Impact of HIV-1 Envelope Conformation on ADCC Responses

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.

Trends

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 [23], 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 [891011]. 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 [1213141516171819202122], but not in all studies [232425]. 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 [27282930], 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.

Env Conformation

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 [333435]. 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 [3637383940414243]. 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.

Env is a metastable molecule that transits from its unliganded ‘closed’ high-energy conformation (State 1) to its ‘open’ CD4-bound low-energy conformation (State 3). CD4 engagement drives Env into an intermediate ‘partially open’ conformation (State 2) and then into State 3 [4546]. Env represents the only virus-specific antigen exposed at the surface of infected cells and, thus, represents a major target for ADCC. The unliganded Env of most primary clinical HIV-1 isolates assumes a ‘closed’ State 1 conformation, which renders them relatively resistant to Ab attack (Figure 1) [46. Despite different modes of recognition, multiple bNAbs preferentially recognize and stabilize this ‘closed’ conformation. By contrast, CD4 binding ‘opens’ Env by reorganizing the V1/V2 and V3 loops, resulting in the adoption of the CD4-bound conformation, referred to as State 3 (Figure 1) [4546]. This conformation is efficiently recognized by ADCC-mediating Abs present in sera from HIV-1-infected individuals [47. To avoid the exposure of these vulnerable epitopes, Env tightly controls its transition from State 1 to States 2/3. For instance, the V1/V2 and V3 loops have a critical role in keeping the trimer ‘closed’ [484950], with well-conserved V2 residues restraining Env from sampling downstream States 2/3 conformations [45. Additional elements participate in keeping Env in State 1, including the Phe 43 cavity, a highly conserved approximately 150-Å3 pocket located at the interface between the inner and outer domain of the gp120, which allows engagement to CD4 via its Phe43 residue [51. Within this cavity, residue 375 impacts the conformation spontaneously sampled by Env. Most HIV-1 group M Envs have an ‘empty’ Phe 43 cavity due to the presence of a small residue, such as serine, at position 375 (S375), which favors the adoption of State 1, therefore preventing transitions to downstream conformations [5253] (Figure 1). Interestingly, substitution of S375 by large hydrophobic residues, such as histidine or tryptophan, ‘fills’ the Phe 43 cavity and predisposes Env to spontaneously assume a state closer to the CD4-bound conformation [52 (Figure 1). Accordingly, CRF01_AE Envs, which have a naturally occurring Phe 43 cavity-filling residue at this position (H375), are better recognized by CD4-induced (CD4i) Abs than CRF01_AE Envs having this residue replaced by a serine (H375S), resulting in enhanced ADCC responses mediated by HIV+ sera and anticluster A Abs [54.

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