Abstract
Impairment of Nef function, including reduced CD4 downregulation, was described in a subset of HIV-1-infected individuals that control viral replication without antiretroviral treatment (elite controllers [EC]). Elimination of HIV-1-infected cells by antibody-dependent cellular cytotoxicity (ADCC) requires the presence of envelope glycoproteins (Env) in the CD4-bound conformation, raising the possibility that accumulating CD4 at the surface of virus-infected cells in EC could interact with Env and thereby sensitize these cells to ADCC. We observed a significant increase in the exposure of Env epitopes targeted by ADCC-mediating antibodies at the surface of cells expressing Nef isolates from EC; this correlated with enhanced susceptibility to ADCC. Altogether, our results suggest that enhanced susceptibility of HIV-1-infected cells to ADCC may contribute to the EC phenotype. Nef clones derived from elite controllers (EC) have been shown to be attenuated for CD4 downregulation; how this contributes to the nonprogressor phenotype of these infected individuals remains uncertain. Increasing evidence supports a role for HIV-specific antibody-dependent cellular cytotoxicity (ADCC) in controlling viral infection and replication. Here, we show that residual CD4 left at the surface of cells expressing Nef proteins isolated from ECs are sufficient to allow Env-CD4 interaction, leading to increased exposure of Env CD4-induced epitopes and increased susceptibility of infected cells to ADCC. Our results suggest that ADCC might be an active immune mechanism in EC that helps to maintain durable suppression of viral replication and low plasma viremia level in this rare subset of infected individuals. Therefore, targeting Nef's ability to downregulate CD4 could render HIV-1-infected cells susceptible to ADCC and thus have therapeutic utility.
Highlights
Impairment of Nef function, including reduced CD4 downregulation, was described in a subset of HIV-1-infected individuals that control viral replication without antiretroviral treatment
To evaluate the effect of CD4 downregulation mediated by Nef clones isolated from previously characterized elite controllers (EC) (47 clones) or chronic progressors (48 clones) [10, 11, 49, 50], on the exposure of envelope glycoproteins (Env) antibody-dependent cellular cytotoxicity (ADCC)-mediating epitopes, we used a previously described cell-based enzyme-linked immunosorbent assay (ELISA) which allows measurement of Env conformation at the cell surface [22]
As previously reported [10, 11], Nef clones isolated from EC were less efficient for CD4 downregulation compared to Nef clones from chronic progressive infections (CP) (Fig. 1A), but no difference was observed in the overall levels of Env, as measured by the outer-domain recognizing 2G12 Ab (Fig. 1B) or anti-gp41 Abs (Fig. 2)
Summary
Impairment of Nef function, including reduced CD4 downregulation, was described in a subset of HIV-1-infected individuals that control viral replication without antiretroviral treatment (elite controllers [EC]). We observed a significant increase in the exposure of Env epitopes targeted by ADCC-mediating antibodies at the surface of cells expressing Nef isolates from EC; this correlated with enhanced susceptibility to ADCC. Nef possesses several activities that are important for viral replication and pathogenesis, including downregulation of CD4 [5, 6] and HLA class I [7] molecules and enhancement of viral infectivity and replication [8, 9] Impairment of these Nef activities was demonstrated in HIV-1 elite controllers (EC), rare infected individuals who spontaneously suppress plasma viremia to Ͻ50 RNA copies/ml without antiretroviral therapy [10]. Increasing evidence supports a role for HIV-specific antibody (Ab)-dependent cellular cytotoxicity (ADCC) in controlling viral infection and replication [12,13,14,15,16,17,18]. We evaluated whether the inability of EC Nef clones to fully downregulate CD4 results in the adoption of a CD4-bound Env conformation on HIV-1-infected cells and enhanced susceptibility of these cells to ADCC
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