Generation of Transmitted/Founder HIV-1 Infectious Molecular Clones and Characterization of Their Replication Capacity in CD4 T Lymphocytes and Monocyte-Derived Macrophages

Ochsenbauer, Christina; Edmonds, Tara G.; Ding, Haitao; Keele, Brandon F.; Decker, Julie M.; Salazar, Maria G.; Salazar-Gonzalez, Jesus F.; Shattock, Robin J.; Haynes, Barton F.; Shaw, George M.; Hahn, Beatrice H.; Kappes, John C.

doi:10.1128/jvi.06157-11

Cited by 305 publications

(390 citation statements)

References 71 publications

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“…pNL43-ADA(Env)-GFP.IRES.Nef proviral vectors (deleted for vpu, nef, and nef and vpu or expressing the D368R Env variant) and the VSVG-encoding plasmid (pSVCMV-IN-VSV-G) were previously described (12,51). T/F and corresponding 6-mo consensus IMCs of patients CH58 and CH77 were inferred, constructed, and biologically characterized as described (36)(37)(38)(39).…”

Section: Methodsmentioning

confidence: 99%

“…To ensure that sensitization of HIV-1-infected cells by CD4 mimetics was also observed when using full-length clinically relevant primary HIV-1 isolates, we infected primary CD4 T cells with extensively characterized infectious molecular clones (IMCs) constructed from two transmitted/founder (T/F) and their corresponding 6-mo consensus sequences (36)(37)(38)(39). Primary viruses are known to exhibit low Env reactivity and, as such, have little or no intrinsic exposure of CD4i epitopes (40).…”

Section: Cd4 Mimetics Enhance Recognition and Killing Of Cells Infectmentioning

confidence: 99%

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CD4 mimetics sensitize HIV-1-infected cells to ADCC

Richard

Veillette

Brassard

et al. 2015

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

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291

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HIV-1-infected cells presenting envelope glycoproteins (Env) in the CD4-bound conformation on their surface are preferentially targeted by antibody-dependent cell-mediated cytotoxicity (ADCC). HIV-1 has evolved a sophisticated mechanism to avoid exposure of ADCC-mediating Env epitopes by down-regulating CD4 and by limiting the overall amount of Env at the cell surface. Here we report that small-molecule CD4-mimetic compounds induce the CD4-bound conformation of Env, and thereby sensitize cells infected with primary HIV-1 isolates to ADCC mediated by antibodies present in sera, cervicovaginal lavages, and breast milk from HIV-1-infected individuals. Importantly, we identified one CD4 mimetic with the capacity to sensitize endogenously infected ex vivo-amplified primary CD4 T cells to ADCC killing mediated by autologous sera and effector cells. Thus, CD4 mimetics hold the promise of therapeutic utility in preventing and controlling HIV-1 infection.

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Section: Methodsmentioning

confidence: 99%

Section: Cd4 Mimetics Enhance Recognition and Killing Of Cells Infectmentioning

confidence: 99%

CD4 mimetics sensitize HIV-1-infected cells to ADCC

Richard

Veillette

Brassard

et al. 2015

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

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123

291

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“…Viral plasmids (courtesy of Dr John Kappes [24]) for two T/F viruses, CH040 and CH077 (both subtype B), were derived from single genome amplification of viral RNA from acutely infected individuals. Two laboratory-adapted strains, NL4·3 and YU2, came from the UAB Center for AIDS Research (courtesy of Dr John Kappes).…”

Section: Hiv-1 Virus Stocksmentioning

confidence: 99%

Dimorphic HLA-B signal peptides differentially influence HLA-E- and natural killer cell-mediated cytolysis of HIV-1-infected target cells

Merino

Sabbaj

Easlick

et al. 2013

Clinical and Experimental Immunology

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SummaryAs a mechanism of self-protection, signal peptides cleaved from human leukocyte antigen (HLA) class I products bind to HLA-E before the complex interacts with the natural killer (NK) cell receptor CD94/NKG2A to inhibit NK-mediated cell lysis. Two types of the signal peptides differ in their position 2 (P2) anchor residue, with P2-methionine (P2-M) having higher HLA-E binding affinity than P2-threonine (P2-T). All HLA-A and HLA-C molecules carry P2-M, whereas HLA-B products have either P2-M or P2-T. Epidemiological evidence suggests that P2-M is unfavourable in the context of HIV-1 infection, being associated with accelerated acquisition of HIV-1 infection in two African cohorts. To begin elucidating the functional mechanism, we studied NK-mediated killing of CD4 + T cells and monocyte-derived macrophages infected with two laboratory-adapted HIV-1 strains and two transmitted/founder (T/F) viruses. In the presence of target cells derived from individuals with the three HLA-B P2 genotypes (M/M, M/T and T/T), NK-mediated cytolysis was elevated consistently for P2-T in a dosedependent manner for all cell and virus combinations tested (P =0·008

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“…in activated CD4 + T cells but not macrophages (14,(22)(23)(24)(25). Moreover, analysis of a comprehensive panel of infectious molecular clones (IMCs) showed that TF viruses packaged more envelope glycoprotein (Env), exhibited greater infectivity, bound to monocyte-derived dendritic cells more efficiently, and replicated to higher titers in CD4 + T cells in the presence of the type 1 interferon IFNα2 than chronic control (CC) viruses (26).…”

mentioning

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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Generation of Transmitted/Founder HIV-1 Infectious Molecular Clones and Characterization of Their Replication Capacity in CD4 T Lymphocytes and Monocyte-Derived Macrophages

Cited by 305 publications

References 71 publications

CD4 mimetics sensitize HIV-1-infected cells to ADCC

CD4 mimetics sensitize HIV-1-infected cells to ADCC

Dimorphic HLA-B signal peptides differentially influence HLA-E- and natural killer cell-mediated cytolysis of HIV-1-infected target cells

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

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