Resistance of Transmitted Founder HIV-1 to IFITM-Mediated Restriction

Foster, Toshana L.; Wilson, Harry; Iyer, Shilpa S.; Coss, Karen P.; Doores, Katie J.; Smith, Sarah E.; Kellam, Paul; Finzi, Andrés; Borrow, Persephone; Hahn, Beatrice H.; Neil, Stuart J. D.

doi:10.1016/j.chom.2016.08.006

Cited by 157 publications

(266 citation statements)

References 46 publications

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“…In this context, it is critical to know whether transmitted viruses possess unique biological properties that predispose them to establish new infections more efficiently. This is a controversial topic, because some studies have reported TF-specific traits (22,24,26,52,(55)(56)(57), whereas others have failed to confirm these results (27,28,53,58,59). Some of these discrepancies are likely due to the fact that most previous analyses did not compare HIV-1 strains from transmission pairs.…”

Section: Discussionmentioning

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.

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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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Section: Discussionmentioning

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.

Self Cite

132

180

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“…This suggests that resisting IFNα‐induced antiviral effects provides a selection advantage during HIV‐1 transmission and the acute phase of infection. It was also shown that TF HIV‐1 strains are particularly resistant to inhibition by IFN‐induced transmembrane proteins (IFITMs), which impair viral entry into target cells . Furthermore, pandemic group M (major) HIV‐1 strains counteract the IFN‐inducible restriction factor tetherin more efficiently than rare group N and P HIV‐1 isolates, which resulted from independent zoonotic transmissions .…”

Section: Interferonsmentioning

confidence: 99%

Interferons and beyond: Induction of antiretroviral restriction factors

Hotter

Kirchhoff

2017

Journal of Leukocyte Biology

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Antiviral restriction factors are structurally and functionally diverse cellular proteins that play a key role in the first line of defense against viral pathogens. Although many cell types constitutively express restriction factors at low levels, their induction in response to viral exposure and replication is often required for potent control and repulse of the invading pathogens. It is well established that type I IFNs efficiently induce antiviral restriction factors. Accumulating evidence suggests that other types of IFN, as well as specific cytokines, such as IL-27, and other activators of the cell are also capable of enhancing the expression of restriction factors and hence to establish an antiviral cellular state. Agents that efficiently induce restriction factors, increase their activity, and/or render them resistant against viral antagonists without causing general inflammation and significant side effects hold some promise for novel therapeutic or preventive strategies. In the present review, we summarize some of the current knowledge on the induction of antiretroviral restriction factors and perspectives for therapeutic application.

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“…In particular, transmitter/founder viruses have been found to be more resistant to IFITM restriction than viruses isolated from later times during infection; the later viruses may gain sensitivity as a result of escape from concomitant neutralizing antibody responses [17], although this in turn raises the question as to the relative relevance of IFITM as an in vivo restriction mechanism compared to antibody-driven selection.…”

Section: Introductionmentioning

confidence: 99%

Mechanisms of HIV-1 Control

2017

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Purpose of review HIV-1 infection is of global importance, and still incurs substantial morbidity and mortality. Although major pharmacologic advances over the past two decades have resulted in remarkable HIV-1 control, a cure is still forthcoming. One approach to a cure is to exploit natural mechanisms by which the host restricts HIV-1. Herein, we review past and recent discoveries of HIV-1 restriction factors, a diverse set of host proteins that limit HIV-1 replication at multiple levels, including entry, reverse transcription, integration, translation of viral proteins and packaging and release of virions. Recent findings Recent studies of intracellular HIV-1 restriction have offered unique molecular insights into HIV-1 replication and biology. Most recently, studies have revealed insights of how restriction factors drive HIV-1 evolution. Although HIV-1 restriction factors only partially control the virus, their importance is underscored by their effect on HIV-1 evolution and adaptation. Summary The list of host restriction factors that control HIV-1 infection is likely to expand with future discoveries. A deeper understanding of the molecular mechanisms of regulation by these factors will uncover new targets for therapeutic control of HIV-1 infection.

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Resistance of Transmitted Founder HIV-1 to IFITM-Mediated Restriction

Cited by 157 publications

References 46 publications

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

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

Interferons and beyond: Induction of antiretroviral restriction factors

Mechanisms of HIV-1 Control

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