Structural Definition of an Antibody-Dependent Cellular Cytotoxicity Response Implicated in Reduced Risk for HIV-1 Infection

Acharya, Priyamvada; Tolbert, W.D.; Gohain, Neelakshi; Wu, Xueji; Yu, Long-Chuan; Liu, Tongyun; Huang, Wensheng; Huang, Chien‐Yi; Kwon, Young Do; Louder, Robert K.; Luongo, Timothy S.; McLellan, Jason S.; Pancera, Marie; Yang, Yongping; Zhang, Baoshan; Flinko, Robin; Foulke, James S.; Sajadi, Mohammad M.; Kamin-Lewis, Roberta; Robinson, James E.; Martin, Loı̈c; Kwong, Peter D.; Guan, Yongjun; DeVico, Anthony L.; Lewis, George K.; Pazgier, Marzena

doi:10.1128/jvi.02194-14

Cited by 97 publications

(220 citation statements)

References 67 publications

(105 reference statements)

Supporting

Mentioning

211

Contrasting

Order By: Relevance

“…Numerous CD4i MAbs have been described, whose dependence on CD4 for gp120 binding ranges from marginal to absolute (18,21,23,42,62,(64)(65)(66). These MAbs are generally designated CD4i MAbs.…”

Section: Resultsmentioning

confidence: 99%

Range of CD4-Bound Conformations of HIV-1 gp120, as Defined Using Conditional CD4-Induced Antibodies

Kaplan

Roitburd-Berman

Lewis

et al. 2016

J Virol

Self Cite

View full text Add to dashboard Cite

The HIV envelope binds cellular CD4 and undergoes a range of conformational changes that lead to membrane fusion and delivery of the viral nucleocapsid into the cellular cytoplasm. This binding to CD4 reveals cryptic and highly conserved epitopes, the molecular nature of which is still not fully understood. The atomic structures of CD4 complexed with gp120 core molecules (a form of gp120 in which the V1, V2, and V3 loops and N and C termini have been truncated) have indicated that a hallmark feature of the CD4-bound conformation is the bridging sheet minidomain. Variations in the orientation of the bridging sheet hairpins have been revealed when CD4-liganded gp120 was compared to CD4-unliganded trimeric envelope structures. Hence, there appears to be a number of conformational transitions possible in HIV-1 monomeric gp120 that are affected by CD4 binding. The spectrum of CD4-bound conformations has been interrogated in this study by using a well-characterized panel of conditional, CD4-induced (CD4i) monoclonal antibodies (MAbs) that bind HIV-1 gp120 and its mutations under various conditions. Two distinct CD4i epitopes of the outer domain were studied: the first comprises the bridging sheet, while the second contains elements of the V2 loop. Furthermore, we show that the unliganded extended monomeric core of gp120 (core e ) assumes an intermediate CD4i conformation in solution that further undergoes detectable rearrangements upon association with CD4. These discoveries impact both accepted paradigms concerning gp120 structure and the field of HIV immunogen design. IMPORTANCE Elucidation of the conformational transitions that the HIV-1 envelope protein undergoes during the course of entry into CD4؉ cells is fundamental to our understanding of HIV biology. The binding of CD4 triggers a range of gp120 structural rearrangements that could present targets for future drug design and development of preventive vaccines. Here we have systematically interrogated and scrutinized these conformational transitions using a panel of antibody probes that share a specific preference for the CD4i conformations. These have been employed to study a collection of gp120 mutations and truncations. Through these analyses, we propose 4 distinct sequential steps in CD4i transitions of gp120 conformations, each defined by antibody specificities and structural requirements of the HIV envelope monomer. As a result, we not only provide new insights into this dynamic process but also define probes to further investigate HIV infection. V iral tropism is mediated by the specific binding of the viral spike protein to its corresponding cell surface receptor. Evolution has driven human immunodeficiency virus (HIV) to elaborate on this canonical paradigm, introducing a series of orchestrated sequential events involving two receptors: CD4 as a primary receptor (1-3) and a chemokine receptor (CXCR4 or CCR5) as a subsequent coreceptor (4-10). However, many critical details of the molecular mechanisms by which CD4 triggers a number of conformati...

show abstract

Section: Resultsmentioning

confidence: 99%

Range of CD4-Bound Conformations of HIV-1 gp120, as Defined Using Conditional CD4-Induced Antibodies

Kaplan

Roitburd-Berman

Lewis

et al. 2016

J Virol

Self Cite

View full text Add to dashboard Cite

show abstract

“…It is possible that differential expression of this receptor between NK subsets might account for the higher ADCC activity of the FcRg 2 population observed in some HIV patients, but the has not been examined in the present study. The expansion of a population of NK cells with increased ADCC activity in HIV + individuals has relevance to vaccine strategies aimed at generating ADCC-promoting Ab responses (41)(42)(43).…”

Section: Discussionmentioning

confidence: 99%

An NK Cell Population Lacking FcRγ Is Expanded in Chronically Infected HIV Patients

Zhou

Amran

Kramski

et al. 2015

The Journal of Immunology

View full text Add to dashboard Cite

We previously demonstrated that NK cells from HIV-infected individuals have elevated expression of activation markers, spontaneously degranulate ex vivo, and decrease expression of a signal-transducing protein for NK-activating receptors, FcRγ. Importantly, these changes were maintained in virologically suppressed (VS) individuals receiving combination antiretroviral therapy (cART). In this study, we show that loss of FcRγ is caused by the expansion of a novel subset of FcRγ−CD56dim NK cells with an altered activation receptor repertoire and biological properties. In a cross-sectional study, FcRγ− NK cells as a proportion of total CD56dim NK cells increased in cART-naive viremic HIV-infected individuals (median [interquartile range] = 25.9 [12.6–56.1] compared with 3.80 [1.15–11.5] for HIV− controls, p < 0.0001) and in VS HIV-infected individuals (22.7 [13.1–56.2] compared with 3.80 [1.15–11.5], p = 0.0004), with no difference between cART-naive and VS patients (p = 0.93). FcRγ− NK cells expressed no NKp30 or NKp46. They showed greater Ab-dependent cellular cytotoxicity activity against rituximab-opsonized Raji cells and in a whole-blood assay measuring NK responses to overlapping HIV peptides, despite having reduced CD16 expression compared with conventional NK cells. Their prevalence correlated with CMV Ab titers in HIV− subjects but not in HIV+ individuals, and with the inflammatory marker CXCL10 in both groups. The expansion of a subset of NK cells that lacks NKp30 and NKp46 to ∼90% of CD56dim NK cells in some VS HIV+ individuals may influence NK-mediated immunosurveillance in patients receiving cART.

show abstract

“…sCD4 is the recombinant human CD4 protein lacking the transmembrane domain and cytoplasmic tail, and it is known to induce conformational changes in Env to some extent, similar to those induced by CD4 expressed on target cells. sCD4 induces formation of the bridging sheet and the coreceptor binding site, but certain gp120 epitopes, including potent ADCC targets in the C1-C2 region (A32-like epitopes), remain occluded in sCD4-triggered Env trimers (34,35). These epitopes become exposed on virions only on the interaction of Env trimers with host CD4, indicating that binding membrane-anchored CD4 provides an additional energy component that is not provided by sCD4 (35).…”

Section: Cd4 Mimetics Sensitize Hiv-1-infected Cells To Adcc Mediated Bymentioning

confidence: 99%

“…sCD4 induces formation of the bridging sheet and the coreceptor binding site, but certain gp120 epitopes, including potent ADCC targets in the C1-C2 region (A32-like epitopes), remain occluded in sCD4-triggered Env trimers (34,35). These epitopes become exposed on virions only on the interaction of Env trimers with host CD4, indicating that binding membrane-anchored CD4 provides an additional energy component that is not provided by sCD4 (35). Rationally designed CD4mc (JP-III-48, DMJ-I-228) engage gp120 within the Phe-43 cavity (22) and can act as CD4 agonists, inducing thermodynamic changes in the Env trimer more similar to those observed during membrane CD4 binding (20,24).…”

Section: Cd4 Mimetics Sensitize Hiv-1-infected Cells To Adcc Mediated Bymentioning

confidence: 99%

CD4 mimetics sensitize HIV-1-infected cells to ADCC

Richard

Veillette

Brassard

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

121

291

View full text Add to dashboard Cite

HIV-1-infected cells presenting envelope glycoproteins (Env) in the CD4-bound conformation on their surface are preferentially targeted by antibody-dependent cell-mediated cytotoxicity (ADCC). HIV-1 has evolved a sophisticated mechanism to avoid exposure of ADCC-mediating Env epitopes by down-regulating CD4 and by limiting the overall amount of Env at the cell surface. Here we report that small-molecule CD4-mimetic compounds induce the CD4-bound conformation of Env, and thereby sensitize cells infected with primary HIV-1 isolates to ADCC mediated by antibodies present in sera, cervicovaginal lavages, and breast milk from HIV-1-infected individuals. Importantly, we identified one CD4 mimetic with the capacity to sensitize endogenously infected ex vivo-amplified primary CD4 T cells to ADCC killing mediated by autologous sera and effector cells. Thus, CD4 mimetics hold the promise of therapeutic utility in preventing and controlling HIV-1 infection.

show abstract

Structural Definition of an Antibody-Dependent Cellular Cytotoxicity Response Implicated in Reduced Risk for HIV-1 Infection

Cited by 97 publications

References 67 publications

Range of CD4-Bound Conformations of HIV-1 gp120, as Defined Using Conditional CD4-Induced Antibodies

Range of CD4-Bound Conformations of HIV-1 gp120, as Defined Using Conditional CD4-Induced Antibodies

An NK Cell Population Lacking FcRγ Is Expanded in Chronically Infected HIV Patients

CD4 mimetics sensitize HIV-1-infected cells to ADCC

Contact Info

Product

Resources

About