Protective Efficacy of Broadly Neutralizing Antibodies with Incomplete Neutralization Activity against Simian-Human Immunodeficiency Virus in Rhesus Monkeys.

HIV broadly neutralizing antibodies (bnAbs) have been shown to occasionally display unusual virus neutralization profiles with nonsigmoidal slopes and plateaus at <100% neutralization against a variety of viruses. The significance of incomplete neutralization for the ability of bnAbs to mediate protective effects in vivo, however, is undetermined. In the current study, we selected two bnAbs, PGT121 and 3BNC117, as they incompletely neutralize the clade C simian-human immunodeficiency virus (SHIV) stock (SHIV-327c) at 85% and 70%, respectively, and performed a protection study in rhesus macaques. The animals were intravenously (i.v.) administered PGT121 or 3BNC117 at 10 and 2 mg/kg of body weight before being rectally challenged with a single high dose of SHIV-327c. PGT121 protected 6 out of 7 monkeys, while 6 out of 7 3BNC117-pretreated animals became infected, although with significantly delayed plasma viremia compared to the control animals. These data suggest that complete neutralization is not imperative for bnAbs to prevent infection but that with increasing levels of incomplete neutralization the sterilizing activity diminishes.IMPORTANCE Multiple antibodies have been identified that potently neutralize a broad range of circulating HIV strains. However, not every virus-antibody combination results in complete neutralization of the input virus, suggesting that a fraction of virus particles are resistant to antibody neutralization despite high antibody concentrations. This observation of "incomplete neutralization" is associated with nonsigmoidal neutralization curves plateauing below 100% neutralization, but the significance of the phenomenon for the ability of neutralizing antibodies to mediate protective effects in vivo is undetermined. In this study, we show that the broadly neutralizing antibody PGT121, which neutralized only up to 85% of the SHIV-327c challenge stock in vitro, protected 6 out of 7 rhesus macaques against infection while the antibody 3BNC117, which neutralized up to 70% of SHIV-327c in vitro, did not prevent, though it significantly delayed, establishment of infection, suggesting that with increasing levels of incomplete neutralization the ability of a bnAb to mediate sterilizing protection diminishes.

Reduced Potency and Incomplete Neutralization of Broadly Neutralizing Antibodies against Cell-to-Cell Transmission of HIV-1 with Transmitted Founder Envs.

Broadly neutralizing antibodies (bNAbs) have been isolated from HIV-1 patients and can potently block infection of a wide spectrum of HIV-1 subtypes. These antibodies define common epitopes shared by many viral isolates. While bNAbs potently antagonize infection with cell-free virus, inhibition of HIV-1 transmission from infected to uninfected CD4+ T cells through virological synapses (VS) has been found to require greater amounts of antibody. In this study, we examined two well-studied molecular clones and two transmitted/founder (T/F) clones for their sensitivities to a panel of bNAbs in cell-free and cell-to-cell infection assays. We observed resistance of cell-to-cell transmission to antibody neutralization that was reflected not only by reductions of antibody potency but also by decreases in maximum neutralization capacity relative to the levels seen with cell-free infections. BNAbs targeting different epitopes exhibited incomplete neutralization against cell-associated virus with T/F Envs, which was not observed with the cell-free form of the same virus. We further identified the membrane-proximal internal tyrosine-based sorting motif as a determinant that can affect the incomplete neutralization of these T/F clones in cell-to-cell infection. These findings indicate that the signal that affects surface expression and/or internalization of Env from the plasma membrane can modulate the presentation of neutralizing epitopes on infected cells. These results highlight that a fraction of virus can escape from high concentrations of antibody through cell-to-cell infection while remaining sensitive to neutralization in cell-free infection. The ability to fully inhibit cell-to-cell transmission may represent an important consideration in the development of antibodies for treatment or prophylaxis.IMPORTANCE In recent years, isolation of new-generation HIV-1 bNAbs has invigorated HIV vaccine research. These bNAbs display remarkable potency and breadth of coverage against cell-free virus; however, they exhibit a diminished ability to block HIV-1 cell-to-cell transmission. The mechanism(s) by which HIV-1 resists neutralization when transmitting through VS remains uncertain. We examined a panel of bNAbs for their ability to neutralize HIV-1 T/F viruses in cell-to-cell infection assays. We found that some antibodies exhibit not only reduced potency but also decreased maximum neutralization capacity or in vitro efficacy against cell-to-cell infection of HIV-1 with T/F Envs compared to cell-free infection of the same virus. We further identified the membrane-proximal internal tyrosine-based sorting motif YXXL as a determinant that can affect the incomplete neutralization phenotype of these T/F clones. When the maximum neutralization capacity falls short of 100%, this can have a major impact on the ability of antibodies to halt viral replication.

The Non-Coalescence of /h/ and Incomplete Neutralization in South Jeolla Korean.

This study examines articulatory and acoustic data in order to investigate the non-coalescence of /h/ in South Jeolla. Seoul Korean speakers produce /pap/ "rice" followed by /hana/ "one" as [pa.pha.na] with the coalescence of /p/ and /h/; this is called an aspiration merger. In South Jeolla Korean, this merger may be blocked, as in cases where speakers produce /pap+hana/ as [pa.ba.na]. Electroglottographic (EGG) data indicate the existence of two groups of South Jeolla speakers: one that merges the plosive and /h/ (the merger group), and the other with the canonical South Jeolla Korean pronunciation that does not merge the two consonants (the non-merger group). The production of non-coalesced lenis stops in the non-merger group is phonetically comparable with an underlying lenis stop produced by both of the groups. However, in the non-merger group, the open quotient (OQ) of a vowel following a non-coalesced lenis stop is higher (breathier) than that of an underlying lenis stop. Spectral tilt results display a similarly increased breathiness when the vowel follows a non-coalesced lenis stop. As for the non-merger group of South Jeolla, we argue that speakers display incomplete neutralization such that the non-merger group produces two types of voiced lenis stops differing in the phonation of the following vowel. These findings suggest that previous phonological analyses that posit the /h/-deletion in the non-merger group of South Jeolla Korean need to be revisited.

Unstressed Vowel Reduction Across Majorcan Catalan Dialects: Production and Spoken Word Recognition.

This study investigates the production and auditory lexical processing of words involved in a patterned phonological alternation in two dialects of Catalan spoken on the island of Majorca, Spain. One of these dialects, that of Palma, merges /ɔ/ and /o/ as [o] in unstressed position, and it maintains /u/ as an independent category, [u]. In the dialect of Sóller, a small village, speakers merge unstressed /ɔ/, /o/, and /u/ to [u]. First, a production study asks whether the discrete, rule-based descriptions of the vowel alternations provided in the dialectological literature are able to account adequately for these processes: are mergers complete? Results show that mergers are complete with regards to the main acoustic cue to these vowel contrasts, that is, F1. However, minor differences are maintained for F2 and vowel duration. Second, a lexical decision task using cross-modal priming investigates the strength with which words produced in the phonetic form of the neighboring (versus one's own) dialect activate the listeners' lexical representations during spoken word recognition: are words within and across dialects accessed efficiently? The study finds that listeners from one of these dialects, Sóller, process their own and the neighboring forms equally efficiently, while listeners from the other one, Palma, process their own forms more efficiently than those of the neighboring dialect. This study has implications for our understanding of the role of lifelong linguistic experience on speech performance.