HIV-specific CD4-induced Antibodies Mediate Broad and Potent Antibody-dependent Cellular Cytotoxicity Activity and are Commonly Detected in Plasma from HIV-infected Humans

Abstract

HIV-specific antibodies (Abs) can reduce viral burden by blocking new rounds of infection or by destroying infected cells via activation of effector cells through Fc–FcR interaction. This latter process, referred to as antibody-dependent cellular cytotoxicity (ADCC), has been associated with viral control and improved clinical outcome following both HIV and SIV infections. Here we describe an HIV viral-like particle (VLP)-based sorting strategy that led to identification of HIV-specific memory B cells encoding Abs that mediate ADCC from a subtype A-infected Kenyan woman at 914 days post-infection. Using this strategy, 12 HIV-envelope-specific monoclonal antibodies (mAbs) were isolated and three mediated potent ADCC activity when compared to well-characterized ADCC mAbs. The ADCC-mediating Abs also mediated antibody-dependent cell-mediated virus inhibition (ADCVI), which provides a net measure of Fc receptor-triggered effects against replicating virus. Two of the three ADCC-mediating Abs targeted a CD4-induced (CD4i) epitope also bound by the mAb C11; the third antibody targeted the N-terminus of V3. Both CD4i Abs identified here demonstrated strong cross-clade breadth with activity against 10 of 11 envelopes tested, including those from clades A, B, C, A/D and C/D, whereas the V3-specific antibody showed more limited breadth. Variants of these CD4i, C11-like mAbs engineered to interrupt binding to FcγRs inhibited a measurable percentage of the donor's ADCC activity starting as early as 189 days post-infection. C11-like antibodies also accounted for between 18–78% of ADCC activity in 9 chronically infected individuals from the same cohort study. Further, the two CD4i Abs originated from unique B cells, suggesting that antibodies targeting this epitope can be commonly produced. Taken together, these data provide strong evidence that CD4i, C11-like antibodies develop within the first 6 months of infection and they can arise from unique B-cell lineages in the same individual. Further, these mAbs mediate potent plasma IgG-specific ADCC breadth and potency and contribute to ADCC activity in other HIV-infected individuals.

Lack of ADCC Breadth of Human Nonneutralizing Anti-HIV-1 Antibodies

“…We then examined how the prototypic CD4i anti-cluster A A32 antibody (25) behaves in our assays, since A32-like antibodies constitute the majority of the ADCC activity observed in HIV-1-infected or RV144-vaccinated individuals (21,26,50,68,71,82). Using lymphocytes infected with KB18v, we observed that the profile of A32 binding was comparable to that of CD4i CoRBS antibodies 4-8 and 4-42, with preferential staining for Gag-low or -negative cells (Fig.…”

“…However, we show that the prototypic anti-cluster A CD4i antibody A32 (22) does not display strong ADCC against cells infected by a virus isolated from one patient. Numerous other nnAbs have been isolated and tested in ADCC assays (57,65,67,68,71,87). It will be worth determining whether they display a broader recognition of HIV-1-infected cells, since most previous studies were based on a relatively low number of primary cross-clade viral isolates or used gp120-coated cells as ADCC targets (24,39,50,60,(65)(66)(67)(68)(69)(70).…”

“…It is noteworthy that most of the studies regarding the ADCC activity of nnAbs in animal models or in cell culture systems have been performed by using a relatively limited number of different HIV-1 strains (24, 39, 49-51, 59, 60, 65-70). Moreover, the frequent use of gp120-coated cells (26,57,68,71,72) as targets in ADCC assays is a convenient tool, but it does not fully recapitulate the levels or conformation of Env at the surface of infected cells. Indeed, levels of Env at the surface of cells infected with a wild-type virus are relatively low.…”

BST-2 Expression Modulates Small CD4-Mimetic Sensitization of HIV-1-Infected Cells to Antibody-Dependent Cellular Cytotoxicity

“…Increasing evidence suggests that Fc␥ receptor-dependent functions of antibodies play a role in controlling human immunodeficiency virus type 1 (HIV-1) infection and replication (32)(33)(34)(35)(36)(37)(38)(39)(40). Analysis of the correlates of protection in the RV144 vaccine trial suggested that decreased HIV-1 acquisition was linked to increased ADCC activity in protected vaccinees (41).…”

HIV-1 Env- and Vpu-Specific Antibody-Dependent Cellular Cytotoxicity Responses Associated with Elite Control of HIV

“…However, Env has proven to be a difficult target due to its wide diversity across the globe, its high mutation rate, and often poor access of NAbs to critical conserved epitopes (12,13). Since the partial efficacy seen in the RV144 trial and the results of the subsequent post hoc analyses, HIV-specific ADCC responses have gained importance as potential targets for prevention and control of infection (14). These responses have several possible advantages over NAbs, in that they can target cells within which HIV is replicating and they can also target non-Env proteins such as Pol and Vpu (10,15).…”