Partial efficacy of a broadly neutralizing antibody against cell-associated SHIV infection

Abstract

Broadly neutralizing antibodies (BnAbs) protect macaques from cell-free simian/human immunodeficiency virus (SHIV) challenge, but their efficacy against cell-associated SHIV is unclear. Virus in cell-associated format is highly infectious, present in transmission-competent bodily fluids, and potentially capable of evading antibody-mediated neutralization. The PGT121 BnAb, which recognizes an epitope consisting of the V3 loop and envelope glycans, mediates antibody-dependent cellular cytotoxicity and neutralization of cell-to-cell HIV-1 transmission. To evaluate whether a BnAb can prevent infection after cell-associated viral challenge, we infused pigtail macaques with PGT121 or an isotype control and challenged animals 1 hour later intravenously with SHIV-infected splenocytes. All five controls had high viremia 1 week after challenge. Three of six PGT121-infused animals were completely protected, two of six animals had a 1-week delay in onset of high viremia, and one animal had a 7-week delay in onset of viremia. The infused antibody had decayed on average to 2.0 μg/ml by 1 week after infusion and was well below 1 μg/ml (range, <0.1 to 0.8 μg/ml) by 8 weeks. The animals with a 1-week delay before high viremia had relatively lower plasma concentrations of PGT121. Transfer of 22 million peripheral blood mononuclear cells (PBMCs) stored at weeks 1 to 4 from the animal with the 7-week delayed onset of viremia into uninfected macaques did not initiate infection. Our results show that HIV-1-specific neutralizing antibodies have partial efficacy against cell-associated virus exposure in macaques. We conclude that sustaining high concentrations of bioavailable BnAb is important for protecting against cell-associated virus.

MAIT Cells Upregulate α4β7 in Response to Acute Simian Immunodeficiency Virus/Simian HIV Infection but Are Resistant to Peripheral Depletion in Pigtail Macaques

“…with 40 TCID SIV mac251 (26) (n = 4), and animals challenged i.v. with 2.45 3 10 7 SHIV SF162P3infected macaque splenocytes in combination with the broadly neutralizing Ab (BnAb) PGT121 or isotype control (27) (n = 7). Samples were also selected from n = 9 animals (n = 6 infected and n = 3 uninfected) that were vaccinated with a fowlpox virus/modified vaccinia virus Ankara SIV vaccine or sham vector 98 d prior to challenge with intrarectal challenge with 10 3 TCID 50 SIV mac251 .…”

“…Plasma SIV and SHIV RNA levels were quantified as previously described (25)(26)(27). Whole blood samples were analyzed on a Cell-Dyn Emerald hematology analyzer (Abbott, Chicago, IL), and absolute lymphocyte counts were used to calculate CD4 + T cell and MAIT cell counts using flow cytometry analysis of CD4 + T cell and MAIT cell frequency.…”

Fc-dependent functions are redundant to efficacy of anti-HIV antibody PGT121 in macaques

“…The infectious nature of cell-associated virus is concerning, given that many BnAbs exhibit diminished neutralization capacity against cellassociated virus in in vitro assays (9,10). We recently established a cell-associated SHIV infection model in pigtail macaques (11). Passive administration of the human PGT121 BnAb to macaques provided only partial protection from a very high-dose challenge with cell-associated SHIV.…”

Dimeric FcγR ectodomains detect pathogenic anti‐platelet factor 4–heparin antibodies in heparin‐induced thromobocytopenia

“…Dimeric rsFcγRIIa binding requires closely spaced pairs of antibodies, as occurs in ICs , and has been used to detect FcγR functional antibodies against influenza virus and HIV envelope proteins . HIT pathogenesis requires Fc‐mediated clustering of platelet FcγRIIa, but two SRA‐positive samples were not detected with the dimeric rsFcγRIIa‐binding assay.…”