HIV-1 envelope glycoproteins (Env) represent the only virus-specific antigen exposed at the surface of infected cells. In its unliganded form, Env from primary viruses samples a ‘closed’ conformation (State 1), which is preferentially recognized by broadly neutralizing antibodies (bNAbs). CD4 engagement drives Env into an intermediate ‘partially open’ (State 2) and then into the ‘open’ CD4-bound conformation (State 3). Emerging evidence suggests a link between Env conformation and Ab-dependent cellular cytotoxicity (ADCC). HIV-1-infected cells exposing Env in the CD4-bound conformation are susceptible to ADCC mediated by CD4-induced Abs and HIV + sera. Cells exposing State 1 Env are susceptible to ADCC mediated by bNAbs. Here, we discuss how Env conformation affects ADCC responses and in vitro measurements.
bNAbs preferentially recognize Env in its ‘closed’ conformation, while non-neutralizing CD4-induced Abs target the ‘open’ CD4-bound conformation.
Env tightly controls its transition from the unbound to the CD4-bound conformation to avoid recognition by host CD4-induced Abs.
Nef and Vpu accessory proteins protect HIV-1-infected cells from ADCC by preventing Env–CD4 interactions and by reducing the expression levels of cell surface NKG2D ligands.
Gp120 shed from infected cells binds CD4 on uninfected bystander CD4+ T cells, sensitizing them to ADCC and influencing in vitro ADCC measurements.
Targeting the Env ‘closed’ conformation with bispecific Abs and/or proteins or exposing vulnerable ADCC-mediating epitopes using CD4 mimetics are emerging approaches to eliminate HIV-1-infected cells.
Impact of Antibody-Dependent Cellular Cytotoxicity on HIV-1 Replication and Transmission
HIV-1 continues to infect more than 1,8 million individuals annually, with an estimated total of 36,7 million people living with this virus in 2016i. Enormous effort has been made to improve the clinical management of HIV/AIDS through highly active antiretroviral therapy (HAART). Accordingly, HIV-1 infection can be controlled with HAART and, in most cases, allows for a significant increase in the life expectancy of infected individuals [1. However, viral rebounds can occur upon HAART interruption due to the presence of latent viral reservoirs [2, 3], persisting mainly in long-lived memory CD4+ T cells [4. Efforts to design efficient preventive or curative strategies have yet to produce results in the clinic. Identifying and characterizing the immune functions needed to establish a protective immunity and understanding how the virus responds and protects itself from these immune functions represent a highly complex, multifaceted problem.
At the time of writing, only one anti-HIV-1 vaccine trial, the RV144 Thai trial (see Glossary), has presented a modest (31.2%) efficacy in preventing infection by HIV-1 [5. Interestingly, correlates of protection in this trial suggested that increased ADCCcould be linked with decreased HIV-1 acquisition [6 and Abs with potent ADCC activity were isolated from some RV144 vaccinees [7. ADCC is thought to represent an important immune effector function in the protection and control of different viral infections and could be mediated by natural killer (NK) cells, monocytes/macrophages, or neutrophils [8, 9, 10, 11]. Decreased viral load, rate of disease progression, and decreased mother–child transmission correlated with Fc-mediated effector functions in HIV-1 and simian immunodeficiency virus (SIV) infections in some [12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22], but not in all studies [23, 24, 25]. Of note, Fc-mediated effector functions appear to be important against not only infected cells, but also free virus [26. While some studies failed to show that passive administration of non-neutralizing Abs (nnAbs) presenting ADCC activity could confer protection against SIV or simian-HIV (SHIV) challenges in macaque models [27, 28, 29, 30], a recent study clearly indicated that nnAbs could alter the course of HIV-1 infection in humanized mice [31. Supporting an important role of ADCC in preventing viral transmission, a recent pentavalent HIV-1 vaccine was shown to protect 55% of pentavalent vaccine-immunized rhesus macaques from SHIV challenge. Systems serology of the Ab responses in this study identified ADCC activity as one of the four main immunological parameters able to predict decreased infection risk [32.
The HIV-1 Env trimer mediates viral entry. HIV-1 Env is formed by three exterior gp120 and three transmembrane gp41 subunits, which are noncovalently associated [33, 34, 35]. Interaction of gp120 with the CD4 receptor triggers major conformational changes in Env, including movement of the V1/V2 and V3 loops, and formation of the co-receptor binding site (CoRBS) and the bridging sheet [36, 37, 38, 39, 40, 41, 42, 43]. CD4 interaction also leads to the exposure of the gp41 helical heptad repeat (HR1) [44. CCR5 or CXCR4 co-receptor interaction with gp120 promotes additional conformational changes in gp41, resulting in the formation of a six-helix bundle formed by HR1 and HR2 heptad repeats and in the fusion of viral and cellular membranes.
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