Cellular Superspreaders: An Epidemiological Perspective on HIV Infection inside the Body

Talbert-Slagle, Kristina; Atkins, Katherine E.; Khurana, Ekta; Gerstein, Mark; Bradley, Elizabeth H.; Berg, David N.; Galvani, Alison P.; Townsend, Jeffrey P.

doi:10.1371/journal.ppat.1004092

Cited by 20 publications

(25 citation statements)

References 92 publications

(123 reference statements)

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“…Efficient infection of B-1 cells was required for subsequent amplification of infection in B-2 cells. In this scenario, B-1 cells functioned like cellular superspreaders of FrMLV infection (32). Our data highlight the importance of characterizing early target cells and factors that govern their permissivity to develop effective antiviral strategies for curtailing virus colonization of the host.…”

Section: Discussionmentioning

confidence: 80%

Murine Leukemia Virus Exploits Innate Sensing by Toll-Like Receptor 7 in B-1 Cells To Establish Infection and Locally Spread in Mice

Iwasaki

Sewald

et al. 2019

J Virol

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Lymph-borne Friend murine leukemia virus (FrMLV) exploits the sentinel macrophages in the draining popliteal lymph node (pLN) to infect highly permissive innate-like B-1 cells and establish infection in mice. The reason for FrMLV sensitivity of B-1 cells and their impact on viral spread is unknown. Here we demonstrate that Toll-like receptor 7 (TLR7) sensing and type I interferon (IFN-I) signaling in B-1 cells contribute to FrMLV susceptibility. FrMLV infection in B-1 cell-deficient mice (bumble; IκBNS dysfunctional) was significantly lower than that in the wild-type mice and was rescued by adoptive transfer of wild-type B-1 cells. This rescue of FrMLV infection in bumble mice was dependent on intact TLR7 sensing and IFN-I signaling within B-1 cells. Analyses of infected cell types revealed that the reduced infection in bumble mice was due predominantly to compromised virus spread to the B-2 cell population. Our data reveal how FrMLV exploits innate immune sensing and activation in the B-1 cell population for infection and subsequent spread to other lymphocytes. IMPORTANCE Viruses establish infection in hosts by targeting highly permissive cell types. The retrovirus Friend murine leukemia virus (FrMLV) infects a subtype of B cells called B-1 cells that permit robust virus replication. The reason for their susceptibility had remained unknown. We found that innate sensing of incoming virus and the ensuing type I interferon response within B-1 cells are responsible for their observed susceptibility. Our data provide insights into how retroviruses coevolved with the host to co-opt innate immune sensing pathways designed to fight virus infections for establishing infection. Understanding early events in viral spread can inform antiviral intervention strategies that prevent the colonization of a host.

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Section: Discussionmentioning

confidence: 80%

Murine Leukemia Virus Exploits Innate Sensing by Toll-Like Receptor 7 in B-1 Cells To Establish Infection and Locally Spread in Mice

Iwasaki

Sewald

et al. 2019

J Virol

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“…HIV infection after sexual exposure is thought to be caused by the infection of a small number of highly susceptible mucosal target cells, 27 with subsequent slow local expansion leading to eventual systemic dissemination. 28,29 However, the low risk of HIV acquisition after sexual exposure has hampered the study of mucosal HIV transmission/susceptibility in human cohorts, and the identification of optimal HIV targets in the FGT.…”

Section: Discussionmentioning

confidence: 99%

Identification of preferential CD4+ T-cell targets for HIV infection in the cervix

et al. 2016

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A better understanding of the cellular targets of HIV infection in the female genital tract may inform HIV prevention efforts. Proposed correlates of cellular susceptibility include the HIV co-receptor CCR5, peripheral homing integrins, and immune activation. We used a CCR5-tropic pseudovirus to quantify HIV entry into unstimulated endocervical CD4(+) T cells collected by cytobrush. Virus entry was threefold higher into cervix-derived CD4(+) T cells than blood, but was strongly correlated between these two compartments. Cervix-derived CD4(+) T cells expressing CD69, α(4)β(7), or α(4)β(1) were preferential HIV targets; this enhanced susceptibility was strongly correlated with increased CCR5 expression in α(4)β(7)(+) and CD69(+) CD4(+) T cells, and to a lesser extent in α(4)β(1)(+) CD4(+) T cells. Direct binding of gp140 to integrins was not observed, integrin inhibitors had no effect on virus entry, and pseudotypes with an env that preferentially binds α(4)β(7) still demonstrated enhanced entry into α(4)β(1)(+) cells. In summary, a rapid and sensitive HIV entry assay demonstrated enhanced susceptibility of activated endocervical CD4(+) T cells, and those expressing α(4)β(7) or α(4)β(1). This may relate to increased CCR5 expression by these cell subsets, but did not appear to be due to direct interaction of α(4)β(7) or α(4)β(1) with HIV envelope.

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“…Since HIV predominantly infects CD4 T cells [11, 13, 44], both the availability and the HIV-permissivity of local CD4 T cells may dictate whether or not infection is established, with a limited number of highly susceptible cells driving initial mucosal infection [45, 46]. Therefore, recruitment or activation of specific subsets of CD4 T cells that are especially permissive to HIV may be important; Th17 and Th1 cells are highly HIV-permissive in vitro and are preferentially depleted in vivo during acute infection [47–50], and Th17 cells have recently been shown to be the primary targets of SIV, representing 64% of infected cells 48 hours after vaginal challenge [44].…”

Section: Discussionmentioning

confidence: 99%

Chemokine Levels in the Penile Coronal Sulcus Correlate with HIV-1 Acquisition and Are Reduced by Male Circumcision in Rakai, Uganda

et al. 2016

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Individual susceptibility to HIV is heterogeneous, but the biological mechanisms explaining differences are incompletely understood. We hypothesized that penile inflammation may increase HIV susceptibility in men by recruiting permissive CD4 T cells, and that male circumcision may decrease HIV susceptibility in part by reducing genital inflammation. We used multi-array technology to measure levels of seven cytokines in coronal sulcus (penile) swabs collected longitudinally from initially uncircumcised men enrolled in a randomized trial of circumcision in Rakai, Uganda. Coronal sulcus cytokine levels were compared between men who acquired HIV and controls who remained seronegative. Cytokines were also compared within men before and after circumcision, and correlated with CD4 T cells subsets in foreskin tissue. HIV acquisition was associated with detectable coronal sulcus Interleukin-8 (IL-8 aOR 2.26, 95%CI 1.04–6.40) and Monokine Induced by γ-interferon (MIG aOR 2.72, 95%CI 1.15–8.06) at the visit prior to seroconversion, and the odds of seroconversion increased with detection of multiple cytokines. Coronal sulcus chemokine levels were not correlated with those in the vagina of a man’s female sex partner. The detection of IL-8 in swabs was significantly reduced 6 months after circumcision (PRR 0.59, 95%CI 0.44–0.87), and continued to decline for at least two years (PRR 0.29, 95%CI 0.16–0.54). Finally, prepuce IL-8 correlated with increased HIV target cell density in foreskin tissues, including highly susceptible CD4 T cells subsets, as well as with tissue neutrophil density. Together, these data suggest that penile inflammation increases HIV susceptibility and is reduced by circumcision.

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Cellular Superspreaders: An Epidemiological Perspective on HIV Infection inside the Body

Cited by 20 publications

References 92 publications

Murine Leukemia Virus Exploits Innate Sensing by Toll-Like Receptor 7 in B-1 Cells To Establish Infection and Locally Spread in Mice

Murine Leukemia Virus Exploits Innate Sensing by Toll-Like Receptor 7 in B-1 Cells To Establish Infection and Locally Spread in Mice

Identification of preferential CD4+ T-cell targets for HIV infection in the cervix

Chemokine Levels in the Penile Coronal Sulcus Correlate with HIV-1 Acquisition and Are Reduced by Male Circumcision in Rakai, Uganda

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