Intradermal injection of a Tat Oyi-based therapeutic HIV vaccine reduces of 1.5 log copies/mL the HIV RNA rebound median and no HIV DNA rebound following cART interruption in a phase I/II randomized controlled clinical trial
- Erwann P. Loret1Email author,
- Albert Darque1, 3,
- Elisabeth Jouve4,
- Elvenn A. Loret1,
- Corinne Nicolino-Brunet1,
- Sophie Morange2,
- Elisabeth Castanier2,
- Josiane Casanova2,
- Christine Caloustian2,
- Charléric Bornet3,
- Julie Coussirou3,
- Jihen Boussetta3,
- Vincent Couallier5,
- Olivier Blin4,
- Bertrand Dussol2 and
- Isabelle Ravaux1
© Loret et al. 2016
Received: 1 February 2016
Accepted: 13 March 2016
Published: 1 April 2016
A Tat Oyi vaccine preparation was administered with informed consent to 48 long-term HIV-1 infected volunteers whose viral loads had been suppressed by antiretroviral therapy (cART). These volunteers were randomized in double-blind method into four groups (n = 12) that were injected intradermally with 0, 11, 33, or 99 µg of synthetic Tat Oyi proteins in buffer without adjuvant at times designated by month 0 (M0), M1 and M2, respectively. The volunteers then underwent a structured treatment interruption between M5 and M7.
The primary outcomes of this phase I/IIa clinical trial were the safety and lowering the extent of HIV RNA rebound after cART interruption. Only one undesirable event possibly due to vaccination was observed. The 33 µg dose was most effective at lowering the extent of HIV RNA and DNA rebound (Mann and Whitney test, p = 0.07 and p = 0.001). Immune responses against Tat were increased at M5 and this correlated with a low HIV RNA rebound at M6 (p = 0.01).
This study suggests in vivo that extracellular Tat activates and protects HIV infected cells. The Tat Oyi vaccine in association with cART may provide an efficient means of controlling the HIV-infected cell reservoir.
KeywordsHIV Tat Vaccine Clinical trial ART interruption
The quest for an efficient vaccine against HIV has been a major issue since the initial cloning and identification of HIV-1 as the causative agent of AIDS [1, 2]. Although there is consensus that HIV eradication will require elimination of HIV infected cells that are mainly CD4 T lymphocytes (CD4), no cART and/or vaccine approaches have been able to reduce significantly the level of HIV infected cells in peripheral blood until now . Different reasons to explain this lack of efficacy include the possibility that HIV variability is too high for the immune system . The development of cART from 1996 showed that even with a low HIV-1 variability, the immune system is still unable to eradicate HIV infected cells . The reservoir of HIV infected cells in the peripheral blood is made of cells at the latent state, which is remarkably stable since its eradication even with successful cART would require at least 70 years . Why cytotoxic or CD8 T Lymphocytes (CTL) can not eliminate HIV infected cells remains controversial and it has been proposed that the central nervous system (CNS) could be a sanctuary (CTL have no access to CNS due to the blood–brain barrier) that would refresh peripheral blood with activated HIV infected cells . However, the development of HIV DNA measurements points out CNS as a minor reservoir, while guts and rectal tissues called GALT and RALT are the major tissue reservoirs and CTL have access to theses tissues [8, 9]. Only GALT and RALT have HIV sequences compatible with the refreshment of peripheral blood with activated HIV infected cells . Even patients with undetectable viraemia show evidence of ongoing viral replication in these tissue reservoirs and there is equilibrium with the peripheral blood compartment . It was shown recently that HIV infected cells become rapidly resistant to CTL following HIV infection . It could be possible that the capacity for HIV infected cells to survive in an environment containing CTL is due to the secretion from HIV infected cells of a HIV protein called Tat . The presence of extracellular Tat in peripheral blood has been demonstrated in different clinical studies showing the presence of antibodies against Tat . Extracellular Tat goes on to be secreted under ART and might protect HIV infected cells from CTL dues to its capacity to cross CTL membranes to trigger apoptosis . Furthermore, extra cellular Tat might activate latent HIV infected cells and explain the rapid HIV rebound when cART is stopped . However, there is a paucity of information on the role that extracellular Tat plays in infected subjects.
A single individual termed the “Berlin patient”, who was infected by HIV in 1995 is acknowledged to have been cured of HIV after having received a hematopoietic stem cell transplantation in 2007 from a compatible donor possessing the delta 32 mutation in CCR5 . HIV DNA was no longer detectable in his peripheral blood in 2009 . The complete eradication of HIV in this patient was demonstrated in 2012 by a retro seroconversion that is characterized by a significant decrease of antibodies against HIV . A similar retro seroconversion was reported for the child termed the “Mississippi baby” at age of three . HIV-1 antibodies were not detected in the child at 24, 26, and 28 months of age, but were found when she was 4 years old in 2014 due to a viral rebound . Retro seroconversion has never been observed in patients receiving cART with no detectable viraemia and is therefore considered to be a marker for the elimination of HIV infected cell [11, 13]. In contrast, low-level viraemia that is below the limit of detection of viral RNA can be enough to sustain a high level of antibodies against HIV in spite of efficient ART .
Retro seroconversions were also observed after a survey of 2 years in 23 of 25 women who were seropositive in 1986 in Gabon but at the time this was interpreted as due to mutations in the HIV envelope protein . A HIV strain termed HIV-1 Oyi was cloned from one of these women while she was still seropositive . It was later shown that HIV Oyi had envelope proteins similar to other HIV strains and a correlation was established between the retro seroconvertion of these 23 women and the capacity for Tat Oyi to have immune properties never observed in other Tat variants . This led to the testing of a Tat Oyi vaccine on rhesus macaques that were challenged by mucosal inoculation with a heterologous recombinant SHIV. The results showed that SHIV infected CD4 cells were no longer detectable in the peripheral blood 2 months after SHIV challenge in all macaques vaccinated with Tat Oyi and one of these animals retro seroconverted . The efficacy of Tat Oyi was recently confirmed in another heterologous SHIV challenge . It was also possible to identify a highly conserved surface on Tat variants and Tat Oyi has specific mutations that transform this highly conserved surface in a 3D épitope . Tat Oyi can generate neutralizing antibodies against Tat variants whatever their mutations establishing a rational for testing Tat Oyi as active principle of a therapeutic vaccine in human trials .
This study describes the first clinical trial with Tat Oyi in a phase I/II double blinded and randomized controlled clinical trial. The primary outcome of phase I was the absence of serious adverse events (SAE) due to vaccination. The primary outcome for phase II was the capacity to control HIV RNA rebound in a vaccine group following treatment interruption. The secondary outcome for phase I and phase II was a specific immune response against Tat related to the vaccine and characterized by amplification and/or cross recognition of six Tat variants (including Tat Oyi) that are representative of the five main HIV-1 subtypes .
Study design and eligibility criteria
The hypothesis was that neutralizing antibodies against Tat induced by this vaccine may help CTL to eliminate HIV infected cells. The Tat Oyi vaccine rationale is not to develop a Tat specific CTL response since HIV infected cells have GP120 at their surfaces and not Tat. Free extracellular Tat may constitute a screen that protects HIV infected cells from CTL. Neutralizing antibodies against Tat may destroy this screen. We proposed to test the Tat Oyi vaccine to HIV-1 infected volunteers who were virologically suppressed for at least 1 year while on ART. Three double blinded intradermal injections (500 µL) at Month 0 (M0), M1 and M2 of a solution having respectively 0, 11, 33 or 99 µg in four groups of volunteers. The vaccine was composed essentially of a synthetic Tat Oyi in 100 mM Phosphate buffer pH 4.5 and 9 g/L NaCl. Three intradermal injections were carried out in each group and the only difference with the placebo group was the absence of Tat Oyi. No adjuvant or other compounds were added. Volunteers agreed to stop cART for 2 months between M5 and M7, but cART could be resumed if a volunteer was >100 copies/mL HIV RNA at M6. Observance of cART and cART interruption between M5 and M7 were monitored by detection of antiretroviral levels in blood samples over the course of the study.
Volunteers had been recruited from among long term suppressed HIV infected patients who did not experience cART in early infection. cART interruption of 2 months is considered to be safe for these HIV infected patients with a CD4 counts >350 cells/mm3 and in whom a limited decrease of about 65 CD4 cells/mm3 has been observed [21, 22]. HIV RNA rebound, following cART interruption for these patients is characterized by the appearance of detectable HIV RNA at day 15 that increases until stabilization (up to 30 days) with a mean 10,000 (log 4) HIV RNA copies/mL . This dynamic can be different for HIV patients who received cART during primary infection [15, 23, 24], perhaps because early initiation of cART may reduce the size of the HIV DNA reservoir [<1.5 log HIV DNA copies per 106 peripheral blood mononuclear cells (PBMC)] potentially influencing HIV RNA rebound when cART is interrupted . Levels of HIV DNA in peripheral blood of patients receiving cART (without early initiation) since <10 years appear to be constant with a median of 1.9 log HIV DNA copies per 106 PBMC and a mean difference of 0.2 log copies per 10 years of effective cART [25, 26].
Base line and safety
Total (n = 46)
Sexe n (%) woman
13 (27 %)
HIV infection diagnosis (years)
Years since HIV RNA <40 copies/mL
1 (2.1 %)
28 (58.3 %)
15 (31.3 %)
4 (8.3 %)
HIV DNA (copies/106 PBMC)
Log HIV DNA
CD4 (cells per µL)
CD8 (cells per µL)
Nadir (CD4 <350 cells per µL) (years)
Nadir CD4 (cells per µL)
Serious adverse events (SAE) (phase I primary end point)
Due to vaccine
Hernia hiatus repair
Vaccine efficacy to prevent HIV RNA rebound (phase II primary end point)
0 (n = 12)
11 µg (n = 12)
33 µg (n = 12)
99 µg (n = 10)
39–0.9 × 106
39–1.2 × 106
39–0.4 × 106
81–0.1 × 106
CD4 and CD8 cell
IgG anti Tat response
The only successful phase II vaccine clinical trial against HIV used a recombinant virus triggering envelope proteins (RV144), and demonstrated an efficacy of about 30 % at preventing HIV infection . Two previous phase II clinical trials were performed with Tat fragments (TUTI-16)  or with recombinant Tat (ISST-02) . Interestingly, in these two clinical trials as in this one, a dose of 30 µg of Tat yielded the best results [28, 29]. Three years after vaccination in the ISST-02 protocol, a significant increase in CD4 cells and a HIV DNA decrease of 0.2 log copies/106 PBMC occurred but there was no placebo group to determine if these results were related to the vaccine . Another phase II clinical trial with the same vaccine (ISST-03) is ongoing in South Africa .
The Tat Oyi vaccine is entirely synthetic and no adjuvant or compounds such as interleukins were added to amplify the immune response. The results presented in this study are therefore due only to Tat Oyi, and the differences observed between the three different doses employed and the placebo are related only to the quantity of Tat Oyi injected. HIV RNA rebound following treatment interruption was chosen as a primary outcome to evaluate vaccine efficacy in phase II (M5 to M12). Tat Oyi is the first vaccine to demonstrate efficacy in the context of cART interruption, even though 21 other trials have tried and failed to show differences from the placebo group . It is important to outline that lowering the extent of HIVRNA rebound to <0.5 log copies is considered as significant . Since we have 8 volunteers <3.5 log copies/mL in the 33 µg group, it suggests an efficacy of 66 % for the Tat Oyi vaccine regarding the HIV RNA rebound. The immune response against Tat was monitored by ELISA test using Tat variants representative of the five main HIV-1 subtypes . Previously, we showed using this ELISA test that an immune response against Tat variants was present for at least 50 % of HIV infected patients in African and European cohorts due to endogenous extracellular Tat . Furthermore, we showed that this anti-Tat immune response could often be transient . This study shows that anti-Tat immunity can help to control HIV RNA rebound and that the anti-Tat Oyi response may help to lower HIV DNA.
This study confirms in humans the important role of extracellular Tat in activating latent cells. Latency is a way for HIV, as other defective viruses, to maximize gene expression while avoiding global T cell activation that would involve the rapid elimination of HIV infected cells since activated T cells can survive for only a few days . Different molecular mechanisms of HIV latency have been recently reviewed including Tat and other transcription factors such as NF-κB, the cyclin dependent kinases CDK13 and CDK11, and the positive transcription elongation factor b (P-TEFb) . It is interesting that different strategies called “shock and kill” have been proposed to cure AIDS with agents that activate these proteins or release P-TEFb . An anti-Tat compound such as Dihydro-cortistatin A can suppress HIV transcription but also inhibits HIV-1 mediated neuro inflammation . The blood–brain barrier appears to be damaged in HIV infected patients, and extracellular Tat may be involved in this process . This damage may be due to CTLs that are present in the CNS in the mouse model . This recent discovery does not fit well with the role of sanctuary that the CNS is thought by some to play for HIV infected cells. The Tat Oyi vaccine may help to diminish HIV-associated neurocognitive disorders.
The intradermal administration of the Tat Oyi vaccine was safe and could attain the effects described without adjuvant. The lack of efficacy of the vaccine at a dose of 99 µg from M5 may be due to a collapse of the Tat immune response before M5. Tat Oyi is the first therapeutic vaccine to show a measure of success in regard to both HIV RNA and DNA in a phase II clinical trial. The Tat Oyi vaccine appears to reduce HIV DNA and potentially the numbers of HIV infected cells in peripheral blood. Preliminary results show that three volunteers who received 33 or 99 µg are still HIV DNA undetectable at M24. The Tat Oyi vaccine together with cART may provide a means of control of HIV infection.
The protocol was entitled: “Evaluation in seropositive patients of a synthetic vaccine targeting the HIV Tat protein” with the acronym: “EVATAT”. The protocol was registered in the European Clinical trial data base (EudraCT) with the ID number: 2012-000374-36. The protocol got a favorable advice from an ethic committee (CPP SudMed 2) on November 9th, 2012 and an authorization from the French drug agency (ANSM) on January 14th, 2013 and was registered in clinicaltrial.gov with the reference NCT01793818. A written informed consent was obtained from all participants. This was a monocentric clinical trial located in the University Hospital Center “la Conception” in Marseille (Provence). All the volunteers were French citizens living in different cities in Provence, the average age was 46 years old with the oldest being 64 years old and the youngest 32 years old. The main inclusion criteria were: Age from 18 to 64 years old, on effective ART for at least 12 months with a viral load <40 copies/mL. The main exclusion criteria: Patients in HIV-1 primo infection, HIV-2 infected, having antibodies against HBV, HCV or HTLV-1 viruses, chronic active infections, immunosuppressive therapy, cancer, pregnancy and breastfeeding. Adverse events were monitored and clinical examination performed at each visit, with blood sampling for safety (general biochemistry and hematology). HIV RNA was analyzed by conventional methods with respectively a cut off of 40 copies per mL and HIV DNA HIV-1 DNA levels were measured by using the Generic HIV® assay (Biocentric, Bandol, Provence) with a cut off of 20 copies/million of PBMC. CD4+ and CD8+ T cell counts were analyzed by conventional methods.
The active principle is a synthetic protein of 101 amino acid residues termed Tat Oyi . Tat Oyi was synthesized in the ETRAV laboratory (Faculty of Pharmacy, Marseille, Provence) in Fmoc solid phase synthesis with a synthesizer APPLIED 433A in one run as previously described . Two clinical lots (Freeze dried 33 µg Tat Oyi and Phosphate buffer 100 mM pH 4.5 NaCl 9 g/L) were produced by the pharmaceutical company ELIAPHARM at Sofia Antipolis (Provence). The two clinical lots were sterile and stable for 3 years at 4 °C. The vaccine was reconstituted by the CHU Conception hospital pharmacy on the day of administration by mixing freeze dried Tat Oyi (0, 11, 33 or 99 µg) with the buffer.
Immune response against Tat
The antibody response against Tat was monitored with an ELISA test using Tat variants representative of the five main HIV-1 subtypes and Tat Oyi  in the ETRAV laboratory. For each volunteer, six blood samplings were carried out at M0, M2, M5, M7, M9 and M12 and sera were extracted and stored at—25 °C. For each patient and for each blood sampling the presence of IgG against six Tat variants was tested on six sera dilutions (1/3, 1/9, 1/27, 1/81, 1/243, 1/729, 1/2181, 1/6561). The ELISA tests were made in 2 days and the first day the six Tat variants were coated on 96 wheels NUNC plates in duplicate. We had six sera from each patient at M0, M2, M5, M7, M9 & M12 and one plate per serum was used. The second day, the six sera of a same volunteer were added with the same dilutions (one sera for one plate) and the association Tat variants/Human IgG in the six dilutions was revealed with peroxide conjugate Goat anti Human IgG and the colorimetric ABTS reaction at 433 nm, measured with a BIOTEK spectrophotometer. The six plates were measured the same day with a delay of 45 min corresponding to the time of incubation for each plate with ABTS. The intra assay variability of the ELISA test was monitored at the end of the second day with OD values that had to have a standard deviation <0.2 OD between a same Tat variant and a same dilution in the duplicate of a same plate. Inter assay variability was monitored with ELISA test that had to be reproducible at least twice for each volunteer with a delay of 6 months between two experiments. After vaccination, a specific response due to the vaccine was characterized by the apparition of an immune response against Tat variants for volunteers who had no response before vaccination. For volunteers who had an immune response against Tat before vaccination, a specific response due to the vaccine was characterized by recognition at a lower dilution of the same Tat variant and/or recognition of new Tat variants.
Randomization and masking
It was a mono centric clinical study and it was double-blind with respect to vaccine dose assignment. The injections occurred in the “Centre d’Investigation Clinique” (CIC) in the UCH “la Conception”. The volunteers and the investigators in the CIC were unaware of the content in the syringes. Pharmacists, from the “Pharmacie à Usage Interne” (PUI) in the UCH “la Conception”, prepared and distributed the syringe the morning of the arrival of each volunteer in the CIC according to a schedule previously planned with the volunteer and in agreement with the EVATAT protocol. Volunteers (n = 48) were randomly assigned (1:1:1:1) to receive either 0, 11, 33 or 99 µg of a synthetic Tat Oyi complemented with a saline buffer. Randomization was carried with volunteers stratified in four block size named A, B, C and D and the vaccine doses corresponding to each letter was not known. The randomization scheme was prepared by Dr. Albert Darque in the PUI and securely stored with restricted access. No request to unmask study participants was asked for EVATAT study and the randomization was unmasked only on September 15th, 2015 after the “freezing” of EVATAT data from all investigators.
The sample sizes have not been evaluated with a statistical methodology including power analysis. Nonparametric testing procedures were planned, and multifactorial analysis of RNA, DNA, CD4, CD8 was the core of the study. It was not possible to use standard tools to determine sample sizes according to a pre-specified power of the analysis (that requires a given value for the detectable difference). A total amount of 48 participants divided in four groups was accepted by authorities for a phase I/IIa clinical trial, and ensured enough sample sizes for an exploratory statistical analysis. Volunteers with undetectable HIV RNA (<40 copies/mL) or HIV DNA (<20 copies/106 PBMC) were counted according to the “worst case scenario”, which were 39 copies for HIV RNA and 19 copies for HIV DNA (respectively 1.6 log and 1.3 log. The non parametric Mann and Whitney test  was used as a standard test. All p values are one-sided because of an a priori knowledge of the expected variation between placebo and vaccine groups. To compare vaccinated groups with a placebo require multiple comparisons that may induce type I family wise errors when non adjusted p values are used to detect significant differences between groups [37–39]. This is especially the case for large number of groups and unforeseen comparisons. Our analyses do not suffer from this problem because only three groups are compared to the placebo. Moreover, these comparisons were planned in the statistical analysis plan of the study and have not to be considered as unplanned subgroup comparisons. Thus, despite the fact that the sample sizes was most of the time not sufficient enough to ensure a statistical significance of the observed differences by adjusting for multiples comparisons, we provided non adjusted p values for one-sided Mann and Whitney tests as elements for discussion. An overall Kruskal–Wallis test would not have revealed a statistically significant difference among groups, mainly due to a lack of power in comparison of one control group versus the three other groups with 48 patients. The Consort 2010  warns against the risk of spurious findings, that is why these statistical data must be seen as an exploratory analysis.
EPL and IR conceived the clinical trial, IR was the main investigator, EPL wrote the manuscript. AD made the randomization. AD, CB, JC and JB prepared the syringes, JC and CC made the injections, EPL and EAL made ELISA test to study the Tat response. CNB made the data management. EJ and VC made statistical analyses. SM, OB and BD, oversaw the clinical trial and the manuscript. All authors read and approved the final manuscript.
This manuscript is dedicated to the memory of Roger Treger, first president of BIOSANTECH. BIOSANTECH is the sponsor of this study and is the exclusive licensee of patents covering the use of TAT-Oyi for preventing or treating aids and promoter of clinical trials aiming the development of an anti-HIV vaccine using TAT-Oyi. The authors thank all the volunteers who participate to the clinical trial. EPL thanks Dr. Jean de Mareuil and Dr. Karim Boulhimez for fruitful discussions. EPL thanks the members of the EVATAT watching committee Dr. Martine Barré, Dr. Frank Tollinchi and Dr. Jean Gugliotta. EPL thanks Estelle Charles for the data management. EPL thanks the students of Pharmacy and Biotechnology for their help to carry out ELISA tests to determine the Tat immune response.
The authors declare that they have no competing interests.
Role of the funding source
The sponsor of the study was not involved in study design, data analysis, data interpretation and writing of this manuscript. The corresponding author had fully access to all the data in the study and had final responsibility for the decision to submit the manuscript.
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- Barré-Sinoussi F, Chermann JC, Rey F, Nugeyre MT, Chamaret S, Gruest J, Dauguet C, Axler-Blin C, Vézinet-Brun F, Rouzioux C, Rozenbaum W, Montagnier L. Isolation of a T-lymphotropic retrovirus from a patient at risk for acquired immune deficiency syndrome (AIDS). Science. 1983;220:868–71.View ArticlePubMedGoogle Scholar
- Gallo RC, Salahuddin SZ, Popovic M, Shearer GM, Kaplan M, Haynes BF, Palker TJ, Redfield R, Oleske J, Safai B, et al. Frequent detection and isolation of cytopathic retroviruses (HTLV-III) from patients with AIDS and at risk for AIDS. Science. 1984;224:500–3.View ArticlePubMedGoogle Scholar
- Deng K, Pertea M, Rongvaux A, Wang L, Durand CM, Ghiaur G, Lai J, McHugh HL, Hao H, Zhang H, Margolick JB, Gurer C, Murphy AJ, Valenzuela DM, Yancopoulos GD, Deeks SG, Strowig T, Kumar P, Siliciano JD, Salzberg SL, Flavell RA, Shan L, Siliciano RF. Broad CTL response is required to clear latent HIV-1 due to dominance of escape mutations. Nature. 2015;517:381–5.View ArticlePubMedPubMed CentralGoogle Scholar
- Ho DD, Neumann AU, Perelson AS, Chen W, Leonard JM, Markowitz M. Rapid turnover of plasma virions and CD4 lymphocytes in HIV-1 infection. Nature. 1995;373:123–6.View ArticlePubMedGoogle Scholar
- Chun TW, Davey RT Jr, Engel D, Lane HC, Fauci AS. Re-emergence of HIV after stopping therapy. Nature. 1999;401:874–5.View ArticlePubMedGoogle Scholar
- Siliciano JD, Kajdas J, Finzi D, Quinn TC, Chadwick K, Margolick JB, Kovacs C, Gange SJ, Siliciano RF. Long-term follow-up studies confirm the stability of the latent reservoir for HIV-1 in resting CD4+ T cells. Nat Med. 2003;9:727–8.View ArticlePubMedGoogle Scholar
- Hellmuth J, Valcour V, Spudich S. CNS reservoirs for HIV: implications for eradication. J Virus Erad. 2015;1:67–71.PubMedPubMed CentralGoogle Scholar
- Bruner KM, Hosmane NN, Siliciano RF. Toward an HIV-1 cure: measuring the latent reservoir. Trends Microbiol. 2015;23:192–203.View ArticlePubMedPubMed CentralGoogle Scholar
- Chun TW, Nickle DC, Justement JS, Meyers JH, Roby G, Hallahan CW, Kottilil S, Moir S, Mican JM, Mullins JI, Ward DJ, Kovacs JA, Mannon PJ, Fauci AS. Persistence of HIV in gut-associated lymphoid tissue despite long-term antiretroviral therapy. J Infect Dis. 2008;197:714–20.View ArticlePubMedGoogle Scholar
- Imamichi H, Degray G, Asmuth DM, Fischl MA, Landay AL, Lederman MM, Sereti I. Lack of compartmentalization of HIV-1 quasi species between the gut and peripheral blood compartments. J Infect Dis. 2011;204:309–14.View ArticlePubMedPubMed CentralGoogle Scholar
- Loret EP. HIV extracellular tat: myth or reality ? Curr HIV Res. 2015;13:90–7.View ArticlePubMedGoogle Scholar
- Allers K, Hütter G, Hofmann J, Loddenkemper C, Rieger K, Thiel E, Schneider T. Evidence for the cure of HIV infection by CCR5Delta32/Delta32 stem cell transplantation. Blood. 2011;117:2791–9.View ArticlePubMedGoogle Scholar
- Yukl SA, Boritz E, Busch M, Bentsen C, Chun TW, Douek D, Eisele E, Haase A, Ho YC, Hütter G, Justement JS, Keating S, Lee TH, Li P, Murray D, Palmer S, Pilcher C, Pillai S, Price RW, Rothenberger M, Schacker T, Siliciano J, Siliciano R, Sinclair E, Strain M, Wong J, Richman D, Deeks SG. Challenges in detecting HIV persistence during potentially curative interventions: a study of the Berlin patient. PLoS Pathog. 2013;9:e1003347.View ArticlePubMedPubMed CentralGoogle Scholar
- Persaud D, Gay H, Ziemniak C, Chen YH, Piatak M Jr, Chun TW, Strain M, Richman D, Luzuriaga K. Absence of detectable HIV-1 viraemia after treatment cessation in an infant. N Engl J Med. 2013;369:1828–35.View ArticlePubMedPubMed CentralGoogle Scholar
- Hill AL, Rosenbloom DI, Fu F, Nowak MA, Siliciano RF. Predicting the outcomes of treatment to eradicate the latent reservoir for HIV-1. Proc Natl Acad Sci USA. 2014;111:13475–80.View ArticlePubMedPubMed CentralGoogle Scholar
- Huet T, Dazza MC, Brun-Vézinet F, Roelants GE, Wain-Hobson S. A highly defective HIV-1 strain isolated from a healthy Gabonese individual presenting an atypical western blot. AIDS. 1989;3:707–15.View ArticlePubMedGoogle Scholar
- Opi S, Péloponèse JM Jr, Esquieu D, Campbell G, de Mareuil J, Walburger A, Solomiac M, Grégoire C, Bouveret E, Yirrell DL, Loret EP. Tat HIV-1 primary and tertiary structures critical to immune response against non-homologous variants. J Biol Chem. 2002;277:35915–9.View ArticlePubMedGoogle Scholar
- Watkins J, Esquieu D, Campbell GR, Lancelot S, de Mareuil J, Opi S, Annappa S, Salles JP, Loret EP. Reservoir cells no longer detectable after a heterologous SHIV challenge with the synthetic HIV-1 Tat Oyi vaccine. Retrovirology. 2006;3:8–18.View ArticlePubMedPubMed CentralGoogle Scholar
- Lakhashe SK, Byrareddy SN, Zhou M, Bachler BC, Hemashettar G, Hu SL, Villinger F, Else JG, Stock S, Lee SJ, Vargas-Inchaustegui DA, Cofano EB, Robert-Guroff M, Johnson WE, Polonis VR, Forthal DN, Loret EP, Rasmussen RA, Ruprecht RM. Multimodality vaccination against clade C SHIV: partial protection against mucosal challenges with a heterologous tier 2 virus. Vaccine. 2014;32:6527–36.View ArticlePubMedPubMed CentralGoogle Scholar
- Mediouni S, Baillat G, Darque A, Ravaux I, Loret E. Identification of a highly conserved surface on Tat variants. J Biol Chem. 2013;288:19072–80.View ArticlePubMedPubMed CentralGoogle Scholar
- Davey RT Jr, Bhat N, Yoder C, Chun TW, Metcalf JA, Dewar R, Natarajan V, Lempicki RA, Adelsberger JW, Miller KD, Kovacs JA, Polis MA, Walker RE, Falloon J, Masur H, Gee D, Baseler M, Dimitrov DS, Fauci AS, Lane HC. HIV-1 and T cell dynamics after interruption of highly active antiretroviral therapy (HAART) in patients with a history of sustained viral suppression. Proc Natl Acad Sci USA. 1999;96:15109–14.View ArticlePubMedPubMed CentralGoogle Scholar
- El-Sadr WM, Lundgren J, Neaton JD, Gordin F, Abrams D, Arduino RC, Babiker A, Burman W, Clumeck N, Cohen CJ, Cohn D, Cooper D, Darbyshire J, Emery S, Fätkenheuer G, Gazzard B, Grund B, Hoy J, Klingman K, Losso M, Markowitz N, Neuhaus J, Phillips A, Rappoport C, Strategies for management of antiretroviral therapy (SMART) study group. CD4+ count-guided interruption of antiretroviral treatment. N Engl J Med. 2006;355:2283–96.View ArticlePubMedGoogle Scholar
- Skiest DJ, Morrow P, Allen B, McKinsey J, Crosby C, Foster B, Hardy RD. It is safe to stop antiretroviral therapy in patients with preantiretroviral CD4 cell counts >250 cells/microL. J Acquir Immune Defic Syndr. 2004;37:1351–7.View ArticlePubMedGoogle Scholar
- Assoumou L, Weiss L, Piketty C, Burgard M, Melard A, Girard PM, Rouzioux C, Costagliola D, ANRS 116 SALTO study group. A low HIV-DNA level in peripheral blood mononuclear cells at antiretroviral treatment interruption predicts a higher probability of maintaining viral control. AIDS. 2015;29:2003–7.View ArticlePubMedGoogle Scholar
- Hurst J, Hoffmann M, Pace M, Williams JP, Thornhill J, Hamlyn E, Meyerowitz J, Willberg C, Koelsch KK, Robinson N, Brown H, Fisher M, Kinloch S, Cooper DA, Schechter M, Tambussi G, Fidler S, Babiker A, Weber J, Kelleher AD, Phillips RE, Frater J. Immunological biomarkers predict HIV-1 viral rebound after treatment interruption. Nat Commun. 2015;6:8495–503.View ArticlePubMedPubMed CentralGoogle Scholar
- Ruggiero A, De Spiegelaere W, Cozzi-Lepri A, Kiselinova M, Pollakis G, Beloukas A, Vandekerckhove L, Strain M, Richman D, Phillips A, Geretti AM, ERAS Study Group. During stably suppressive antiretroviral therapy integrated HIV-1 DNA load in peripheral blood is associated with the frequency of CD8 cells expressing HLA-DR/DP/DQ. Ebiomedicine. 2015;2:1153–9.View ArticlePubMedPubMed CentralGoogle Scholar
- Rolland M, Edlefsen PT, Larsen BB, Tovanabutra S, Sanders-Buell E, Hertz T, deCamp AC, Carrico C, Menis S, Magaret CA, Ahmed H, Juraska M, Chen L, Konopa P, Nariya S, Stoddard JN, Wong K, Zhao H, Deng W, Maust BS, Bose M, Howell S, Bates A, Lazzaro M, O’Sullivan A, Lei E, Bradfield A, Ibitamuno G, Assawadarachai V, O’Connell RJ, deSouza MS, Nitayaphan S, Rerks-Ngarm S, Robb ML, McLellan JS, Georgiev I, Kwong PD, Carlson JM, Michael NL, Schief WR, Gilbert PB, Mullins JI, Kim JH. Increased HIV-1 vaccine efficacy against viruses with genetic signatures in Env V2. Nature. 2012;490:417–20.View ArticlePubMedPubMed CentralGoogle Scholar
- Goldstein G, Damiano E, Donikyan M, Pasha M, Beckwith E, Chicca J. HIV-1 Tat B-cell epitope vaccination was ineffectual in preventing viral rebound after ART cessation. Hum Vaccin Immunother. 2012;8:1425–30.View ArticlePubMedPubMed CentralGoogle Scholar
- Bellino S, Tripiciano A, Picconi O, Francavilla V, Longo O, Sgadari C, Paniccia G, Arancio A, Angarano G, Ladisa N, Lazzarin A, Tambussi G, Nozza S, Torti C, Focà E, Palamara G, Latini A, Sighinolfi L, Mazzotta F, Di Pietro M, Di Perri G, Bonora S, Mercurio VS, Mussini C, Gori A, Galli M, Monini P, Cafaro A, Ensoli F, Ensoli B. 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. Retrovirology. 2014;11:49–57.View ArticlePubMedPubMed CentralGoogle Scholar
- Ensoli F, Cafaro A, Casabianca A, Tripiciano A, Bellino S, Longo O, Francavilla V, Picconi O, Sgadari C, Moretti S, Cossut MR, Arancio A, Orlandi C, Sernicola L, Maggiorella MT, Paniccia G, Mussini C, Lazzarin A, Sighinolfi L, Palamara G, Gori A, Angarano G, Di Pietro M, Galli M, Mercurio VS, Castelli F, Di Perri G, Monini P, Magnani M, Garaci E, Ensoli B. HIV-1 Tat immunization restores immune homeostasis and attacks the HAART-resistant blood HIV DNA: results of a randomized phase II exploratory clinical trial. Retrovirology. 2015;12:33–62.View ArticlePubMedPubMed CentralGoogle Scholar
- Pollard RB, Rockstroh JK, Pantaleo G, Asmuth DM, Peters B, Lazzarin A, Garcia F, Ellefsen K, Podzamczer D, van Lunzen J, Arastéh K, Schürmann D, Clotet B, Hardy WD, Mitsuyasu R, Moyle G, Plettenberg A, Fisher M, Fätkenheuer G, Fischl M, Taiwo B, Baksaas I, Jolliffe D, Persson S, Jelmert O, Hovden AO, Sommerfelt MA, Wendel-Hansen V, Sørensen B. Safety and efficacy of the peptide-based therapeutic vaccine for HIV-1, Vacc-4x: a phase 2 randomised, double-blind, placebo-controlled trial. Lancet. 2014;14:291–300.View ArticlePubMedGoogle Scholar
- Cary DC, Fujinaga K, Peterlin BM. Molecular mechanisms of HIV latency. J Clin Invest. 2016;126:448–54.View ArticlePubMedGoogle Scholar
- Mediouni S, Jablonski J, Paris JJ, Clementz MA, Thenin-Houssier S, McLaughlin JP, Valente ST. Didehydro-cortistatin A inhibits HIV-1 Tat mediated neuroinflammation and prevents potentiation of cocaine reward in Tat transgenic mice. Curr HIV Res. 2015;13:64–79.View ArticlePubMedPubMed CentralGoogle Scholar
- Richards MH, Narasipura SD, Seaton MS, Lutgen V, Al-Harthi L. Migration of CD8+ T cells into the central nervous system gives rise to highly potent anti-HIVCD 4dimCD8 bright T cells in a Wnt signaling-dependent manner. J Immunol. 2016;196:317–27.View ArticlePubMedGoogle Scholar
- Péloponèse J-M, Collette Y, Gregoire C, Bailly C, Campèse D, Meurs E, Olive D, Loret EP. Full peptide synthesis, purification and characterization of six Tat variants: differences observed between HIV-1 isolates from Africa and other continents. J Biol Chem. 1999;274:11473–9.View ArticlePubMedGoogle Scholar
- Siegel S, Castellan NJ. Nonparametric statistics for the behavioral sciences. New York: McGraw-Hill; 1988. p. 399.Google Scholar
- Benjamini Y, Hochberg Y. Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Stat Soc B. 1995;57:289.Google Scholar
- Hochberg Y. A sharper Bonferonni procedure for multiple tests of significance. Biometrika. 1988;75:800–3.View ArticleGoogle Scholar
- Holm S. A simple sequentially rejective multiple test procedure. Scand J Stat. 1979;6:65–70.Google Scholar
- Moher D, Hopewell S, Schulz KF, Montori V, Gøtzsche PC, Devereaux PJ, Altman DG. CONSORT 2010 explanation and elaboration: updated guidelines for reporting parallel group randomised trials. J Clin Epidemiol. 2010;63:e1–37.View ArticlePubMedGoogle Scholar
- Moher D, Hopewell S, Schulz KF, Montori V, Gøtzsche PC, Devereaux PJ, Elbourne D, Egger M, Altman DGCONSORT. Explanation and Elaboration: updated guidelines for reporting parallel group randomised trials. Int J Surg. 2010;2012(10):28–55.Google Scholar