Characterisation of simian immunodeficiency virus-infected cells in pigtail macaques

Winnall, Wendy Rachael; Sexton, Amy; Alcântara, Sheilajen; Roath, Sarah; Rose, Robert De; Kent, Stephen J.

doi:10.1016/j.virol.2012.03.016

Cited by 4 publications

(4 citation statements)

References 46 publications

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“…The LLOQs of the assay are denoted for both SOFT (solid line) and CUM (dotted line) analyses. ***, P Ͻ 0.001. and SIV mac251 (52). The frequency (ϳ10%) of SHIV-RT-infected cells within the infected PBMC stock in our study was within the reported range (0.002 to 16%) (13) of HIV-infected cells in human semen.…”

Section: Discussionsupporting

confidence: 80%

MIV-150/Zinc Acetate Gel Inhibits Cell-Associated Simian-Human Immunodeficiency Virus Reverse Transcriptase Infection in a Macaque Vaginal Explant Model

Barnable

Calenda

Bonnaire

et al. 2015

Antimicrob Agents Chemother

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The transmission of both cell-free and cell-associated immunodeficiency viruses has been demonstrated directly in multiple animal species and possibly occurs in humans, as suggested by genotyping of the infecting human immunodeficiency virus (HIV) in acutely infected women and in semen from their partners. Therefore, a microbicide may need to block both mechanisms of HIV transmission to achieve maximum efficacy. To date, most of the preclinical evaluation of candidate microbicides has been performed using cell-free HIV. New models of mucosal transmission of cell-associated HIV are needed to evaluate candidate microbicide performance. The MIV-150/zinc acetate/carrageenan (MZC) gel protects Depo-Provera-treated macaques against cell-free simian-human immunodeficiency virus reverse transcriptase (SHIV-RT) infection when applied vaginally up to 8 h before challenge. We recently demonstrated the potent activity of MZC gel against cell-free SHIV-RT in macaque vaginal explants. In the current study, we established a cell-associated SHIV-RT infection model of macaque vaginal tissues and tested the activity of MZC gel in this model. MZC gel protected tissues against cell-associated SHIV-RT infection when present at the time of viral exposure or when applied up to 4 days prior to viral challenge. These data support clinical testing of the MZC gel. Overall, our ex vivo model of cell-associated SHIV-RT infection in macaque vaginal mucosa complements the cell-free infection models, providing tools for prioritization of products that block both modes of HIV transmission. Women account for about half of human immunodeficiency virus type 1 (HIV-1) infections, with the majority of infections transmitted via sexual intercourse (1). A longitudinal study reported that the genotype of the infecting HIV-1 in acutely infected women closely matches the virus in the seminal plasma and seminal cells from their chronically infected sexual partners (2), suggesting that transmission of both cell-free and cell-associated HIV-1 occurs in vivo. Furthermore, transmitter/founder donor variants were identified in peripheral blood mononuclear cells (PBMCs) and blood plasma, also suggesting that both cell-free transmission and cell-associated HIV transmission occur in vivo (3, 4). Which mode of transmission has a primary role in the establishment of mucosal infection is yet to be determined (5).Cell-to-cell HIV transmission is associated with efficient in vitro viral transfer through virological synapses (6-9). Cell-associated HIV was shown to pass the epithelial monolayer and infect the underlying target cells in vitro (10, 11). In agreement with this information, seminal cells (12) and macrophages (13) were shown to penetrate the epithelium in cervical explant tissues and thus could potentially deliver HIV to target cells. Recent studies mimicking HIV transmission in the intestinal tract in a rectal explant model revealed that ex vivo transmission of cell-associated simian immunodeficiency virus (SIV mac251 ) is more efficient than transmission o...

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Section: Discussionsupporting

confidence: 80%

MIV-150/Zinc Acetate Gel Inhibits Cell-Associated Simian-Human Immunodeficiency Virus Reverse Transcriptase Infection in a Macaque Vaginal Explant Model

Barnable

Calenda

Bonnaire

et al. 2015

Antimicrob Agents Chemother

View full text Add to dashboard Cite

show abstract

“…CEM-NKR-CCR5 cells were washed extensively after 48 h to remove the original virus and then cultured for a further 5 days. To confirm SIV infection, qRT-PCR of SIV gag showed an exponential increase in virus production up to at least 7 days (data not shown), as described previously [29].…”

Section: Virus Production In Vitrosupporting

confidence: 57%

“…Blood samples were taken regularly (1-4 weekly) until autopsy. Infection of animals was confirmed by qRT-PCR of SIV gag in plasma samples, as described previously [29]. Animals were euthanized with pentobarbitone (0.5 ml/kg i.v.)…”

Section: Infection Of Animals and Tissue Samplingmentioning

confidence: 99%

Simian immunodeficiency virus infection and immune responses in the pig-tailed macaque testis

Winnall

Lloyd

Rose

et al. 2015

Journal of Leukocyte Biology

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The testis is a site of immune privilege in rodents, and there is evidence that T cell responses are also suppressed in the primate testis. Local immunosuppression is a potential mechanism for HIV persistence in tissue reservoirs that few studies have examined. The response of the pig-tailed macaque testis to SIVmac239 infection was characterized to test this possibility. Testes were surgically removed during early-chronic (10 wk) and late-chronic (24-30 wk) SIV infection in 4 animals and compared with those from 7 uninfected animals. SIV infection caused only minor disruption to the seminiferous epithelium without marked evidence of inflammation or consistent changes in total intratesticular leukocyte numbers. Infection also led to an increase in the relative proportion of testicular effector memory CD8(+) T cell numbers and a corresponding reduction in central memory CD4(+) T cells. A decrease in the relative proportion of resident-type CD163(+) macrophages and DCs was also observed. SIV-specific CD8(+) T cells were detectable in the testis, 10-11 wk after infection by staining with SIV Gag-specific or Tat-specific MHC-I tetramers. However, testicular CD8(+) T cells from the infected animals had suppressed cytokine responses to mitogen activation. These results support the possibility that local immunosuppression in the testis may be restricting the ability of T cells to respond to SIV or HIV infection. Local immunosuppression in the testis may be an underexplored mechanism allowing HIV persistence.

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“…Nonhuman primates represent the best available animal model of HIV infection in vivo and provide important preclinical data for various anti‐HIV intervention strategies. Over the past decade, the pigtailed macaque ( Macaca nemestrina ) model has emerged as a useful system in which to study viral pathogenesis, host immune response, and vaccine efficacy . Additionally, this species of macaque serves as a well‐established large animal model of hematopoietic stem cell transplant gene therapy .…”

Section: Introductionmentioning

confidence: 99%

Robust suppression of env‐SHIV viremia in Macaca nemestrina by 3‐drug ART is independent of timing of initiation during chronic infection

Peterson

Younan

Polacino

et al. 2013

J of Medical Primatology

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Background Nonhuman primates (NHPs) are an important model organism for studies of HIV pathogenesis and pre-clinical evaluation of anti-HIV therapies. The successful translation of NHP-derived data to clinically relevant anti-HIV studies will require better understanding of the viral strains and NHP species used, and their responses to existing antiretroviral therapies (ART). Methods Five pigtailed macaques (M. nemestrina) were productively infected with the SIV/HIV chimeric virus SHIV-1157ipd3N4 following intravenous challenge. After 8 or 27 weeks, ART (PMPA, FTC, Raltegravir) was initiated. Viral load, T-Cell counts, and production of SHIV-specific antibodies were monitored throughout the course of infection and ART. Results ART led to a rapid and sustained decrease in plasma viral load. Suppression of plasma viremia by ART was independent of the timing of initiation during chronic infection. Conclusions We present a new NHP model of HIV infection on antiretroviral therapy, which should prove applicable to multiple clinically relevant anti-HIV approaches.

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Characterisation of simian immunodeficiency virus-infected cells in pigtail macaques

Cited by 4 publications

References 46 publications

MIV-150/Zinc Acetate Gel Inhibits Cell-Associated Simian-Human Immunodeficiency Virus Reverse Transcriptase Infection in a Macaque Vaginal Explant Model

MIV-150/Zinc Acetate Gel Inhibits Cell-Associated Simian-Human Immunodeficiency Virus Reverse Transcriptase Infection in a Macaque Vaginal Explant Model

Simian immunodeficiency virus infection and immune responses in the pig-tailed macaque testis

Robust suppression of env‐SHIV viremia in Macaca nemestrina by 3‐drug ART is independent of timing of initiation during chronic infection

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