Relevance of Fc-effector functions for prevention of infection of the first cell in the HIV nonhuman primate model
Final Report Abstract
Neutralizing antibodies targeting HIV-1 Env have been shown to protect from systemic infection. To explore whether these antibodies can inhibit infection of the first cells, challenge viruses based on simian immunodeficiency virus (SIV) were developed that use HIV-1 Env for entry into target cells during the first replication cycle, but then switch to SIV Env usage. Since blocking infection of the first cells avoids the formation of latently infected cells and reduces the risk of emergence of antibody-resistant mutants, it may be the best mode of protection. Monoclonal neutralizing antibodies binding to Env of HIV-1, but not SIV, indeed blocked HIV-1 Env-mediated infection events after rectal exposure of non-human primates to the switching challenge virus. After natural exposure to HIV-1, such a reduction of the number of first infection events should be sufficient to provide sterilizing immunity in the strictest sense in most of the exposed individuals. We also explored whether antibody Fc-effector functions contribute to this sterilizing immunity. Therefore, additional challenge viruses were produced that contain SIV Env and graded doses of a fusion-defective trimer of HIV-1 Env, to which the HIV Env antibody, PGT121, can bind, without interfering with the SIV Env based cell entry. After prophylactic administration of either PGT121 or a mutant deficient in Fc effector functions, monkeys were intrarectally exposed to these challenge viruses and to challenge viruses using either HIV-1 Env or SIV Env for entry into the first cells. Both antibodies similarly reduced infection events with the challenge virus using HIV-1 Env by a factor of >100. Incorporating fusion-defective HIV-1 Env trimers at densities observed in primary virus isolates did not reduce SIV Env mediated infection events indicating that Fc-effector functions do not contribute to sterilizing immunity. Therefore, harnessing Fc effector functions for sterilizing immunity against mucosal infection may require strategies to increase the density of antibody opsonization.
Publications
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HIV-1 neutralizing antibodies provide sterilizing immunity by blocking infection of the first cells. Cell Reports Medicine, 4(10), 101201.
Stab, Viktoria; Stahl-Hennig, Christiane; Ensser, Armin; Richel, Elie; Fraedrich, Kirsten; Sauermann, Ulrike; Tippler, Bettina; Klein, Florian; Burton, Dennis R.; Tenbusch, Matthias & Überla, Klaus
