No Evidence for Consistent Virus-Specific Immunity in Simian Immunodeficiency Virus-Exposed, Uninfected Rhesus Monkeys

Letvin, Norman L.; Rao, Srinivas G.; Dang, Vi; Buzby, Adam P.; Korioth-Schmitz, Birgit; Dombagoda, Dilani; Parvani, Jenny G.; Clarke, Ryon H.; Bar, Liat; Carlson, Kevin R.; Kozlowski, Pamela A.; Hirsch, Vanessa M.; Mascola, John R.; Nabel, Gary J.

doi:10.1128/jvi.00822-07

Cited by 51 publications

(45 citation statements)

References 25 publications

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“…Interestingly, the two animals that resisted superinfection had also resisted 18 attempts at the first infection by the intrarectal route and required intravenous inoculation to establish primary infection. This finding raises the possibility that variations in the mucosal barrier rather than specific immunological mechanisms may have contributed to differences in susceptibility to mucosal infection in this cohort of animals (29).…”

Section: Discussionmentioning

confidence: 81%

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Partial Protection of Simian Immunodeficiency Virus (SIV)-Infected Rhesus Monkeys against Superinfection with a Heterologous SIV Isolate

Yeh

Jaru-Ampornpan

Nevidomskyte

et al. 2009

J Virol

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Although there is increasing evidence that individuals already infected with human immunodeficiency virus type 1 (HIV-1) can be infected with a heterologous strain of the virus, the extent of protection against superinfection conferred by the first infection and the biologic consequences of superinfection are not well understood. We explored these questions in the simian immunodeficiency virus (SIV)/rhesus monkey model of HIV-1/AIDS. We infected cohorts of rhesus monkeys with either SIVmac251 or SIVsmE660 and then exposed animals to the reciprocal virus through intrarectal inoculations. Employing a quantitative real-time PCR assay, we determined the replication kinetics of the two strains of virus for 20 weeks. We found that primary infection with a replication-competent virus did not protect against acquisition of infection by a heterologous virus but did confer relative control of the superinfecting virus. In animals that became superinfected, there was a reduction in peak replication and rapid control of the second virus. The relative susceptibility to superinfection was not correlated with CD4 ؉ T-cell count, CD4 ؉ memory T-cell subsets, cytokine production by virus-specific CD8 ؉ or CD4 ؉ cells, or neutralizing antibodies at the time of exposure to the second virus. Although there were transient increases in viral loads of the primary virus and a modest decline in CD4؉ T-cell counts after superinfection, there was no evidence of disease acceleration. These findings indicate that an immunodeficiency virus infection confers partial protection against a second immunodeficiency virus infection, but this protection may be mediated by mechanisms other than classical adaptive immune responses.Superinfection with human immunodeficiency virus type 1 (HIV-1) is the infection of an HIV-seropositive individual with a second heterologous strain of the virus after infection with the first infecting strain is established. There is accruing evidence for HIV-1 intra-and intersubtype superinfection in settings of intravenous drug use, structured treatment interruptions, and with strains that are resistant to antiretroviral drugs (2,4,6,22,26,28,32,39,42,43,52,60,66). Epidemiologic studies have suggested that the frequency of superinfection ranges from rare to as high as 5% per year in high-risk populations (9,10,15,20,24,27,31,40,41,51,59,65,67). However, it remains unclear how readily superinfections occur after exposure of an infected individual to a heterologous strain of virus. Furthermore, the variables that may contribute to susceptibility or resistance to superinfection, such as the timing of exposure to a second virus or the immunologic status of the exposed individual, have not been well defined. It is also uncertain whether superinfection is invariably associated with the loss of HIV containment and clinical deterioration (8,17,21,23,26,27,30,60). Understanding the risks for and the biological consequences of HIV superinfection will not only clarify an important clinical problem, it may also provide important insig...

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Section: Discussionmentioning

confidence: 81%

“…These were doses that were previously shown to reproducibly initiate mucosal infections in rhesus monkeys (29).…”

mentioning

confidence: 99%

Partial Protection of Simian Immunodeficiency Virus (SIV)-Infected Rhesus Monkeys against Superinfection with a Heterologous SIV Isolate

Yeh

Jaru-Ampornpan

Nevidomskyte

et al. 2009

J Virol

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“…For T-cell responses in ferrets, we used a modified RT-PCR assay to quantify cytokine mRNAs (20,21). Humoral immune assays were performed by ELISA as previously described (22).…”

Section: Methodsmentioning

confidence: 99%

Genetic immunization in the lung induces potent local and systemic immune responses

Song

Bolton

Wei

et al. 2010

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

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The authors note the following: "Due to an error in the evaluation of the raw ITC-data, we reported the wrong sign for the enthalpy values and correspondingly incorrect entropy values. The correct values are as follows: at pH 5.7: ΔH −54 ± 4 kJ/ mol, ΔS −68 ± 14 J/mol K and at pH 7.2: ΔH −62 ± 6 kJ/mol and ΔS −98 ± 18 J/mol K (Table 3)." The authors note that on page 5381, left column, first paragraph, line 9 "Two E1 entities dimerize upon their interaction with heparin, requiring 8-12 sugar rings to form the heparin-bridged APP-E1 dimer in an endothermic and pH-dependent process that is characterized by a low micromolar dissociation constant" should have read "Two E1 entities dimerize upon their interaction with heparin, requiring 8-12 sugar rings to form the heparin-bridged APP-E1 dimer in an exothermic and pH-dependent process that is characterized by a low micromolar dissociation constant." On page 5384, right column, third paragraph, line 23 "This reaction is driven by high entropy contributions of around 300 J/mol · K, probably resulting from the release of associated ions and water molecules upon heparin binding, as also observed for other heparin-binding proteins (reviewed, e.g., in ref. 39)" should have read "This reaction is driven by significant enthalpic contributions, probably arising from protein-protein interactions, also observed for other heparin-binding proteins (reviewed, e.g., in ref. 39)." This error does not affect the conclusions of the article.

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“…The cell-free SIVsmE660 isolate used was initially generated by Vanessa Hirsch (11) and then expanded on rhesus macaque PBMCs and used as a virus challenge stock in studies conducted to test the transmission bottleneck and adaptive immune responses in mucosally infected rhesus macaques in naive and vaccinated rhesus macaques (27,41). For this study, the SIVsmE660 isolate was expanded on rhesus macaque CD4 ϩ T cells.…”

Section: Methodsmentioning

confidence: 99%

Heterogeneity in Neutralization Sensitivities of Viruses Comprising the Simian Immunodeficiency Virus SIVsmE660 Isolate and Vaccine Challenge Stock

Lopker

Easlick

Sterrett

et al. 2013

J Virol

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The sooty mangabey-derived simian immunodeficiency virus (SIV) strain E660 (SIVsmE660) is a genetically heterogeneous, pathogenic isolate that is commonly used as a vaccine challenge strain in the nonhuman primate (NHP) model of human immunodeficiency virus type 1 (HIV-1) infection. Though it is often employed to assess antibody-based vaccine strategies, its sensitivity to antibody-mediated neutralization has not been well characterized. Here, we utilize single-genome sequencing and infectivity assays to analyze the neutralization sensitivity of the uncloned SIVsmE660 isolate, individual viruses comprising the isolate, and transmitted/founder (T/F) viruses arising from low-dose mucosal inoculation of macaques with the isolate. We found that the SIVsmE660 isolate overall was highly sensitive to neutralization by SIV-infected macaque plasma samples (50% inhibitory concentration [IC 50 ] < 10 ؊5 ) and monoclonal antibodies targeting V3 (IC 50 < 0.01 g/ml), CD4-induced (IC 50 < 0.1 g/ml), CD4 binding site (IC 50 ϳ 1 g/ml), and V4 (IC 50 , ϳ5 g/ml) epitopes. In comparison, SIVmac251 and SIVmac239 were highly resistant to neutralization by these same antibodies. Differences in neutralization sensitivity between SIVsmE660 and SIVmac251/239 were not dependent on the cell type in which virus was produced or tested. These findings indicate that in comparison to SIVmac251/239 and primary HIV-1 viruses, SIVsmE660 generally exhibits substantially less masking of antigenically conserved Env epitopes. Interestingly, we identified a minor population of viruses (ϳ10%) in both the SIVsmE660 isolate and T/F viruses arising from it that were substantially more resistant (>1,000-fold) to antibody neutralization and another fraction (ϳ20%) that was intermediate in neutralization resistance. These findings may explain the variable natural history and variable protection afforded by heterologous Env-based vaccines in rhesus macaques challenged by high-dose versus low-dose SIVsmE660 inoculation regimens.

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No Evidence for Consistent Virus-Specific Immunity in Simian Immunodeficiency Virus-Exposed, Uninfected Rhesus Monkeys

Cited by 51 publications

References 25 publications

Partial Protection of Simian Immunodeficiency Virus (SIV)-Infected Rhesus Monkeys against Superinfection with a Heterologous SIV Isolate

Partial Protection of Simian Immunodeficiency Virus (SIV)-Infected Rhesus Monkeys against Superinfection with a Heterologous SIV Isolate

Genetic immunization in the lung induces potent local and systemic immune responses

Heterogeneity in Neutralization Sensitivities of Viruses Comprising the Simian Immunodeficiency Virus SIVsmE660 Isolate and Vaccine Challenge Stock

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