Barriers to mucosal transmission of immunodeficiency viruses

Keele, Brandon F.; Estes, Jacob D.

doi:10.1182/blood-2010-12-325860

Cited by 74 publications

(68 citation statements)

References 72 publications

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“…The high genetic diversity identified in these chronic samples confirmed our assumption that the association between seronegativity and high VLs is indeed due to recent infection. We therefore assessed in these samples the number of transmitted founder variants and showed that SIV transmission in the wild is characterized by the same bottleneck as the one described in progressive HIV/SIV infections (49,50,111).…”

Section: Discussionmentioning

confidence: 99%

Factors Associated with Siman Immunodeficiency Virus Transmission in a Natural African Nonhuman Primate Host in the Wild

Jasinska

Feyertag

et al. 2014

J Virol

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African green monkeys (AGMs) are naturally infected with simian immunodeficiency virus (SIV) at high prevalence levels and do not progress to AIDS. Sexual transmission is the main transmission route in AGM, while mother-to-infant transmission (MTIT) is negligible. We investigated SIV transmission in wild AGMs to assess whether or not high SIV prevalence is due to differences in mucosal permissivity to SIV (i.e., whether the genetic bottleneck of viral transmission reported in humans and macaques is also observed in AGMs in the wild). We tested 121 sabaeus AGMs (Chlorocebus sabaeus) from the Gambia and found that 53 were SIV infected (44%). By combining serology and viral load quantitation, we identified 4 acutely infected AGMs, in which we assessed the diversity of the quasispecies by single-genome amplification (SGA) and documented that a single virus variant established the infections. We thus show that natural SIV transmission in the wild is associated with a genetic bottleneck similar to that described for mucosal human immunodeficiency virus (HIV) transmission in humans. Flow cytometry assessment of the immune cell populations did not identify major differences between infected and uninfected AGM. The expression of the SIV coreceptor CCR5 on CD4 ؉ T cells dramatically increased in adults, being higher in infected than in uninfected infant and juvenile AGMs. Thus, the limited SIV MTIT in natural hosts appears to be due to low target cell availability in newborns and infants, which supports HIV MTIT prevention strategies aimed at limiting the target cells at mucosal sites. Combined, (i) the extremely high prevalence in sexually active AGMs, (ii) the very efficient SIV transmission in the wild, and (iii) the existence of a fraction of multiparous females that remain uninfected in spite of massive exposure to SIV identify wild AGMs as an acceptable model of exposed, uninfected individuals. IMPORTANCEWe report an extensive analysis of the natural history of SIVagm infection in its sabaeus monkey host, the African green monkey species endemic to West Africa. Virtually no study has investigated the natural history of SIV infection in the wild. The novelty of our approach is that we report for the first time that SIV infection has no discernible impact on the major immune cell populations in natural hosts, thus confirming the nonpathogenic nature of SIV infection in the wild. We also focused on the correlates of SIV transmission, and we report, also for the first time, that SIV transmission in the wild is characterized by a major genetic bottleneck, similar to that described for HIV-1 transmission in humans. Finally, we report here that the restriction of target cell availability is a major correlate of the lack of SIV transmission to the offspring in natural hosts of SIVs.

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Section: Discussionmentioning

confidence: 99%

Factors Associated with Siman Immunodeficiency Virus Transmission in a Natural African Nonhuman Primate Host in the Wild

Jasinska

Feyertag

et al. 2014

J Virol

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“…These variants could be more efficient than others at any number of steps, including crossing the mucosal epithelium, infecting a susceptible CD4 ϩ target cell, evading innate immunity, expanding locally to infect other CD4 ϩ target cells, or disseminating out of the mucosa (41). However, residues A-K-N are so highly conserved in HIV-2/SIVsmm isolates that only the atypical amino acid composition of the SIVsmE660 challenge stock Env quasispecies allowed this selection event to be observed.…”

Section: Discussionmentioning

confidence: 99%

Signatures in Simian Immunodeficiency Virus SIVsmE660 Envelope gp120 Are Associated with Mucosal Transmission but Not Vaccination Breakthrough in Rhesus Macaques

Smith

Kilgore

Kasturi

et al. 2016

J Virol

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Mucosal surfaces are vulnerable to human immunodeficiency virus (HIV)/simian immunodeficiency virus (SIV) infection IMPORTANCEMost HIV-1 infections occur across a mucosal barrier, and it is therefore important to understand why these sites are vulnerable and how to protect them with a vaccine. To gain insight into these questions, we studied rhesus macaques that were vaccinated with SIVmac239 and unvaccinated controls to determine whether the SIVsmE660 viral variants that infected these two groups were different. We did not find differences between viral variants in the absence versus presence of vaccination-induced immunity, but we did find that the SIVsmE660 viral variants that infected the monkeys, regardless of vaccination, were different from the dominant population found in the viral challenge inoculum. Our data suggest that the mucosal environments of the vagina and rectum both impose a strong selection for the SIVsmE660 variants in the challenge inoculum that are most like SIV and HIVs that circulate in nature.T he majority of human immunodeficiency virus type 1 (HIV-1) transmission events occur across the genital or rectal mucosa and involve a reduction in the diversity of the infecting viral quasispecies (1). This genetic bottleneck of HIV-1 transmission has been attributed to various features of the HIV-1 envelope (Env) glycoproteins (2-8), resistance to interferon (7, 9), and a selection bias toward consensus residues that confer increased in vivo fitness (10). These studies notwithstanding, it has been difficult to pinpoint the attributes that directly facilitate transmission of a particular HIV-1 variant from a genetically diverse quasispecies. A primary focus of nonhuman primate simian immunodeficiency virus (SIV) challenge models is therefore to recapitulate the critical events that occur during HIV-1 transmission so that any observed effect, including protection, is accurately reflected by the model. An approach in which rhesus macaques are inoculated intravaginally or intrarectally at regular intervals with a relatively low dose of SIV has been shown to recapitulate the hallmark reduction in viral diversity characteristic of HIV-1 transmission (11)(12)(13)(14). As a result, the repeated, low-dose challenge method has become widely accepted and commonly utilized to model protection against mucosal SIV infection (14-32). Despite these numerous studies, the characteristics of the virus that influence intravaginal and intrarectal transmission and protection are incompletely understood.We previously demonstrated that an SIVmac239-based regimen consisting of two DNA primes followed by two modified vaccinia virus Ankara (MVA) boosts provided significant protection against repeated, low-dose SIVsmE660 intrarectal challenge. Including granulocyte-macrophage colony-stimulating factor (GM-CSF) or CD40 ligand (CD40L) as an adjuvant with the DNA Citation Smith SA, Kilgore KM, Kasturi SP, Pulendran B, Hunter E, Amara RR, Derdeyn CA. 2016. Signatures in simian immunodeficiency virus SIVsmE660 envelop...

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“…In 2015, ∼2 million individuals were newly infected with HIV-1, the great majority of whom acquired the virus by sexual routes (1). Although a number of factors, such as high donor viral loads, genital inflammation, altered mucosal microbiota, and recipient gender, are known to increase the infection risk (2-4), virus transmission across intact mucosal surfaces is inherently inefficient, with only a small fraction (less than 1%) of unprotected sexual exposures leading to productive infection (5)(6)(7)(8). This inefficiency is exemplified by a stringent population bottleneck, in which only one or a limited number of variants from the diverse quasispecies of the transmitting donor establish the new infection (9).…”

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confidence: 99%

Resistance to type 1 interferons is a major determinant of HIV-1 transmission fitness

Iyer

Bibollet-Ruche

Sherrill-Mix

et al. 2017

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

131

180

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Sexual transmission of HIV-1 is an inefficient process, with only one or few variants of the donor quasispecies establishing the new infection. A critical, and as yet unresolved, question is whether the mucosal bottleneck selects for viruses with increased transmission fitness. Here, we characterized 300 limiting dilution-derived virus isolates from the plasma, and in some instances genital secretions, of eight HIV-1 donor and recipient pairs. Although there were no differences in the amount of virion-associated envelope glycoprotein, recipient isolates were on average threefold more infectious (P = 0.0001), replicated to 1.4-fold higher titers (P = 0.004), were released from infected cells 4.2-fold more efficiently (P < 0.00001), and were significantly more resistant to type I IFNs than the corresponding donor isolates. Remarkably, transmitted viruses exhibited 7.8-fold higher IFNα2 (P < 0.00001) and 39-fold higher IFNβ (P < 0.00001) half-maximal inhibitory concentrations (IC 50 ) than did donor isolates, and their odds of replicating in CD4 + T cells at the highest IFNα2 and IFNβ doses were 35-fold (P < 0.00001) and 250-fold (P < 0.00001) greater, respectively. Interestingly, pretreatment of CD4 + T cells with IFNβ, but not IFNα2, selected donor plasma isolates that exhibited a transmitted virus-like phenotype, and such viruses were also detected in the donor genital tract. These data indicate that transmitted viruses are phenotypically distinct, and that increased IFN resistance represents their most distinguishing property. Thus, the mucosal bottleneck selects for viruses that are able to replicate and spread efficiently in the face of a potent innate immune response.

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Barriers to mucosal transmission of immunodeficiency viruses

Cited by 74 publications

References 72 publications

Factors Associated with Siman Immunodeficiency Virus Transmission in a Natural African Nonhuman Primate Host in the Wild

Factors Associated with Siman Immunodeficiency Virus Transmission in a Natural African Nonhuman Primate Host in the Wild

Signatures in Simian Immunodeficiency Virus SIVsmE660 Envelope gp120 Are Associated with Mucosal Transmission but Not Vaccination Breakthrough in Rhesus Macaques

Resistance to type 1 interferons is a major determinant of HIV-1 transmission fitness

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