Rhesus Macaque Resistance to Mucosal Simian Immunodeficiency Virus Infection Is Associated with a Postentry Block in Viral Replication

Peng, Bo; Voltan, Rebecca; Lim, Lulu; Edghill-Smith, Yvette; Phogat, Sanjay; Dimitrov, Dimiter S.; Arora, Kamalpreet; Leno, Michel; Than, Soe; Woodward, Ruth A.; Markham, Phillip D.; Cranage, Martin; Robert-Guroff, Marjorie

doi:10.1128/jvi.76.12.6016-6026.2002

Cited by 11 publications

(9 citation statements)

References 58 publications

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“…While it is possible that immunization with MVA Gag may have contributed to the resistance of 256.90 to SIV infection, this is also unlikely to be the sole explanation for this result, since such solid protection against challenge with pathogenic SIVmac strains is rarely, if ever, observed in animals immunized with recombinant poxviruses. Resistance to mucosal SIV infection among control animals has been observed in other vaccine studies and often complicates the interpretation of protection data obtained from mucosal challenges (29). Thus, some animals may have an inherent resistance to mucosal infection that is poorly understood at present (29).…”

Section: Fig 6 Siv Rna In Plasma and Cd4mentioning

confidence: 99%

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Mucosal Priming of Simian Immunodeficiency Virus-Specific Cytotoxic T-Lymphocyte Responses in Rhesus Macaques by theSalmonellaType III Secretion Antigen Delivery System

Evans

Chen

Gillis

et al. 2003

J Virol

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Nearly all human immunodeficiency virus (HIV) infections are acquired mucosally, and the gut-associated lymphoid tissues are important sites for early virus replication. Thus, vaccine strategies designed to prime virus-specific cytotoxic T lymphocyte (CTL) responses that home to mucosal compartments may be particularly effective at preventing or containing HIV infection. The Salmonella type III secretion system has been shown to be an effective approach for stimulating mucosal CTL responses in mice. We therefore tested ⌬phoP-phoQ attenuated strains of Salmonella enterica serovar Typhimurium and S. enterica serovar Typhi expressing fragments of the simian immunodeficiency virus (SIV) Gag protein fused to the type III-secreted SopE protein for the ability to prime virus-specific CTL responses in rhesus macaques. Mamu-A*01 ؉ macaques were inoculated with three oral doses of recombinant Salmonella, followed by a peripheral boost with modified vaccinia virus Ankara expressing SIV Gag (MVA Gag). Transient low-level CTL responses to the Mamu-A*01 Gag 181-189 epitope were detected following each dose of Salmonella. After boosting with MVA Gag, strong Gag-specific CTL responses were consistently detected, and tetramer staining revealed the expansion of Gag 181-189 -specific CD8 ؉ T-cell responses in peripheral blood. A significant percentage of the Gag 181-189 -specific T-cell population in each animal also expressed the intestinal homing receptor ␣4␤7. Additionally, Gag 181-189 -specific CD8 ؉ T cells were detected in lymphocytes isolated from the colon. Yet, despite these responses, Salmonella-primed/MVA-boosted animals did not exhibit improved control of virus replication following a rectal challenge with SIVmac239. Nevertheless, this study demonstrates the potential of mucosal priming by the Salmonella type III secretion system to direct SIV-specific cellular immune responses to the gastrointestinal mucosa in a primate model.

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Section: Fig 6 Siv Rna In Plasma and Cd4mentioning

confidence: 99%

“…Resistance to mucosal SIV infection among control animals has been observed in other vaccine studies and often complicates the interpretation of protection data obtained from mucosal challenges (29). Thus, some animals may have an inherent resistance to mucosal infection that is poorly understood at present (29).…”

Section: Fig 6 Siv Rna In Plasma and Cd4mentioning

confidence: 99%

Mucosal Priming of Simian Immunodeficiency Virus-Specific Cytotoxic T-Lymphocyte Responses in Rhesus Macaques by theSalmonellaType III Secretion Antigen Delivery System

Evans

Chen

Gillis

et al. 2003

J Virol

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“…Some studies indicate that differences in host genetics or virus-specific immunity participate in virus control [1-3], but it is unlikely that a single factor is responsible.…”

Section: Introductionmentioning

confidence: 99%

Resistance to simian immunodeficiency virus low dose rectal challenge is associated with higher constitutive TRIM5α expression in PBMC

et al. 2014

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BackgroundAt least six host-encoded restriction factors (RFs), APOBEC3G, TRIM5α, tetherin, SAMHD1, schlafen 11, and Mx2 have now been shown to inhibit HIV and/or SIV replication in vitro. To determine their role in vivo in the resistance of macaques to mucosally-acquired SIV, we quantified both pre-exposure (basal) and post-exposure mRNA levels of these RFs, Mx1, and IFNγ in PBMC, lymph nodes, and duodenum of rhesus macaques undergoing weekly low dose rectal exposures to the primary isolate, SIV/DeltaB670.ResultsRepetitive challenge divided the monkeys into two groups with respect to their susceptibility to infection: highly susceptible (2–3 challenges, 5 monkeys) and poorly susceptible (≥6 challenges, 3 monkeys). Basal RF and Mx1 expression varied among the three tissues examined, with the lowest expression generally detected in duodenal tissues, and the highest observed in PBMC. The one exception was A3G whose basal expression was greatest in lymph nodes. Importantly, significantly higher basal expression of TRIM5α and Mx1 was observed in PBMC of animals more resistant to mucosal infection. Moreover, individual TRIM5α levels were stable throughout a year prior to infection. Post-exposure induction of these genes was also observed after virus appearance in plasma, with elevated levels in PBMC and duodenum transiently occurring 7–10 days post infection. They did not appear to have an effect on control of viremia. Interestingly, minimal to no induction was observed in the resistant animal that became an elite controller.ConclusionsThese results suggest that constitutively expressed TRIM5α appears to play a greater role in restricting mucosal transmission of SIV than that associated with type I interferon induction following virus entry. Surprisingly, this association was not observed with the other RFs. The higher basal expression of TRIM5α observed in PBMC than in duodenal tissues emphasizes the understated role of the second barrier to systemic infection involving the transport of virus from the mucosal compartment to the blood. Together, these observations provide a strong incentive for a more comprehensive examination of the intrinsic, variable control of constitutive expression of these genes in the sexual transmission of HIV.

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“…As far as a genetic predisposition to control virus replication is concerned, we observed that the PBMC of monkey 954, when infected in vitro, were equally susceptible to virus infection as were the PBMC of other monkeys. Thus, any genetic restriction factor of virus replication at the level of virus entry or post-entry (Peng et al, 2002;Pal et al, 2002) was ruled out. Conversely, it is very likely that the limited infection observed in monkey 954 was due to the very low amount of virus taken up by the rectal mucosa, as a consequence of the incomplete delivery of virus inoculum.…”

Section: Discussionmentioning

confidence: 99%

Protective efficacy of a multicomponent vector vaccine in cynomolgus monkeys after intrarectal simian immunodeficiency virus challenge

Negri

Baroncelli

Catone

et al. 2004

Journal of General Virology

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We investigated the protective efficacy of a systemic triple vector (DNA/rSFV/rMVA)-based vaccine against mucosal challenge with pathogenic simian immunodeficiency virus (SIV) in cynomolgus monkeys. Animals were immunized at week 0 with DNA (intradermally), at weeks 8 and 16 with recombinant Semliki Forest virus (rSFV, subcutaneously) and finally, at week 24, with recombinant modified vaccinia virus Ankara strain (rMVA, intramuscularly). Both DNA and recombinant viral vectors expressed a wide range of SIV proteins (Gag, Pol, Tat, Rev, Env and Nef). This immunization strategy elicited cell-mediated rather than humoral responses that were especially increased following the last boost. Upon intrarectal challenge with pathogenic SIVmac251, three of the four vaccinated monkeys dramatically abrogated virus load to undetectable levels up to 41 weeks after challenge. A major contribution to this vaccine effect appeared to be the T-cell-mediated immune response to vaccine antigens (Gag, Rev, Tat, Nef) seen in the early phase of infection in three of the four vaccinated monkeys. Indeed, the frequency of T-cells producing antigen-induced IFN-c mirrored virus clearance in the vaccinated and protected monkeys. These results, reminiscent of the efficacy of live attenuated virus vaccines, suggest that vaccination with a combination of many viral antigens can induce a robust and stable vaccine-induced immunity able to abrogate virus replication.

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Rhesus Macaque Resistance to Mucosal Simian Immunodeficiency Virus Infection Is Associated with a Postentry Block in Viral Replication

Cited by 11 publications

References 58 publications

Mucosal Priming of Simian Immunodeficiency Virus-Specific Cytotoxic T-Lymphocyte Responses in Rhesus Macaques by theSalmonellaType III Secretion Antigen Delivery System

Mucosal Priming of Simian Immunodeficiency Virus-Specific Cytotoxic T-Lymphocyte Responses in Rhesus Macaques by theSalmonellaType III Secretion Antigen Delivery System

Resistance to simian immunodeficiency virus low dose rectal challenge is associated with higher constitutive TRIM5α expression in PBMC

Protective efficacy of a multicomponent vector vaccine in cynomolgus monkeys after intrarectal simian immunodeficiency virus challenge

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