Nonhuman Primate Models for Cell-Associated Simian Immunodeficiency Virus Transmission: The Need to Better Understand the Complexity of HIV Mucosal Transmission

Bernard-Stoecklin, Sibylle; Gommet, Céline; Cavarelli, Mariangela; Grand, Roger Le

doi:10.1093/infdis/jiu536

Cited by 17 publications

(11 citation statements)

References 57 publications

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“…Also, the characteristics of infection and specific viral life cycle changes are still unknown. Such studies have been hampered by the limited availability of tissue from individuals at varying disease stages or by whether SIV infections truly paralleled what is present in a human host 35 36 37 38 . In humanized mice, available techniques lacked both cell specificity and sensitivity for low copy viral DNA detection especially when small numbers of cells were made available 39 40 .…”

Section: Discussionmentioning

confidence: 99%

HIV-1 cellular and tissue replication patterns in infected humanized mice

Araínga

Poluektova

et al. 2016

Sci Rep

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Humanized mice have emerged as a testing platform for HIV-1 pathobiology by reflecting natural human disease processes. Their use to study HIV-1 biology, virology, immunology, pathogenesis and therapeutic development has served as a robust alternative to more-well developed animal models for HIV/AIDS. A critical component in reflecting such human pathobiology rests in defining the tissue and cellular sites for HIV-1 infection. To this end, we examined the tissue sites for viral infection in bone marrow, blood, spleens, liver, gut, brain, kidney and lungs of human CD34+ hematopoietic stem cell engrafted virus-infected NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ mice. Cells were analyzed by flow cytometry and sorted from species mixtures defined as CD34+ lineage negative progenitor cells, CD14+CD16+ monocyte-macrophages and central, stem cell and effector memory T cells. The cell distribution and viral life cycle were found dependent on the tissue compartment and time of infection. Cell subsets contained HIV-1 total and integrated DNA as well as multi-spliced and unspliced RNA in divergent proportions. The data support the idea that humanized mice can provide a means to examine the multifaceted sites of HIV-1 replication including, but not limited to progenitor cells and monocyte-macrophages previously possible only in macaques and human.

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Section: Discussionmentioning

confidence: 99%

HIV-1 cellular and tissue replication patterns in infected humanized mice

Araínga

Poluektova

et al. 2016

Sci Rep

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“…It is possible that vaccine-elicited antibodies capable of potent neutralization in the TZM-bl assay lack certain biological properties that are essential for preventing acquisition in vivo (14,47). Cell-to-cell transmission could play a more prominent role in intrarectal SIV infection than is currently recognized (48)(49)(50)(51), and higher concentrations of antibodies with certain specificities could then be necessary to prevent establishment of infection (52,53). It is similarly possible that the atypically high neutralization sensitivity of SIVsmE660 Env variants involves antibody specificities that are greatly enhanced in the TZM-bl assay and have limited relevance to those that neutralize HIV-1 (27).…”

Section: Discussionmentioning

confidence: 99%

Breakthrough of SIV strain smE660 challenge in SIV strain mac239-vaccinated rhesus macaques despite potent autologous neutralizing antibody responses

Burton

Kilgore

Smith

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Although the correlates of immunological protection from human immunodeficiency virus or simian immunodeficiency virus infection remain incompletely understood, it is generally believed that medium to high titers of serum neutralizing antibodies (nAbs) against the challenge virus will prevent infection. This paradigm is based on a series of studies in which passive transfer of HIV-specific nAbs protected rhesus macaques (RMs) from subsequent mucosal challenge with a chimeric human/simian immunodeficiency virus. However, it is unknown whether nAb titers define protection in the setting of active immunization. Here we determined serum nAb titers against breakthrough transmitted/founder (T/F) SIVsmE660-derived envelope glycoprotein (Env) variants from 14 RMs immunized with SIVmac239-based DNA-prime/modified vaccinia virus Ankara-boost vaccine regimens that included GM-CSF or CD40L adjuvants and conferred significant but incomplete protection against repeated low-dose intrarectal challenge. A single Env variant established infection in all RMs except one, with no identifiable genetic signature associated with vaccination breakthrough compared with T/F Envs from four unvaccinated monkeys. Breakthrough T/F Env pseudoviruses were potently neutralized in vitro by heterologous pooled serum from chronically SIVsmE660-infected monkeys at IC50 titers exceeding 1:1,000,000. Remarkably, the T/F Env pseudoviruses from 13 of 14 monkeys were also susceptible to neutralization by autologous prechallenge serum at in vitro IC50 titers ranging from 1:742–1:10,832. These titers were similar to those observed in vaccinated RMs that remained uninfected. These data suggest that the relationship between serum nAb titers and protection from mucosal SIV challenge in the setting of active immunization is more complex than previously recognized, warranting further studies into the balance between immune activation, target cell availability, and protective antibody responses.

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“…Also, humans areinfected through biological fluids that do notonlycontain freevirus, but also infectedcells andother components, suchasinflammatorycytokines.Studies are ongoingto evaluate if therearedifferences dependingon the composition of the inoculum 130,131 .…”

Section: Limitations Perspectivesandconclusionmentioning

confidence: 99%

Non-human primates in HIV research: Achievements, limits and alternatives

García-Téllez

Huot

Ploquin

et al. 2016

Infection, Genetics and Evolution

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An ideal model for HIV-1 research is still unavailable. However, infection of non-human primates (NHP), such as macaques, with Simian Immunodeficiency Virus (SIV) recapitulates most virological, immunological and clinical hallmarks of HIV infection in humans. It has become the most suitable model to study the mechanisms of transmission and physiopathology of HIV/AIDS. On the other hand, natural hosts of SIV, such as African green monkeys and sooty mangabeys that when infected do not progress to AIDS, represent an excellent model to elucidate the mechanisms involved in the capacity of controlling inflammation and disease progression. The use of NHP-SIV models has indeed enriched our knowledge in the fields of: i) viral transmission and viral reservoirs, ii) early immune responses, iii) host cell-virus interactions in tissues, iv) AIDS pathogenesis, v) virulence factors, vi) prevention and vii) drug development. The possibility to control many variables during experimental SIV infection, together with the resemblance between SIV and HIV infections, make the NHP model the most appropriate, so far, for HIV/AIDS research. Nonetheless, some limitations in using these models have to be considered. Alternative models for HIV/AIDS research, such as humanized mice and recombinant forms of HIV-SIV viruses (SHIV) for NHP infection, have been developed. The improvement of SHIV viruses that mimic even better the natural history of HIV infection and of humanized mice that develop a greater variety of human immune cell lineages, is ongoing. None of these models is perfect, but they allow contributing to the progress in managing or preventing HIV infection.

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Nonhuman Primate Models for Cell-Associated Simian Immunodeficiency Virus Transmission: The Need to Better Understand the Complexity of HIV Mucosal Transmission

Cited by 17 publications

References 57 publications

HIV-1 cellular and tissue replication patterns in infected humanized mice

HIV-1 cellular and tissue replication patterns in infected humanized mice

Breakthrough of SIV strain smE660 challenge in SIV strain mac239-vaccinated rhesus macaques despite potent autologous neutralizing antibody responses

Non-human primates in HIV research: Achievements, limits and alternatives

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