Antibody-Dependent Cellular Cytotoxicity-Competent Antibodies against HIV-1-Infected Cells in Plasma from HIV-Infected Subjects

Abstract

HIV Env-specific nonneutralizing Abs (NnAbs) able to mediate ADCC have been implicated in protection from HIV infection. However, Env-specific NnAbs have the capacity to support ADCC of both HIV-infected and HIV-uninfected bystander cells, potentially leading to misinterpretations when the assay used to measure ADCC does not distinguish between the two target cell types present in HIV cultures. Using a novel ADCC assay, which simultaneously quantifies the killing activity of Env-specific Abs on both infected and uninfected bystander cells, we observed that only a minority of Env-specific Abs in HIV+ plasma mediated ADCC of genuinely HIV-infected cells displaying Env in its native closed conformation. This assay can be used for the development of vaccine strategies aimed at eliciting Env-specific Ab responses capable of controlling HIV infection.

Polyfunctional Fc Dependent Activity of Antibodies to Native Trimeric Envelope in HIV Elite Controllers

“…The Env CD4bs epitopes are highly conserved and Abs to these epitopes are among the most potent BnAbs (21)(22)(23). HIV infected cells have also been used as target cells for AD function assays (24)(25)(26)(27). In HIV infected cell cultures only a fraction of CD4 + T cells are truly infected (28,29).…”

“…In HIV infected cell cultures only a fraction of CD4 + T cells are truly infected (28,29). The infected cells shed gp120, which binds CD4 on uninfected bystander cells (20,27). The interaction of shed gp120 with CD4 on bystander cells not only occludes CD4bs epitopes but also opens the Env conformation exposing CD4i epitopes (20,27).…”

“…The infected cells shed gp120, which binds CD4 on uninfected bystander cells (20,27). The interaction of shed gp120 with CD4 on bystander cells not only occludes CD4bs epitopes but also opens the Env conformation exposing CD4i epitopes (20,27). Anti-Env Abs present in HIV + plasma bind these bystander cells preferentially leading to the targeting of healthy bystander cells rather than HIV infected cells by AD functions (30).…”

“…This cell line was used to quantify the concentration of anti-Env specific Abs in plasma from HIV-infected ECs, untreated progressors (UTPs) and treated subjects (TPs) (46). We showed that HIV + plasma contained Abs able to recognize Env on siCEM cells, though at lower concentrations than that of Abs binding to the open conformation of Env exposing CD4i epitopes (27). Here, we used siCEM target cells to determine the relative concentration of Abs specific for the closed conformation of Env that were ADCC-, ADCD-, and ADCT-competent.…”

Effects of gp120 Inner Domain (ID2) Immunogen Doses on Elicitation of Anti-HIV-1 Functional Fc-Effector Response to C1/C2 (Cluster A) Epitopes in Mice

“…Non-neutralizing Ab (nnAb) responses to C1/C2 have been evaluated primarily in the context of natural infection as Cluster A Env sites are highly immunogenic and the Ab response to this region is detected in most infected individuals [ 13 , 14 , 31 , 32 , 33 ]. Interestingly, ADCC against this region has also been shown to be the major ADCC response in chronically infected individuals [ 13 , 26 , 31 , 34 , 35 ] and CD4i Abs with ADCC activity are known to be passively transferred in utero via placental transfer to babies born to HIV-infected mothers [ 36 ]; however, it is still unclear whether these responses are protective and/or beneficial [ 13 , 14 , 34 , 35 , 36 , 37 , 38 ].…”