scholarly journals Effects of Fecal Microbial Transplantation on Microbiome and Immunity in Simian Immunodeficiency Virus-Infected Macaques

2016 ◽  
Vol 90 (10) ◽  
pp. 4981-4989 ◽  
Author(s):  
Tiffany Hensley-McBain ◽  
Alexander S. Zevin ◽  
Jennifer Manuzak ◽  
Elise Smith ◽  
Jillian Gile ◽  
...  
Keyword(s):  
Hiv Infection ◽  
Simian Immunodeficiency Virus ◽  
Antibiotic Treatment ◽  
T Cell Activation ◽  
Rhesus Macaques ◽  
Bacterial Community Composition ◽  
Intestinal Microbiome ◽  
Th22 Cells ◽  
Immunodeficiency Virus ◽  
Taxonomic Groups

ABSTRACTAn altered intestinal microbiome during chronic human immunodeficiency virus (HIV) infection is associated with mucosal dysfunction, inflammation, and disease progression. We performed a preclinical evaluation of the safety and efficacy of fecal microbiota transplantation (FMT) as a potential therapeutic in HIV-infected individuals. Antiretroviral-treated, chronically simian immunodeficiency virus (SIV)-infected rhesus macaques received antibiotics followed by FMT. The greatest microbiota shift was observed after antibiotic treatment. The bacterial community composition at 2 weeks post-FMT resembled the pre-FMT community structure, although differences in the abundances of minor bacterial populations remained. Immunologically, we observed significant increases in the number of peripheral Th17 and Th22 cells and reduced CD4+T cell activation in gastrointestinal tissues post-FMT. Importantly, the transplant was well tolerated with no negative clinical side effects. Although this pilot study did not control for the differential contributions of antibiotic treatment and FMT to the observed results, the data suggest that FMT may have beneficial effects that should be further evaluated in larger studies.IMPORTANCEDue to the immunodeficiency and chronic inflammation that occurs during HIV infection, determination of the safety of FMT is crucial to prevent deleterious consequences if it is to be used as a treatment in the future. Here we used the macaque model of HIV infection and performed FMT on six chronically SIV-infected rhesus macaques on antiretroviral treatment. In addition to providing a preclinical demonstration of the safety of FMT in primates infected with a lentivirus, this study provided a unique opportunity to examine the relationships between alterations to the microbiome and immunological parameters. In this study, we found increased numbers of Th17 and Th22 cells as well as decreased activation of CD4+T cells post-FMT, and these changes correlated most strongly across all sampling time points with lower-abundance taxonomic groups and other taxonomic groups in the colon. Overall, these data provide evidence that changes in the microbiome, particularly in terms of diversity and changes in minor populations, can enhance immunity and do not have adverse consequences.

scholarly journals Immunization of Newborn Rhesus Macaques with Simian Immunodeficiency Virus (SIV) Vaccines Prolongs Survival after Oral Challenge with Virulent SIVmac251

2003 ◽  
Vol 77 (1) ◽  
pp. 179-190 ◽  
Author(s):  
Koen K. A. Van Rompay ◽  
Jennifer L. Greenier ◽  
Kelly Stefano Cole ◽  
Patricia Earl ◽  
Bernard Moss ◽  
...  
Keyword(s):  
Hiv Infection ◽  
Simian Immunodeficiency Virus ◽  
Rhesus Macaques ◽  
Disease Free Survival ◽  
Active Immunization ◽  
Pediatric Hiv ◽  
Maternal Antibodies ◽  
Immunization Strategies ◽  
Modified Vaccinia Virus Ankara ◽  
Immunodeficiency Virus

ABSTRACT There is an urgent need for active immunization strategies that, if administered shortly after birth, could protect infants in developing countries from acquiring human immunodeficiency virus (HIV) infection through breast-feeding. Better knowledge of the immunogenic properties of vaccine candidates in infants and of the effect of maternal antibodies on vaccine efficacy will aid in the development of such a neonatal HIV vaccine. Simian immunodeficiency virus (SIV) infection of infant macaques is a useful animal model of pediatric HIV infection with which to address these questions. Groups of infant macaques were immunized at birth and 3 weeks of age with either modified vaccinia virus Ankara (MVA) expressing SIV Gag, Pol, and Env (MVA-SIVgpe) or live-attenuated SIVmac1A11. One MVA-SIVgpe-immunized group had maternally derived anti-SIV antibodies prior to immunization. Animals were challenged orally at 4 weeks of age with a genetically heterogeneous stock of virulent SIVmac251. Although all animals became infected, the immunized animals mounted better antiviral antibody responses, controlled virus levels more effectively, and had a longer disease-free survival than the unvaccinated infected monkeys. Maternal antibodies did not significantly reduce the efficacy of the MVA-SIVgpe vaccine. In conclusion, although the tested vaccines delayed the onset of AIDS, further studies are warranted to determine whether a vaccine that elicits stronger early immune responses at the time of virus exposure may be able to prevent viral infection or AIDS in infants.

scholarly journals SIV/SHIV-Zika coinfection does not alter disease pathogenesis in adult non-pregnant Rhesus Macaques

2018 ◽  
Author(s):  
Mehdi R. M. Bidokhti ◽  
Debashis Dutta ◽  
Lepakshe S. V. Madduri ◽  
Shawna M. Woollard ◽  
Robert Norgren ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Hiv Infection ◽  
Simian Immunodeficiency Virus ◽  
Zika Virus ◽  
Rhesus Macaques ◽  
Epidemiological Studies ◽  
Disease Pathogenesis ◽  
Viral Loads ◽  
Immunodeficiency Virus ◽  
Tropical Infectious Diseases

AbstractDue to the large geographical overlap of populations exposed to Zika virus (ZIKV) and human immunodeficiency virus (HIV), understanding disease pathogenesis in such coinfections is urgently needed. We used chronically infected simian immunodeficiency virus and chimeric simian human immunodeficiency virus (SIV/SHIV) macaques and inoculated with ZIKV. Plasma viral loads of both SIV/SHIV and ZIKV showed no significant changes as compared to ZIKV alone-infected animals. Tissue clearance of ZIKV was observed similarly. Furthermore, minimal changes in cytokines/chemokines were observed. Collectively, these data suggest that coinfection may not alter disease pathogenesis and warrants large HIV-ZIKV epidemiological studies to validate these findings.Author SummaryThe co-infection incidence of human immunodeficiency virus (HIV) infection and neglected tropical infectious diseases is increasing due to the large geographical overlap of populations exposed to both of these viruses. Thus, researching on such coinfection is of particular importance. In this study, we investigated HIV-ZIKV coinfection dynamics in adult non-pregnant Rhesus Macaques model chronically infected with simian immunodeficiency virus (SIV) - or chimeric simian human immunodeficiency virus (SHIV). We found that post ZIKV inoculation, plasma viral loads were similar to ZIKV alone infected animals in addition to minimal changes of cytokines. Dynamics of SIV and SHIV also did not change. Tissue clearance of ZIKV was found 67 months later. Our findings provide insights into HIV-ZKIV coinfection to determine the alteration of their pathogenesis.

scholarly journals Evaluating the Intactness of Persistent Viral Genomes in Simian Immunodeficiency Virus-Infected Rhesus Macaques after Initiating Antiretroviral Therapy within One Year of Infection

2019 ◽  
Vol 94 (1) ◽  
Author(s):  
Samuel Long ◽  
Christine M. Fennessey ◽  
Laura Newman ◽  
Carolyn Reid ◽  
Sean P. O’Brien ◽  
...  
Keyword(s):  
Antiretroviral Therapy ◽  
Hiv Infection ◽  
Simian Immunodeficiency Virus ◽  
Genome Sequencing ◽  
Real Time Pcr ◽  
Rhesus Macaques ◽  
Viral Reservoir ◽  
Combination Antiretroviral Therapy ◽  
Viral Dna ◽  
Immunodeficiency Virus

ABSTRACT The major obstacle to more-definitive treatment for HIV infection is the early establishment of virus that persists despite long-term combination antiretroviral therapy (cART) and can cause recrudescent viremia if cART is interrupted. Previous studies of HIV DNA that persists despite cART indicated that only a small fraction of persistent viral sequences was intact. Experimental simian immunodeficiency virus (SIV) infections of nonhuman primates (NHPs) are essential models for testing interventions designed to reduce the viral reservoir. We studied the viral genomic integrity of virus that persists during cART under conditions typical of many NHP reservoir studies, specifically with cART started within 1 year postinfection and continued for at least 9 months. The fraction of persistent DNA in SIV-infected NHPs starting cART during acute or chronic infection was assessed with a multiamplicon, real-time PCR assay designed to analyze locations that are regularly spaced across the viral genome to maximize coverage (collectively referred to as “tile assay”) combined with near-full-length (nFL) single-genome sequencing. The tile assay is used to rapidly screen for major deletions, with nFL sequence analysis used to identify additional potentially inactivating mutations. Peripheral blood mononuclear cells (PBMC) from animals started on cART within 1 month of infection, sampled at least 9 months after cART initiation, contained at least 80% intact genomes, whereas those from animals started on cART 1 year postinfection and treated for 1 year contained intact genomes only 47% of the time. The most common defect identified was large deletions, with the remaining defects caused by APOBEC-mediated mutations, frameshift mutations, and inactivating point mutations. Overall, this approach can be used to assess the intactness of persistent viral DNA in NHPs. IMPORTANCE Molecularly defining the viral reservoir that persists despite antiretroviral therapy and that can lead to rebound viremia if antiviral therapy is removed is critical for testing interventions aimed at reducing this reservoir. In HIV infection in humans with delayed treatment initiation and extended treatment duration, persistent viral DNA has been shown to be dominated by nonfunctional genomes. Using multiple real-time PCR assays across the genome combined with near-full-genome sequencing, we defined SIV genetic integrity after 9 to 18 months of combination antiretroviral therapy in rhesus macaques starting therapy within 1 year of infection. In the animals starting therapy within a month of infection, the vast majority of persistent DNA was intact and presumptively functional. Starting therapy within 1 year increased the nonintact fraction of persistent viral DNA. The approach described here allows rapid screening of viral intactness and is a valuable tool for assessing the efficacy of novel reservoir-reducing interventions.

scholarly journals Enhanced Intestinal TGF-β/SMAD-Dependent Signaling in Simian Immunodeficiency Virus Infected Rhesus Macaques

Cells ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 806
Author(s):  
Nongthombam Boby ◽  
Alyssa Ransom ◽  
Barcley T. Pace ◽  
Kelsey M. Williams ◽  
Christopher Mabee ◽  
...  
Keyword(s):  
Gene Expression ◽  
Simian Immunodeficiency Virus ◽  
Transforming Growth Factor ◽  
Rhesus Macaques ◽  
Transforming Growth Factor Β ◽  
Immunodeficiency Virus ◽  
Cellular Source ◽  
Siv Infection ◽  
Β Receptor ◽  
Differentiation And Proliferation

Transforming growth factor-β signaling (TGF-β) maintains a balanced physiological function including cell growth, differentiation, and proliferation and regulation of immune system by modulating either SMAD2/3 and SMAD7 (SMAD-dependent) or SMAD-independent signaling pathways under normal conditions. Increased production of TGF-β promotes immunosuppression in Human Immunodeficiency Virus (HIV)/Simian Immunodeficiency Virus (SIV) infection. However, the cellular source and downstream events of increased TGF-β production that attributes to its pathological manifestations remain unknown. Here, we have shown increased production of TGF-β in a majority of intestinal CD3−CD20−CD68+ cells from acute and chronically SIV infected rhesus macaques, which negatively correlated with the frequency of jejunum CD4+ T cells. No significant changes in intestinal TGF-β receptor II expression were observed but increased production of the pSMAD2/3 protein and SMAD3 gene expression in jejunum tissues that were accompanied by a downregulation of SMAD7 protein and gene expression. Enhanced TGF-β production by intestinal CD3−CD20−CD68+ cells and increased TGF-β/SMAD-dependent signaling might be due to a disruption of a negative feedback loop mediated by SMAD7. This suggests that SIV infection impacts the SMAD-dependent signaling pathway of TGF-β and provides a potential framework for further study to understand the role of viral factor(s) in modulating TGF-β production and downregulating SMAD7 expression in SIV. Regulation of mucosal TGF-β expression by therapeutic TGF-β blockers may help to create effective antiviral mucosal immune responses.

scholarly journals A Truncated Form of Nef Selected during Pathogenic Reversion of Simian Immunodeficiency Virus SIVmac239Δnef Increases Viral Replication

2003 ◽  
Vol 77 (2) ◽  
pp. 1245-1256 ◽  
Author(s):  
Lisa A. Chakrabarti ◽  
Karin J. Metzner ◽  
Tijana Ivanovic ◽  
Hua Cheng ◽  
Jean Louis-Virelizier ◽  
...  
Keyword(s):  
T Cell ◽  
Viral Replication ◽  
Simian Immunodeficiency Virus ◽  
Rhesus Macaques ◽  
Premature Stop Codon ◽  
Cell Depletion ◽  
Partial Recovery ◽  
Wild Type ◽  
T Cell Depletion ◽  
Immunodeficiency Virus

ABSTRACT The live, attenuated vaccine simian immunodeficiency virus SIVmac239Δnef efficiently protects rhesus macaques against infection with wild-type SIVmac but occasionally causes CD4+ T-cell depletion and progression to simian AIDS (SAIDS). Virus recovered from a vaccinated macaque (Rh1490) that progressed to SAIDS had acquired an additional deletion in the nef gene, resulting in a frameshift that restored the original nef open reading frame (R. I. Connor, D. C. Montefiori, J. M. Binley, J. P. Moore, S. Bonhoeffer, A. Gettie, E. A. Fenamore, K. E. Sheridan, D. D. Ho, P. J. Dailey, and P. A. Marx, J. Virol. 72:7501-7509, 1998). Intravenous inoculation of the Rh1490 viral isolate into four naive rhesus macaques induced CD4+ T-cell depletion and disease in three out of four animals within 2 years, indicating a restoration of virulence. A DNA fragment encompassing the truncated nef gene amplified from the Rh1490 isolate was inserted into the genetic backbone of SIVmac239. The resulting clone, SIVmac239-Δ2nef, expressed a Nef protein of approximately 23 kDa, while the original SIVmac239Δnef clone expressed a shorter protein of 8 kDa. The revertant form of Nef did not cause downregulation of CD4, CD3, or major histocompatibility complex class I. The infectivity of SIVmac239-Δ2nef was similar to that of SIVmac239Δnef in single-cycle assays using indicator cell lines. In contrast, SIVmac239-Δ2nef replicated more efficiently than SIVmac239Δnef in peripheral blood mononuclear cell (PBMC) cultures infected under unstimulated conditions. The p27 Gag antigen levels in SIVmac239-Δ2nef-infected cultures were still lower than those obtained with wild-type SIVmac239, consistent with a partial recovery of Nef function. The transcriptional activity of long terminal repeat (LTR)-luciferase constructs containing the nef deletions did not differ markedly from that of wild-type LTR. Introduction of a premature stop codon within Nef-Δ2 abolished the replicative advantage in PBMCs, demonstrating that the Nef-Δ2 protein, rather than the structure of the U3 region of the LTR, was responsible for the increase in viral replication. Taken together, these results show that SIV with a deletion in the nef gene can revert to virulence and that expression of a form of nef with multiple deletions may contribute to this process by increasing viral replication.

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 Quintuple Deglycosylation Mutant of Simian Immunodeficiency Virus SIVmac239 in Rhesus Macaques: Robust Primary Replication, Tightly Contained Chronic Infection, and Elicitation of Potent Immunity against the Parental Wild-Type Strain

2001 ◽  
Vol 75 (9) ◽  
pp. 4023-4028 ◽  
Author(s):  
Kazuyasu Mori ◽  
Yasuhiro Yasutomi ◽  
Shinji Ohgimoto ◽  
Tadashi Nakasone ◽  
Shiki Takamura ◽  
...  
Keyword(s):  
Simian Immunodeficiency Virus ◽  
Chronic Infection ◽  
Neutralizing Antibodies ◽  
Rhesus Macaques ◽  
Chronic Phase ◽  
Wild Type ◽  
Live Attenuated Vaccine ◽  
Challenge Virus ◽  
Culture Cells ◽  
Immunodeficiency Virus

ABSTRACT We previously generated a mutant of simian immunodeficiency virus (SIV) lacking 5 of a total of 22 N-glycans in its external envelope protein gp120 with no impairment in viral replication capability and infectivity in tissue culture cells. Here, we infected rhesus macaques with this mutant and found that it also replicated robustly in the acute phase but was tightly, though not completely, contained in the chronic phase. Thus, a critical requirement for the N-glycans for the full extent of chronic infection was demonstrated. No evidence indicating reversion to a wild type was obtained during the observation period of more than 40 weeks. Monkeys infected with the mutant were found to tolerate a challenge infection with wild-type SIV very well. Analyses of host responses following challenge revealed no neutralizing antibodies against the challenge virus but strong secondary responses of cytotoxic T lymphocytes against multiple antigens, including Gag-Pol, Nef, and Env. Thus, the quintuple deglycosylation mutant appeared to represent a novel class of SIV live attenuated vaccine.

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