scholarly journals A Recombinant Attenuated Mycobacterium tuberculosis Vaccine Strain Is Safe in Immunosuppressed Simian Immunodeficiency Virus-Infected Infant Macaques

2012 ◽  
Vol 19 (8) ◽  
pp. 1170-1181 ◽  
Author(s):  
Kara Jensen ◽  
Uma Devi K. Ranganathan ◽  
Koen K. A. Van Rompay ◽  
Don R. Canfield ◽  
Imran Khan ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Simian Immunodeficiency Virus ◽  
Clinical Symptoms ◽  
Pediatric Population ◽  
Vaccine Safety ◽  
Hiv Vaccine ◽  
Safe Alternative ◽  
Content Type ◽  
Infected Infant ◽  
Immunodeficiency Virus

ABSTRACTMany resource-poor countries are faced with concurrent epidemics of AIDS and tuberculosis (TB) caused by human immunodeficiency virus (HIV) andMycobacterium tuberculosis, respectively. Dual infections with HIV andM. tuberculosisare especially severe in infants. There is, however, no effective HIV vaccine, and the only licensed TB vaccine, theMycobacterium bovisbacillus Calmette-Guérin (BCG) vaccine, can cause disseminated mycobacterial disease in HIV-infected children. Thus, a pediatric vaccine to prevent HIV andM. tuberculosisinfections is urgently needed. We hypothesized that a highly attenuatedM. tuberculosisstrain containing HIV antigens could be safely administered at birth and induce mucosal and systemic immune responses to protect against HIV and TB infections, and we rationalized that vaccine safety could be most rigorously assessed in immunocompromised hosts. Of three vaccine candidates tested, the recombinant attenuatedM. tuberculosisstrain mc26435 carrying a simian immunodeficiency virus (SIV) Gag expression plasmid and harboring attenuations of genes critical for replication (panCDandleuCD) and immune evasion (secA2), was found to be safe for oral or intradermal administration to non-SIV-infected and SIV-infected infant macaques. Safety was defined as the absence of clinical symptoms, a lack of histopathological changes indicative ofM. tuberculosisinfection, and a lack of mycobacterial dissemination. These data represent an important step in the development of novel TB vaccines and suggest that a combination recombinant attenuatedM. tuberculosis-HIV vaccine could be a safe alternative to BCG for the pediatric population as a whole and, more importantly, for the extreme at-risk group of HIV-infected infants.

scholarly journals Balancing Trained Immunity with Persistent Immune Activation and the Risk of Simian Immunodeficiency Virus Infection in Infant Macaques Vaccinated with Attenuated Mycobacterium tuberculosis or Mycobacterium bovis BCG Vaccine

2016 ◽  
Vol 24 (1) ◽  
Author(s):  
Kara Jensen ◽  
Myra Grace dela Pena-Ponce ◽  
Michael Piatak ◽  
Rebecca Shoemaker ◽  
Kelli Oswald ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Simian Immunodeficiency Virus ◽  
Mycobacterium Bovis ◽  
Immune Activation ◽  
Myeloid Cell ◽  
Target Cells ◽  
Content Type ◽  
Trained Immunity ◽  
Immunodeficiency Virus ◽  
Siv Infection

ABSTRACT Our goal is to develop a pediatric combination vaccine to protect the vulnerable infant population against human immunodeficiency virus type 1 (HIV-1) and tuberculosis (TB) infections. The vaccine consists of an auxotroph Mycobacterium tuberculosis strain that coexpresses HIV antigens. Utilizing an infant rhesus macaque model, we have previously shown that this attenuated M. tuberculosis (AMtb)-simian immunodeficiency virus (SIV) vaccine is immunogenic, and although the vaccine did not prevent oral SIV infection, a subset of vaccinated animals was able to partially control virus replication. However, unexpectedly, vaccinated infants required fewer SIV exposures to become infected compared to naive controls. Considering that the current TB vaccine, Mycobacterium bovis bacillus Calmette-Guérin (BCG), can induce potent innate immune responses and confer pathogen-unspecific trained immunity, we hypothesized that an imbalance between enhanced myeloid cell function and immune activation might have influenced the outcome of oral SIV challenge in AMtb-SIV-vaccinated infants. To address this question, we used archived samples from unchallenged animals from our previous AMtb-SIV vaccine studies and vaccinated additional infant macaques with BCG or AMtb only. Our results show that vaccinated infants, regardless of vaccine strain or regimen, had enhanced myeloid cell responses. However, CD4+ T cells were concurrently activated, and the persistence of these activated target cells in oral and/or gastrointestinal tissues may have facilitated oral SIV infection. Immune activation was more pronounced in BCG-vaccinated infant macaques than in AMtb-vaccinated infant macaques, indicating a role for vaccine attenuation. These findings underline the importance of understanding the interplay of vaccine-induced immunity and immune activation and its effect on HIV acquisition risk and outcome in infants.

scholarly journals TRIM5α Resistance Escape Mutations in the Capsid Are Transferable between Simian Immunodeficiency Virus Strains

2016 ◽  
Vol 90 (24) ◽  
pp. 11087-11095 ◽  
Author(s):  
Fan Wu ◽  
Andrea Kirmaier ◽  
Ellen White ◽  
Ilnour Ourmanov ◽  
Sonya Whitted ◽  
...  
Keyword(s):  
Amino Acid ◽  
Simian Immunodeficiency Virus ◽  
Rhesus Macaques ◽  
Hiv Vaccine ◽  
Sooty Mangabey ◽  
Virus Acquisition ◽  
Vaccine Trials ◽  
Immunodeficiency Virus ◽  
Distinct Strain ◽  
Virus Strains

ABSTRACT TRIM5α polymorphism limits and complicates the use of simian immunodeficiency virus (SIV) for evaluation of human immunodeficiency virus (HIV) vaccine strategies in rhesus macaques. We previously reported that the TRIM5α-sensitive SIV from sooty mangabeys (SIVsm) clone SIVsmE543-3 acquired amino acid substitutions in the capsid that overcame TRIM5α restriction when it was passaged in rhesus macaques expressing restrictive TRIM5α alleles. Here we generated TRIM5α-resistant clones of the related SIVsmE660 strain without animal passage by introducing the same amino acid capsid substitutions. We evaluated one of the variants in rhesus macaques expressing permissive and restrictive TRIM5α alleles. The SIVsmE660 variant infected and replicated in macaques with restrictive TRIM5α genotypes as efficiently as in macaques with permissive TRIM5α genotypes. These results demonstrated that mutations in the SIV capsid can confer SIV resistance to TRIM5α restriction without animal passage, suggesting an applicable method to generate more diverse SIV strains for HIV vaccine studies. IMPORTANCE Many strains of SIV from sooty mangabey monkeys are susceptible to resistance by common rhesus macaque TRIM5α alleles and result in reduced virus acquisition and replication in macaques that express these restrictive alleles. We previously observed that spontaneous variations in the capsid gene were associated with improved replication in macaques, and the introduction of two amino acid changes in the capsid transfers this improved replication to the parent clone. In the present study, we introduced these mutations into a related but distinct strain of SIV that is commonly used for challenge studies for vaccine trials. These mutations also improved the replication of this strain in macaques with the restrictive TRIM5α genotype and thus will eliminate the confounding effects of TRIM5α in vaccine studies.

scholarly journals Rectal Acquisition of Simian Immunodeficiency Virus (SIV) SIVmac239 Infection despite Vaccine-Induced Immune Responses against the Entire SIV Proteome

2020 ◽  
Vol 94 (24) ◽  
Author(s):  
Mauricio A. Martins ◽  
Lucas Gonzalez-Nieto ◽  
Michael J. Ricciardi ◽  
Varian K. Bailey ◽  
Christine M. Dang ◽  
...  
Keyword(s):  
T Cells ◽  
Virus Infection ◽  
Immune Responses ◽  
Simian Immunodeficiency Virus ◽  
Vaccine Efficacy ◽  
Neutralizing Antibodies ◽  
Vaccine Development ◽  
Hiv Vaccine ◽  
Partial Control ◽  
Immunodeficiency Virus

ABSTRACT Given the complex biology of human immunodeficiency virus (HIV) and its remarkable capacity to evade host immune responses, HIV vaccine efficacy may benefit from the induction of both humoral and cellular immune responses of maximal breadth, potency, and longevity. Guided by this rationale, we set out to develop an immunization protocol aimed at maximizing the induction of anti-Envelope (anti-Env) antibodies and CD8+ T cells targeting non-Env epitopes in rhesus macaques (RMs). Our approach was to deliver the entire simian immunodeficiency virus (SIV) proteome by serial vaccinations. To that end, 12 RMs were vaccinated over 81 weeks with DNA, modified vaccinia Ankara (MVA), vesicular stomatitis virus (VSV), adenovirus type 5 (Ad5), rhesus monkey rhadinovirus (RRV), and DNA again. Both the RRV and the final DNA boosters delivered a near-full-length SIVmac239 genome capable of assembling noninfectious SIV particles and inducing T-cell responses against all nine SIV proteins. Compared to previous SIV vaccine trials, the present DNA-MVA-VSV-Ad5-RRV-DNA regimen resulted in comparable levels of Env-binding antibodies and SIV-specific CD8+ T-cells. Interestingly, one vaccinee developed low titers of neutralizing antibodies (NAbs) against SIVmac239, a tier 3 virus. Following repeated intrarectal marginal-dose challenges with SIVmac239, vaccinees were not protected from SIV acquisition but manifested partial control of viremia. Strikingly, the animal with the low-titer vaccine-induced anti-SIVmac239 NAb response acquired infection after the first SIVmac239 exposure. Collectively, these results highlight the difficulties in eliciting protective immunity against immunodeficiency virus infection. IMPORTANCE Our results are relevant to HIV vaccine development efforts because they suggest that increasing the number of booster immunizations or delivering additional viral antigens may not necessarily improve vaccine efficacy against immunodeficiency virus infection.

scholarly journals Cell Type-Dependent Escape of Capsid Inhibitors by Simian Immunodeficiency Virus SIVcpz

2020 ◽  
Vol 94 (23) ◽  
Author(s):  
Augustin Penda Twizerimana ◽  
Rachel Scheck ◽  
Daniel Becker ◽  
Zeli Zhang ◽  
Marianne Wammers ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Simian Immunodeficiency Virus ◽  
Pan Troglodytes ◽  
Hela Cells ◽  
Cyclophilin A ◽  
Human Pbmcs ◽  
Cell Type ◽  
Content Type ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT Pandemic human immunodeficiency virus type 1 (HIV-1) is the result of the zoonotic transmission of simian immunodeficiency virus (SIV) from the chimpanzee subspecies Pan troglodytes troglodytes (SIVcpzPtt). The related subspecies Pan troglodytes schweinfurthii is the host of a similar virus, SIVcpzPts, which did not spread to humans. We tested these viruses with small-molecule capsid inhibitors (PF57, PF74, and GS-CA1) that interact with a binding groove in the capsid that is also used by CPSF6. While HIV-1 was sensitive to capsid inhibitors in cell lines, human macrophages, and peripheral blood mononuclear cells (PBMCs), SIVcpzPtt was resistant in rhesus FRhL-2 cells and human PBMCs but was sensitive to PF74 in human HOS and HeLa cells. SIVcpzPts was insensitive to PF74 in FRhL-2 cells, HeLa cells, PBMCs, and macrophages but was inhibited by PF74 in HOS cells. A truncated version of CPSF6 (CPSF6-358) inhibited SIVcpzPtt and HIV-1, while in contrast, SIVcpzPts was resistant to CPSF6-358. Homology modeling of HIV-1, SIVcpzPtt, and SIVcpzPts capsids and binding energy estimates suggest that these three viruses bind similarly to the host proteins cyclophilin A (CYPA) and CPSF6 as well as the capsid inhibitor PF74. Cyclosporine treatment, mutation of the CYPA-binding loop in the capsid, or CYPA knockout eliminated the resistance of SIVcpzPts to PF74 in HeLa cells. These experiments revealed that the antiviral capacity of PF74 is controlled by CYPA in a virus- and cell type-specific manner. Our data indicate that SIVcpz viruses can use infection pathways that escape the antiviral activity of PF74. We further suggest that the antiviral activity of PF74 capsid inhibitors depends on cellular cofactors. IMPORTANCE HIV-1 originated from SIVcpzPtt but not from the related virus SIVcpzPts, and thus, it is important to describe molecular infection by SIVcpzPts in human cells to understand the zoonosis of SIVs. Pharmacological HIV-1 capsid inhibitors (e.g., PF74) bind a capsid groove that is also a binding site for the cellular protein CPSF6. SIVcpzPts was resistant to PF74 in HeLa cells but sensitive in HOS cells, thus indicating cell line-specific resistance. Both SIVcpz viruses showed resistance to PF74 in human PBMCs. Modulating the presence of cyclophilin A or its binding to capsid in HeLa cells overcame SIVcpzPts resistance to PF74. These results indicate that early cytoplasmic infection events of SIVcpzPts may differ between cell types and affect, in an unknown manner, the antiviral activity of capsid inhibitors. Thus, capsid inhibitors depend on the activity or interaction of currently uncharacterized cellular factors.

scholarly journals Fatal Case of Polymicrobial Meningitis Caused by Cryptococcus liquefaciens and Mycobacterium tuberculosis Complex in a Human Immunodeficiency Virus-Infected Patient

2015 ◽  
Vol 53 (8) ◽  
pp. 2753-2755 ◽  
Author(s):  
César Conde-Pereira ◽  
Lia Rodas-Rodríguez ◽  
Manuel Díaz-Paz ◽  
Hilda Palacios-Rivera ◽  
Carolina Firacative ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Mycobacterium Tuberculosis ◽  
Infected Patient ◽  
Mycobacterium Tuberculosis Complex ◽  
Fatal Case ◽  
Central Nervous System Infections ◽  
Tuberculosis Complex ◽  
Content Type ◽  
Immunodeficiency Virus ◽  
Disseminated Disease

We describe a fatal case of polymicrobial meningitis in a human immunodeficiency virus-infected patient from Guatemala caused byCryptococcus liquefaciensandMycobacterium tuberculosiscomplex. Central nervous system infections caused concurrently by these species are extremely rare. This is also the first report of disseminated disease caused byC. liquefaciens.

scholarly journals Trained Immunity and Susceptibility to HIV

2016 ◽  
Vol 24 (1) ◽  
Author(s):  
Steven C. Derrick
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cells ◽  
Mycobacterium Tuberculosis ◽  
Cd4 T Cell ◽  
Dual Purpose ◽  
Content Type ◽  
Trained Immunity ◽  
Cell Responses ◽  
Immunodeficiency Virus ◽  
Increased Susceptibility

ABSTRACT In this issue of Clinical and Vaccine Immunology, K. Jensen et al. (Clin Vaccine Immunol 24:e00360-16, 2017, https://doi.org/10.1128/CVI.00360-16 ) describe a dual-purpose attenuated Mycobacterium tuberculosis-simian immunodeficiency virus vaccine (AMTB-SIV). Interestingly, immunized infant macaques required fewer oral exposures to SIV to become infected relative to nonimmunized animals. The authors hypothesized that augmented susceptibility to SIV was due to activation of CD4+ T cells through trained immunity. This commentary explores the possible relationship between trained immunity, enhanced CD4 T cell responses, and increased susceptibility to human immunodeficiency virus (HIV).

scholarly journals Killing Kinetics of Simian Immunodeficiency Virus-Specific CD8+T Cells: Implications for HIV Vaccine Strategies

2007 ◽  
Vol 179 (7) ◽  
pp. 4571-4579 ◽  
Author(s):  
Erik Rollman ◽  
Miranda Z. Smith ◽  
Andrew G. Brooks ◽  
Damian F. J. Purcell ◽  
Bartek Zuber ◽  
...  
Keyword(s):  
T Cells ◽  
Simian Immunodeficiency Virus ◽  
Cd8 T Cells ◽  
Hiv Vaccine ◽  
Immunodeficiency Virus ◽  
Kinetics Of

scholarly journals Virulence and Reduced Fitness of Simian Immunodeficiency Virus with the M184V Mutation in Reverse Transcriptase

2002 ◽  
Vol 76 (12) ◽  
pp. 6083-6092 ◽  
Author(s):  
Koen K. A. Van Rompay ◽  
Tim B. Matthews ◽  
Joanne Higgins ◽  
Don R. Canfield ◽  
Ross P. Tarara ◽  
...  
Keyword(s):  
Reverse Transcriptase ◽  
Simian Immunodeficiency Virus ◽  
Viral Fitness ◽  
Wild Type ◽  
Infected Infant ◽  
Immunodeficiency Virus ◽  
Group A ◽  
Initiation Of Therapy ◽  
Group B ◽  
M184v Mutation

ABSTRACT Drug-resistant mutants with a methionine-to-valine substitution at position 184 of reverse transcriptase (M184V) emerged within 5 weeks of initiation of therapy in four newborn macaques infected with simian immunodeficiency virus (SIVmac251) and treated with lamivudine (3TC) or emtricitabine [(−)-FTC] (two animals per drug). Thus, this animal model mimics the rapid emergence of M184V mutants of HIV-1 during 3TC therapy of human patients. One animal of each treatment group developed fatal immunodeficiency at 12 weeks of age, which is similar to the rapid disease course seen in most untreated SIVmac251-infected infant macaques. To further evaluate the effect of the M184V mutation on viral fitness and virulence, groups of juvenile macaques were inoculated with the molecular clone SIVmac239 with either the wild-type sequence (group A [n = 5]) or the M184V sequence (SIVmac239-184V; group B [n = 5] and group C [n = 2]). The two SIVmac239-184V-infected animals of group C did not receive any drug treatment, and in both animals the virus population reverted to predominantly wild type (184M) by 8 weeks after inoculation. The other five SIVmac239-184V-infected animals (group B) were treated with (−)-FTC to prevent reversion. Although virus levels 1 week after inoculation were lower in the SIVmac239-184V-infected macaques than in the SIVmac239-infected animals, no significant differences were observed from week 2 onwards. Two animals in each group developed AIDS and were euthanized, while all other animals were clinically stable at 46 weeks of infection. These data demonstrate that the M184V mutation in SIV conferred a slightly reduced fitness but did not affect disease outcome.

scholarly journals Incorporation of Glycosylphosphatidylinositol-Anchored Granulocyte- MacrophageColony-Stimulating Factor or CD40 Ligand Enhances Immunogenicity of Chimeric Simian Immunodeficiency Virus-Like Particles

2006 ◽  
Vol 81 (3) ◽  
pp. 1083-1094 ◽  
Author(s):  
Ioanna Skountzou ◽  
Fu-Shi Quan ◽  
Sailaja Gangadhara ◽  
Ling Ye ◽  
Andrei Vzorov ◽  
...  
Keyword(s):  
Immune Responses ◽  
Simian Immunodeficiency Virus ◽  
Cd40 Ligand ◽  
Safe Alternative ◽  
Virus Like Particles ◽  
Gm Csf ◽  
Immunodeficiency Virus ◽  
Macrophage Colony ◽  
Stimulating Factor

ABSTRACT The rapid worldwide spread of human immunodeficiency virus (HIV) mandates the development of successful vaccination strategies. Since live attenuated HIV is not accepted as a vaccine due to safety concerns, virus-like particles (VLPs) offer an attractive safe alternative because they lack the viral genome yet they are perceived by the immune system as a virus particle. We hypothesized that adding immunostimulatory signals to VLPs would enhance their efficacy. To accomplish this we generated chimeric simian immunodeficiency virus (SIV) VLPs containing either glycosylphosphatidylinositol (GPI)-anchored granulocyte-macrophage colony-stimulating factor (GM-CSF) or CD40 ligand (CD40L) and investigated their biological activity and ability to enhance immune responses in vivo. Immunization of mice with chimeric SIV VLPs containing GM-CSF induced SIV Env-specific antibodies as well as neutralizing activity at significantly higher levels than those induced by standard SIV VLPs, SIV VLPs containing CD40L, or standard VLPs mixed with soluble GM-CSF. In addition, mice immunized with chimeric SIV VLPs containing either GM-CSF or CD40L showed significantly increased CD4+- and CD8+-T-cell responses to SIV Env, compared to standard SIV VLPs. Taken together, these results demonstrate that the incorporation of immunostimulatory molecules enhances humoral and cellular immune responses. We propose that anchoring immunostimulatory molecules into SIV VLPs can be a promising approach to augmenting the efficacy of VLP antigens.

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