HIV-1 Expressing the Envelopes of Transmitted/Founder or Control/Reference Viruses Have Similar Infection Patterns of CD4 T-Cells in Human Cervical Tissue Ex Vivo

Merbah, Mélanie; Arakelyan, Anush; Edmonds, Tara G.; Ochsenbauer, Christina; Kappes, John C.; Shattock, Robin J.; Grivel, Jean‐Charles; Margolis, Leonid

doi:10.1371/journal.pone.0050839

Cited by 17 publications

(21 citation statements)

References 31 publications

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“…Interestingly, the inhibitory activities (IC 50 ) of 2F5 IgG and Fab were similar in cervical explant cultures despite such tissue containing a high density of macrophages and dendritic cells. This likely reflects previous observations that CD4 T cells represent the primary targets of infection in cervical tissue (59).…”

Section: Discussionsupporting

confidence: 89%

Neutralizing IgG at the Portal of Infection Mediates Protection against Vaginal Simian/Human Immunodeficiency Virus Challenge

Klein

Veazey

Warrier

et al. 2013

J Virol

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Section: Discussionsupporting

confidence: 89%

Neutralizing IgG at the Portal of Infection Mediates Protection against Vaginal Simian/Human Immunodeficiency Virus Challenge

Klein

Veazey

Warrier

et al. 2013

J Virol

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“…The sporadic observations of low or delayed infectivity (Fig. 2a) more likely reflected inherent variation in tissue explant infectivity that has been previously reported (Dezzutti et al, 2013, Merbah et al, 2012). Thus, nnAbs may be less efficient in preventing acute HIV-1 infection, especially those most reliant on ADCC activity, and require additional time or the influx of additional effector cells ( e .…”

Section: Resultssupporting

confidence: 59%

Neutralization Takes Precedence Over IgG or IgA Isotype-related Functions in Mucosal HIV-1 Antibody-mediated Protection

et al. 2016

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HIV-1 infection occurs primarily through mucosal transmission. Application of biologically relevant mucosal models can advance understanding of the functional properties of antibodies that mediate HIV protection, thereby guiding antibody-based vaccine development. Here, we employed a human ex vivo vaginal HIV-1 infection model and a rhesus macaque in vivo intrarectal SHIV challenge model to probe the protective capacity of monoclonal broadly-neutralizing (bnAb) and non-neutralizing Abs (nnAbs) that were functionally modified by isotype switching. For human vaginal explants, we developed a replication-competent, secreted NanoLuc reporter virus system and showed that CD4 binding site bnAbs b12 IgG1 and CH31 IgG1 and IgA2 isoforms potently blocked HIV-1JR-CSF and HIV-1Bal26 infection. However, IgG1 and IgA nnAbs, either alone or together, did not inhibit infection despite the presence of FcR-expressing effector cells in the tissue. In macaques, the CH31 IgG1 and IgA2 isoforms infused before high-dose SHIV challenge were completely to partially protective, respectively, while nnAbs (CH54 IgG1 and CH38 mIgA2) were non-protective. Importantly, in both mucosal models IgG1 isotype bnAbs were more protective than the IgA2 isotypes, attributable in part to greater neutralization activity of the IgG1 variants. These findings underscore the importance of potent bnAb induction as a primary goal of HIV-1 vaccine development.

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“…First, experiments were performed with a single viral isolate (HIV-1 BaL ) known to replicate efficiently in primary cells (CD4 T cells, macrophages, and dendritic cells) while universally targeting CD4 T cells in mucosal models (23, 59, 60). Furthermore, HIV-1 BaL is a tier 1B neutralization-sensitive virus; therefore, while the observed superiority of bnAbs in preventing HIV-1 infection will certainly be generally applicable, the activity of individual monoclonal antibodies is likely to vary with different viral isolates and their neutralization sensitivities.…”

Section: Discussionmentioning

confidence: 99%

Broadly Neutralizing Antibodies Display Potential for Prevention of HIV-1 Infection of Mucosal Tissue Superior to That of Nonneutralizing Antibodies

Cheeseman

Olejniczak

Rogers

et al. 2017

J Virol

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Definition of the key parameters mediating effective antibody blocking of HIV-1 acquisition within mucosal tissue may prove critical to effective vaccine development and the prophylactic use of monoclonal antibodies. Although direct antibody-mediated neutralization is highly effective against cell-free virus, antibodies targeting different sites of envelope vulnerability may display differential activity against mucosal infection. Nonneutralizing antibodies (nnAbs) may also impact mucosal transmission events through Fc-gamma receptor (FcγR)-mediated inhibition. In this study, a panel of broadly neutralizing antibodies (bnAbs) and nnAbs, including those associated with protection in the RV144 vaccine trial, were screened for the ability to block HIV-1 acquisition and replication across a range of cellular and mucosal tissue models. Neutralization potency, as determined by the TZM-bl infection assay, did not fully predict activity in mucosal tissue. CD4-binding site (CD4bs)-specific bnAbs, in particular VRC01, were consistent in blocking HIV-1 infection across all cellular and tissue models. Membrane-proximal external region (MPER) (2F5) and outer domain glycan (2G12) bnAbs were also efficient in preventing infection of mucosal tissues, while the protective efficacy of bnAbs targeting V1-V2 glycans (PG9 and PG16) was more variable. In contrast, nnAbs alone and in combinations, while active in a range of cellular assays, were poorly protective against HIV-1 infection of mucosal tissues. These data suggest that tissue resident effector cell numbers and low FcγR expression may limit the potential of nnAbs to prevent establishment of the initial foci of infection. The solid protection provided by specific bnAbs clearly demonstrates their superior potential over that of nonneutralizing antibodies for preventing HIV-1 infection at the mucosal portals of infection. IMPORTANCE Key parameters mediating effective antibody blocking of HIV-1 acquisition within mucosal tissue have not been defined. While bnAbs are highly effective against cell-free virus, they are not induced by current vaccine candidates. However, nnAbs, readily induced by vaccines, can trigger antibody-dependent cellular effector functions, through engagement of their Fc-gamma receptors. Fc-mediated antiviral activity has been implicated as a secondary correlate of decreased HIV-1 risk in the RV144 vaccine efficacy trial, suggesting that protection might be mediated in the absence of classical neutralization. To aid vaccine design and selection of antibodies for use in passive protection strategies, we assessed a range of bnAbs and nnAbs for their potential to block ex vivo challenge of mucosal tissues. Our data clearly indicate the superior efficacy of neutralizing antibodies in preventing mucosal acquisition of infection. These results underscore the importance of maintaining the central focus of HIV-1 vaccine research on the induction of potently neutralizing antibodies.

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HIV-1 Expressing the Envelopes of Transmitted/Founder or Control/Reference Viruses Have Similar Infection Patterns of CD4 T-Cells in Human Cervical Tissue Ex Vivo

Cited by 17 publications

References 31 publications

Neutralizing IgG at the Portal of Infection Mediates Protection against Vaginal Simian/Human Immunodeficiency Virus Challenge

Neutralizing IgG at the Portal of Infection Mediates Protection against Vaginal Simian/Human Immunodeficiency Virus Challenge

Neutralization Takes Precedence Over IgG or IgA Isotype-related Functions in Mucosal HIV-1 Antibody-mediated Protection

Broadly Neutralizing Antibodies Display Potential for Prevention of HIV-1 Infection of Mucosal Tissue Superior to That of Nonneutralizing Antibodies

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