A Randomized Placebo-Controlled Efficacy Study of a Prime Boost Therapeutic Vaccination Strategy in HIV-1-Infected Individuals: VRI02 ANRS 149 LIGHT Phase II Trial.

In this placebo-controlled phase II randomized clinical trial, 103 human immunodeficiency virus type 1 (HIV-1)-infected patients under cART (combined antiretroviral treatment) were randomized 2:1 to receive either 3 doses of DNA GTU-MultiHIV B (coding for Rev, Nef, Tat, Gag, and gp160) at week 0 (W0), W4, and W12, followed by 2 doses of LIPO-5 vaccine containing long peptides from Gag, Pol, and Nef at W20 and W24, or placebo. Analytical treatment interruption (ATI) was performed between W36 to W48. At W28, vaccinees experienced an increase in functional CD4+ T-cell responses (P < 0.001 for each cytokine compared to W0) measured, predominantly against Gag and Pol/Env, and an increase in HIV-specific CD8+ T cells producing interleukin 2 (IL-2) and tumor necrosis factor alpha (TNF-α) (P = 0.001 and 0.013, respectively), predominantly against Pol/Env and Nef. However, analysis of T-cell subsets by mass cytometry in a subpopulation showed an increase in the W28/W0 ratio for memory CD8+ T cells coexpressing exhaustion and senescence markers such as PD-1/TIGIT (P = 0.004) and CD27/CD57 (P = 0.044) in vaccinees compared to the placebo group. During ATI, all patients experienced viral rebound, with the maximum observed HIV RNA level at W42 (median, 4.63 log10 copies [cp]/ml; interquartile range [IQR], 4.00 to 5.09), without any difference between arms. No patient resumed cART for CD4 cell count drop. Globally, the vaccine strategy was safe. However, a secondary HIV transmission during ATI was observed. These data show that the prime-boost combination of DNA and LIPO-5 vaccines elicited broad and polyfunctional T cells. The contrast between the quality of immune responses and the lack of potent viral control underscores the need for combined immunomodulatory strategies. (This study has been registered at ClinicalTrials.gov under registration no. NCT01492985.)IMPORTANCE In this placebo-controlled phase II randomized clinical trial, we evaluated the safety and immunogenicity of a therapeutic prime-boost vaccine strategy using a recombinant DNA vaccine (GTU-MultiHIV B clade) followed by a boost vaccination with a lipopeptide vaccine (HIV-LIPO-5) in HIV-infected patients on combined antiretroviral therapy. We show here that this prime-boost strategy is well tolerated, consistently with previous studies in HIV-1-infected individuals and healthy volunteers who received each vaccine component individually. Compared to the placebo group, vaccinees elicited strong and polyfunctional HIV-specific CD4+ and CD8+ T-cell responses. However, these immune responses presented some qualitative defects and were not able to control viremia following antiretroviral treatment interruption, as no difference in HIV viral rebound was observed in the vaccine and placebo groups. Several lessons were learned from these results, pointing out the urgent need to combine vaccine strategies with other immune-based interventions.

Differential effects of dopaminergic agents on locomotor sensitisation and on the reinstatement of cocaine-seeking and food-seeking behaviour.

RATIONALE: The dopaminergic pathways are involved in natural and drug reward related processes. OBJECTIVES: To compare the respective involvement of the dopaminergic receptors D1, D2 and D3 in natural-seeking versus drug-seeking behaviour and evaluate any concomitant expression of locomotor sensitisation. METHODS: In separate experiments, male Wistar rats were trained to self-administer cocaine (0.25 mg/infusion) or to press a lever to obtain food pellets. Following a prolonged period of extinction, reinstatement of lever responding was measured following non-contingent food delivery, cocaine (15 mg/kg), D1-like (SKF 82958, 0.25 mg/kg), D2-like (quinelorane, 0.25 mg/kg) and D3-like (7-OHDPAT, 0.25 mg/kg) agonists. To demonstrate parallel expression of behavioural sensitisation, locomotor activity was recorded during the reinstatement sessions. RESULTS: Cocaine and quinelorane administrations reinstated cocaine-seeking behaviour and induced the expression of locomotor sensitisation, whereas SKF 82958 and 7-OHDPAT had either no effect or non-specific effects. In the food-seeking experiment, we found that quinelorane and 7-OHDPAT did not reinstate lever pressing. Cocaine increased responding on both active and inactive levers, whereas SKF 82958 had a more specific effect with higher responding on the previously food-associated lever. CONCLUSIONS: Our results indicate that expression of locomotor sensitisation and reinstatement of cocaine-seeking but not food-seeking behaviours are in part supported by common dopaminergic substrates, among which the D2 receptors play a crucial role.