long form of Tat, commonly found in cell lines and used experimentally. However, in field isolates the 101 aa long form of Tat is mostly found [8].
Figure 2
Figure 2
Role of intracellular and extracellular HIV-1 Tat in the virus life cycle. Tat drives both productive infection and establishment of latent virus reservoirs by increasing permissivity and half-life of resting CD4+ T cells harboring HIV proviral DNA.
Figure 3
Figure 3
Neutralization of Tat/Env complex entry into monocyte-derived DCs (MDDCs) by sera from HIV-infected individuals. (A) Neutralization of trimeric Env ΔV2 entry into MDDCs by sera from HIV-infected subjects in the presence or absence of Tat (0.01 µM) in anti-Tat Ab negative (n = 8) and anti-Tat Ab positive (n = 8) subjects. The bars represent the percentage of entry of Env alone incubated in buffer (in blue) or with Tat (in red). The percentage of Env positive cells is shown. Data are expressed as the mean with standard deviation of experiments performed in duplicate. The codes of the anti-Tat Ab negative or positive sera are indicated at the bottom of the bars. (B) Geometric mean (GM) of the ratio, with 95% confidence interval (CI) of the percentage of MDDCs internalizing Env in the absence (blue bar) or in the presence (red bar) of Tat in anti-Tat Ab negative (n = 8) and anti-Tat Ab positive (n = 8) subjects. Statistical analysis was performed by the two-tailed Student’s t-test.
Figure 4
Figure 4
Tat-mediated entry of HIV and role of antibodies against Env or Tat. By binding Tat, HIV acquires the capability of using RGD binding integrins to enter cells, circumventing neutralization by anti-Env Abs and greatly expanding its spreading potential. Anti-Tat Abs effectively counteract this entry pathway. APC: Antigen-presenting cell; DC: Dendritic cell; DC-SIGN: Dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin; DC-SIGN-R: DC-SIGN-related; EC: Endothelial cell; Mo: Monocyte/macrophage; MR: Mannose receptor; RGD: Arg-Gly-Asp motif; Tat: Transactivator of transcription.
Figure 5
Figure 5
The presence of anti-Tat antibodies is predictive of non-progression to AIDS or AIDS-related events. Data are from 252 HIV+ individuals enrolled in the observational Italian HIV Seroconversion Study conducted from 1985 to 2000. Kaplan-Meier curves show progression to AIDS or to CD4+ T cells count ≤200 cells/μL over 14 years of follow-up in individuals negative or positive for anti-Tat Abs. Anti-Tat Ab positivity: titers ≥100. Subjects were evaluated every three years, stratified by anti-Tat serostatus. The cumulative incidence of AIDS or severe immunodeficiency was calculated for both the anti-Tat Ab positive subjects and the anti-Tat Ab negative subjects; disease progression was significantly slower in the anti-Tat Ab positive subjects than in the anti-Tat Ab negative subjects (p = 0.016, log-rank test).
Figure 6
Figure 6
Virological outcome in Tat/Env-vaccinated vs. control monkeys after intrarectal challenge with the SHIVSF162P4cy (70 MID50). Box plots of (A) viral RNA, (B) proviral DNA in blood at 2, 3, 4 and 5 weeks after challenge, respectively; and, (C) proviral DNA at week 4 after challenge in rectal tissue (RT) and inguinal lymph nodes (LN). Statistical analysis was performed by the one-sided Wilcoxon rank sum test. Red: monkeys vaccinated with Tat/Env (n = 6); blue: control animals (n = 6).
Figure 7
Figure 7
Kinetics parameter estimates of proviral DNA decay in vaccinees stratified by Tat vaccine regimens. Estimates calculated according to Random-effects regression model for decay with first-order kinetics effect, as in Finzi D, et al. Nat Med, 1999 [99]. Estimates of HIV-1 DNA annual decay in all vaccinees expressed as the percentage of HIV-1 DNA decay with 95% confidence interval (upper panel) or years to 50% reduction [half-life (t1/2)], to 90% reduction and to eradication for all vaccinees and by Tat vaccine regimens (lower panel) are shown.

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Source: PubMed

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