Therapeutic DNA Vaccine Induces Broad T Cell Responses in the Gut and Sustained Protection from Viral Rebound and AIDS in SIV-Infected Rhesus Macaques

Fuller, Deborah H.; Rajakumar, Premeela A.; Jenny, W.; Narendran, Amithi; Nyaundi, Julia; Michael, Heather; Yager, Eric J.; Stagnar, Cristy; Wahlberg, Brendon; Taber, Rachel; Haynes, Joel R.; Cook, Fiona C.; Ertl, Peter; Tite, J P; Amedee, Angela M.; Murphey‐Corb, Michael

doi:10.1371/journal.pone.0033715

Cited by 44 publications

(85 citation statements)

References 66 publications

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“…Though it was antibody and not T-cell responses that correlated most significantly with infection risk in the RV144 trial (15), it is possible that lymph node or mucosal T-cell responses, previously thought to be important in SIV vaccines (61,64), were also correlated. Therefore, it may be that A*02-restricted CD8 ϩ T cells played a direct role in increasing vaccine efficacy.…”

Section: Discussionmentioning

confidence: 91%

Analysis of HLA A*02 Association with Vaccine Efficacy in the RV144 HIV-1 Vaccine Trial

Gartland

McNevin

et al. 2014

J Virol

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The RV144 HIV-1 vaccine trial demonstrated partial efficacy of 31% against HIV-1 infection. Studies into possible correlates of protection found that antibodies specific to the V1 and V2 (V1/V2) region of envelope correlated inversely with infection risk and that viruses isolated from trial participants contained genetic signatures of vaccine-induced pressure in the V1/V2 region. We explored the hypothesis that the genetic signatures in V1 and V2 could be partly attributed to selection by vaccine-primed T cells. We performed a T-cellbased sieve analysis of breakthrough viruses in the RV144 trial and found evidence of predicted HLA binding escape that was greater in vaccine versus placebo recipients. The predicted escape depended on class I HLA A*02-and A*11-restricted epitopes in the MN strain rgp120 vaccine immunogen. Though we hypothesized that this was indicative of postacquisition selection pressure, we also found that vaccine efficacy (VE) was greater in A*02-positive (A*02 ؉ ) participants than in A*02 ؊ participants (VE ‫؍‬ 54% versus 3%, P ‫؍‬ 0.05). Vaccine efficacy against viruses with a lysine residue at site 169, important to antibody binding and implicated in vaccine-induced immune pressure, was also greater in A*02 ؉ participants (VE ‫؍‬ 74% versus 15%, P ‫؍‬ 0.02). Additionally, a reanalysis of vaccine-induced immune responses that focused on those that were shown to correlate with infection risk suggested that the humoral responses may have differed in A*02 ؉ participants. These exploratory and hypothesis-generating analyses indicate there may be an association between a class I HLA allele and vaccine efficacy, highlighting the importance of considering HLA alleles and host immune genetics in HIV vaccine trials. IMPORTANCEThe RV144 trial was the first to show efficacy against HIV-1 infection. Subsequently, much effort has been directed toward understanding the mechanisms of protection. Here, we conducted a T-cell-based sieve analysis, which compared the genetic sequences of viruses isolated from infected vaccine and placebo recipients. Though we hypothesized that the observed sieve effect indicated postacquisition T-cell selection, we also found that vaccine efficacy was greater for participants who expressed HLA A*02, an allele implicated in the sieve analysis. Though HLA alleles have been associated with disease progression and viral load in HIV-1 infection, these data are the first to suggest the association of a class I HLA allele and vaccine efficacy. While these statistical analyses do not provide mechanistic evidence of protection in RV144, they generate testable hypotheses for the HIV vaccine community and they highlight the importance of assessing the impact of host immune genetics in vaccine-induced immunity and protection. (This study has been registered at ClinicalTrials.gov under registration no. NCT00223080.)

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Section: Discussionmentioning

confidence: 91%

Analysis of HLA A*02 Association with Vaccine Efficacy in the RV144 HIV-1 Vaccine Trial

Gartland

McNevin

et al. 2014

J Virol

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“…Virion-associated RNA in plasma was quantified by real-time PCR in a Prism 7700 (Applied Biosystems, Inc., Foster City, CA) using primers specific for the SIV long terminal repeat (LTR) as described previously (4,5,6,21). This assay is linear over an 8-log range of template copy numbers and has a sensitivity threshold of 10 copies per reaction.…”

Section: Methodsmentioning

confidence: 99%

“…Full-length cell-associated SIV transcripts were quantified in TRIzolextracted RNA from tissues or purified mononuclear cells as described previously (6). Briefly, reverse-transcribed cellular RNA was subjected to real-time quantitative reverse transcription-PCR (qRT-PCR) using TaqMan chemistry and forward and reverse primers with probe specific for the U5 region of the 5= long terminal repeat (LTR) and the downstream primer binding site.…”

Section: Methodsmentioning

confidence: 99%

Response of Simian Immunodeficiency Virus to the Novel Nucleoside Reverse Transcriptase Inhibitor 4′-Ethynyl-2-Fluoro-2′-Deoxyadenosine In Vitro and In Vivo

Murphey‐Corb

Rajakumar

Michael

et al. 2012

Antimicrob Agents Chemother

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e Nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) are essential components in first-line therapy for human immunodeficiency virus (HIV) infection. However, long-term treatment with existing NRTIs can be associated with significant toxic side effects and the emergence of drug-resistant strains. The identification of new NRTIs for the continued management of HIVinfected people therefore is paramount. In this report, we describe the response of a primary isolate of simian immunodeficiency virus (SIV) to 4=-ethynyl-2-fluoro-2=-deoxyadenosine (EFdA) both in vitro and in vivo. EFdA was 3 orders of magnitude better than tenofovir (TFV), zidovudine (AZT), and emtricitabine (FTC) in blocking replication of SIV in monkey peripheral blood mononuclear cells (PBMCs) in vitro, and in a preliminary study using two SIV-infected macaques with advanced AIDS, it was highly effective at treating SIV infection and AIDS symptoms in vivo. Both animals had 3-to 4-log decreases in plasma virus burden within 1 week of EFdA therapy (0.4 mg/kg of body weight, delivered subcutaneously twice a day) that eventually became undetectable. Clinical signs of disease (diarrhea, weight loss, and poor activity) also resolved within the first month of treatment. No detectable clinical or pathological signs of drug toxicity were observed within 6 months of continuous therapy. Virus suppression was sustained until drug treatment was discontinued, at which time virus levels rebounded. Although the rebound virus contained the M184V/I mutation in the viral reverse transcriptase, EFdA was fully effective in maintaining suppression of mutant virus throughout the drug treatment period. These results suggest that expanded studies with EFdA are warranted. N ucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) have proven highly effective in both the treatment of chronic human immunodeficiency virus (HIV) infection (11) and, more recently, as a promising microbicidal prevention strategy for sexually transmitted virus (12). There are seven NRTIs approved for current clinical use, including the nucleoside emtricitabine (FTC) and the nucleotide tenofovir (TFV). Unfortunately, the frequent use of these drugs has resulted in the emergence of resistant virus strains (7,8,10,18). New compounds with potent activity on a wide range of isolates, including NRTI-resistant strains, are critically needed.We and others have previously described a group of 4=-substituted NRTIs that are more potent and have higher selectivity indices in vitro than existing NRTIs (9,13,14,15,16,17). One of the most potent of these compounds, 4=-ethynyl-2-fluoro-2=de-oxyadenosine (EFdA), inhibits HIV-1 replication in primary peripheral blood mononuclear cells (PBMC) with a 50% effective concentration (EC 50 ) of 50 pM, a potency 4 orders of magnitude greater than that of TFV and 400-fold greater than that of AZT (15). It is also nontoxic in vitro at concentrations as high as 10 M, which results in an in vitro selectivity index greater than 200,000. Furthermore, EFdA retains...

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“…Il est la cible de nombreuses stratégies thérapeutiques ayant pour objectif l'obtention d'une guérison complète. Les techniques d'éra-dication du virus, grâce à la réactivation des formes virales latentes par les inhibiteurs des histone-déacétylases ou les activateurs de la protéine kinase C, sont en cours d'évaluation chez l'homme [50]. Dans l'intervalle, il est certain qu'une guérison fonctionnelle nécessitera de réduire au maximum le réservoir viral digestif.…”

Section: Resultsunclassified

Infection par le virus de l’immunodéficience humaine

et al. 2015

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Therapeutic DNA Vaccine Induces Broad T Cell Responses in the Gut and Sustained Protection from Viral Rebound and AIDS in SIV-Infected Rhesus Macaques

Cited by 44 publications

References 66 publications

Analysis of HLA A*02 Association with Vaccine Efficacy in the RV144 HIV-1 Vaccine Trial

Analysis of HLA A*02 Association with Vaccine Efficacy in the RV144 HIV-1 Vaccine Trial

Response of Simian Immunodeficiency Virus to the Novel Nucleoside Reverse Transcriptase Inhibitor 4′-Ethynyl-2-Fluoro-2′-Deoxyadenosine In Vitro and In Vivo

Infection par le virus de l’immunodéficience humaine

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