Research ArticleHIV

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

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Science Translational Medicine  09 Aug 2017:
Vol. 9, Issue 402, eaaf1483
DOI: 10.1126/scitranslmed.aaf1483

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Antibodies circumvented by cell-associated virus

Antibodies that are able to neutralize a range of HIV-1 strains are being developed to prevent infection in humans. Preclinical testing of these antibodies predominantly uses free virus during the challenge, although natural HIV-1 transmission could involve transfer of infected cells. To determine whether antibodies would still be able to combat this type of transmission, Parsons et al. developed a challenge model in nonhuman primates using SHIV-infected splenocytes. A well-characterized anti–HIV-1 antibody failed to protect all of the animals from the cell-associated viral challenge, although it had protected all animals from cell-free viral challenge. Their findings indicate that sustained high concentrations of circulating antibody may be necessary for prevention of cell-associated HIV-1 acquisition.

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 SHIVSF162P3-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.

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