Nonpathogenic Simian Immunodeficiency Virus Infection of Sooty Mangabeys Is Not Associated with High Levels of Autologous Neutralizing Antibodies

Li, Bing; Stefano-Cole, Kelly; Kuhrt, David; Gordon, Shari N.; Else, James G.; Mulenga, Joseph; Allen, Susan; Sodora, Donald L.; Silvestri, Guido; Derdeyn, Cynthia A.

doi:10.1128/jvi.00295-10

Cited by 35 publications

(28 citation statements)

References 33 publications

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“…SIV smm FFv2.1 and FFv5.1 Envs were cloned from a clade 1 SIV smm -infected sooty mangabey homozygous for the CCR5 wild-type gene (CCR5 wt/wt ) using single-genome amplification (SGA) as previously described (11)(12)(13). SIV smm FPm1.1 Env was SGA cloned from a CCR5 wt/wt clade 5 SIV smm -infected sooty mangabey (12).…”

Section: Methodsmentioning

confidence: 99%

Dualtropic CXCR6/CCR5 Simian Immunodeficiency Virus (SIV) Infection of Sooty Mangabey Primary Lymphocytes: Distinct Coreceptor Use in Natural versus Pathogenic Hosts of SIV

Elliott

Wetzel

Francella

et al. 2015

J Virol

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Natural-host sooty mangabeys (SM) infected with simian immunodeficiency virus (SIV) exhibit high viral loads but do not develop disease, whereas infection of rhesus macaques (RM) causes CD4؉ T cell loss and AIDS. Several mechanisms have been proposed to explain these divergent outcomes, including differences in cell targeting, which have been linked to low expression of the canonical SIV entry receptor CCR5 on CD4 ؉ T cells of SM and other natural hosts. We previously showed that infection and high-level viremia occur even in a subset of SM that genetically lack functional CCR5, which indicates that alternative entry coreceptors are used by SIV in vivo in these animals. We also showed that SM CXCR6 is a robust coreceptor for SIV smm in vitro. Here we identify CXCR6 as a principal entry pathway for SIV in SM primary lymphocytes. We show that ex vivo SIV infection of lymphocytes from CCR5 wild-type SM is mediated by both CXCR6 and CCR5. In contrast, infection of RM lymphocytes is fully dependent on CCR5. These data raise the possibility that CXCR6-directed tropism in CCR5-low natural hosts may alter CD4 ؉ T cell subset targeting compared with that in nonnatural hosts, enabling SIV to maintain high-level replication without leading to widespread CD4 ؉ T cell loss.

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Section: Methodsmentioning

confidence: 99%

Dualtropic CXCR6/CCR5 Simian Immunodeficiency Virus (SIV) Infection of Sooty Mangabey Primary Lymphocytes: Distinct Coreceptor Use in Natural versus Pathogenic Hosts of SIV

Elliott

Wetzel

Francella

et al. 2015

J Virol

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“…Pseudovirus stocks were collected from the 293T cell supernatants at 48-72 h after transfection, clarified by centrifugation, divided into small volumes, and frozen at -80°C. Fivefold serial dilutions of heat-inactivated serum samples were assayed for their inhibitory potential against the Env pseudoviruses using the TZM-bl indicator cell line, with luciferase as the readout, as described previously (57,(59)(60)(61)(62)(63). TZM-bl cells were plated and cultured overnight in flat-bottomed 96-well plates.…”

Section: Methodsmentioning

confidence: 99%

“…An SGA-derived env gene amplicon that was representative of the T/F consensus sequence for each monkey was purified using the Qiagen PCR Purification Kit (Qiagen) and was cloned into pCDNA3.1dV5His TOPO-TA (Invitrogen) using approaches described previously (57)(58)(59)). An env gene clone whose sequence was identical to the matching SGA amplicon was used to generate a pseudovirus by transfecting the Env-expressing plasmid DNA alongside the HIV-1 SG3ΔEnv proviral backbone DNA into 293T cells, using the Fugene HD reagent as recommended (Promega).…”

Section: Methodsmentioning

confidence: 99%

Breakthrough of SIV strain smE660 challenge in SIV strain mac239-vaccinated rhesus macaques despite potent autologous neutralizing antibody responses

Burton

Kilgore

Smith

et al. 2015

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

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Although the correlates of immunological protection from human immunodeficiency virus or simian immunodeficiency virus infection remain incompletely understood, it is generally believed that medium to high titers of serum neutralizing antibodies (nAbs) against the challenge virus will prevent infection. This paradigm is based on a series of studies in which passive transfer of HIV-specific nAbs protected rhesus macaques (RMs) from subsequent mucosal challenge with a chimeric human/simian immunodeficiency virus. However, it is unknown whether nAb titers define protection in the setting of active immunization. Here we determined serum nAb titers against breakthrough transmitted/founder (T/F) SIVsmE660-derived envelope glycoprotein (Env) variants from 14 RMs immunized with SIVmac239-based DNA-prime/modified vaccinia virus Ankara-boost vaccine regimens that included GM-CSF or CD40L adjuvants and conferred significant but incomplete protection against repeated low-dose intrarectal challenge. A single Env variant established infection in all RMs except one, with no identifiable genetic signature associated with vaccination breakthrough compared with T/F Envs from four unvaccinated monkeys. Breakthrough T/F Env pseudoviruses were potently neutralized in vitro by heterologous pooled serum from chronically SIVsmE660-infected monkeys at IC50 titers exceeding 1:1,000,000. Remarkably, the T/F Env pseudoviruses from 13 of 14 monkeys were also susceptible to neutralization by autologous prechallenge serum at in vitro IC50 titers ranging from 1:742–1:10,832. These titers were similar to those observed in vaccinated RMs that remained uninfected. These data suggest that the relationship between serum nAb titers and protection from mucosal SIV challenge in the setting of active immunization is more complex than previously recognized, warranting further studies into the balance between immune activation, target cell availability, and protective antibody responses.

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“…SIVsmm env genes were cloned from virions isolated from plasma of infected SM by employing single-genome amplification (SGA) methods previously described (34,35). Briefly, viral RNA was purified from plasma using the QIAamp viral RNA purification kit (Qiagen), and cDNA was prepared using Superscript III (Invitrogen) and the primer SM-ER1 (5=-CTA TCA CTG TAA TAA ATC CCT TCC AGT CCC-3=).…”

Section: Methodsmentioning

confidence: 99%

Cloning and Analysis of Sooty Mangabey Alternative Coreceptors That Support Simian Immunodeficiency Virus SIVsmm Entry Independently of CCR5

Elliott

Riddick

Francella

et al. 2012

J Virol

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Natural host sooty mangabeys (SM) infected with simian immunodeficiency virus SIVsmm do not develop AIDS despite high viremia. SM and other natural hosts express very low levels of CCR5 on CD4 ؉ T cells, and we recently showed that SIVsmm infection and robust replication occur in vivo in SM genetically lacking CCR5, indicating the use of additional entry pathways. SIVsmm uses several alternative coreceptors of human origin in vitro, but which molecules of SM origin support entry is unknown. We cloned a panel of putative coreceptors from SM and tested their ability to mediate infection, in conjunction with smCD4, by pseudotypes carrying Envs from multiple SIVsmm subtypes. smCXCR6 supported efficient infection by all SIVsmm isolates with entry levels comparable to those for smCCR5, and smGPR15 enabled entry by all isolates at modest levels. smGPR1 and smAPJ supported low and variable entry, whereas smCCR2b, smCCR3, smCCR4, smCCR8, and smCXCR4 were not used by most isolates. In contrast, SIVsmm from rare infected SM with profound CD4 ؉ T cell loss, previously reported to have expanded use of human coreceptors, including CXCR4, used smCXCR4, smCXCR6, and smCCR5 efficiently and also exhibited robust entry through smCCR3, smCCR8, smGPR1, smGPR15, and smAPJ. Entry was similar with both known alleles of smCD4. These alternative coreceptors, particularly smCXCR6 and smGPR15, may support virus replication in SM that have restricted CCR5 expression as well as SM genetically lacking CCR5. Defining expression of these molecules on SM CD4 ؉ subsets may delineate distinct natural host target cell populations capable of supporting SIVsmm replication without CD4 ؉ T cell loss. HIV-1 infection of humans and simian immunodeficiency virus SIVmac infection of non-natural host rhesus macaques (RM) result in high viral loads, peripheral CD4 ϩ T cell loss, and progression to AIDS. In contrast, SIVsmm infection of natural host sooty mangabeys (SM) rarely leads to peripheral CD4 ϩ T cell loss or disease despite viral loads comparable to those measured in non-natural hosts. Identifying the mechanisms responsible for the different outcomes of infection in natural hosts compared with non-natural simian or recent human hosts has become a central focus of efforts to understand AIDS pathogenesis. Although many models of natural host infection exist, SIVsmm is unique because cross-species transmission of SIVsmm from SM to humans and RM gave rise to pathogenic HIV-2 and SIVmac, respectively (2, 28). Similarly, experimental transmission of SIVsmm from infected SM hosts results in AIDS in non-natural host RM (40). While the factors regulating pathogenic versus nonpathogenic outcomes of infection are complex and not fully understood (9), comparison of infected SM with RM recently revealed differential targeting of CD4 ϩ T cell subsets (45). Thus, an understanding of SIVsmm cellular tropism may identify cells in natural host SM that maintain viral replication without leading to CD4 ϩ T cell depletion or AIDS.Classically, SIVsmm was thought to exclus...

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Nonpathogenic Simian Immunodeficiency Virus Infection of Sooty Mangabeys Is Not Associated with High Levels of Autologous Neutralizing Antibodies

Cited by 35 publications

References 33 publications

Dualtropic CXCR6/CCR5 Simian Immunodeficiency Virus (SIV) Infection of Sooty Mangabey Primary Lymphocytes: Distinct Coreceptor Use in Natural versus Pathogenic Hosts of SIV

Dualtropic CXCR6/CCR5 Simian Immunodeficiency Virus (SIV) Infection of Sooty Mangabey Primary Lymphocytes: Distinct Coreceptor Use in Natural versus Pathogenic Hosts of SIV

Breakthrough of SIV strain smE660 challenge in SIV strain mac239-vaccinated rhesus macaques despite potent autologous neutralizing antibody responses

Cloning and Analysis of Sooty Mangabey Alternative Coreceptors That Support Simian Immunodeficiency Virus SIVsmm Entry Independently of CCR5

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