Structure and Function of the HIV Envelope Glycoprotein as Entry Mediator, Vaccine Immunogen, and Target for Inhibitors

Prabakaran, Ponraj; Dimitrov, Antony S.; Fouts, Timothy; Dimitrov, Dimiter S.

doi:10.1016/s1054-3589(07)55002-7

Cited by 35 publications

(33 citation statements)

References 266 publications

(329 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This constitutes the first step in the dynamic process in which structural elements of the envelope shift and rearrange to gain function, ultimately leading to gp41-mediated membrane fusion and the introduction of the viral nucleocapsid into the cytoplasm of target cells (83). A key player in this process is gp120, whose outer domain directly binds CD4 and undergoes a range of conformational transitions.…”

Section: Discussionmentioning

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

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: Discussionmentioning

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

View full text Add to dashboard Cite

show abstract

“…The gp120 exterior envelope glycoprotein is retained on the trimer via noncovalent interactions with the ectodomain of the gp41 transmembrane envelope glycoprotein. [1][2][3] The ectodomain of the gp41 glycoprotein contains a hydrophobic, glycine-rich amino terminus (fusion peptide), and two heptad repeat (HR) regions, designated HR1 and HR2, connected by a 25-to 30-residue region characterized by a disulfide-bonded loop and several N-linked glycosylation sites. HR1 is immediately carboxy-terminal to the fusion peptide and HR2 is close to the viral membranespanning region.…”

Section: Introductionmentioning

confidence: 99%

“…6 Upon the interaction of gp120 with its cellular receptors CD4 and one of the chemokine receptors, CCR5 or CXCR4, the trimeric HIV-1 envelope glycoprotein complex undergoes extensive conformational transitions that culminate in the formation of a gp41 sixhelix bundle, in which the HR2 regions pack into the wellconserved, largely hydrophobic grooves on the outer surface of the HR1 coiled coil. [1][2][3][4][5] The formation of the six-helix bundle structure is thought to approximate the viral and the target cell membranes and eventually drive membrane fusion. 7 The gp41 glycoprotein ectodomain is very immunogenic, inducing high-titer antibodies in essentially all HIV-1-infected individuals.…”

Section: Introductionmentioning

confidence: 99%

Oligomer-Specific Conformations of the Human Immunodeficiency Virus (HIV-1) gp41 Envelope Glycoprotein Ectodomain Recognized by Human Monoclonal Antibodies

Yuan

Xing

Kasterka

et al. 2009

AIDS Research and Human Retroviruses

View full text Add to dashboard Cite

Trimerization of the human immunodeficiency virus (HIV-1) envelope glycoproteins is mediated by the ectodomain of the gp41 transmembrane glycoprotein. Here we investigate oligomer-specific conformations of gp41 by using monoclonal antibodies (MAbs) from HIV-1-infected humans. Human MAbs directed against the cluster I region of gp41 recognized trimeric, dimeric, and monomeric forms of soluble envelope glycoproteins; thus, the integrity of the cluster I epitopes is minimally affected by the oligomeric state. In contrast, human MAbs to the cluster II region were all oligomers specific. One cluster II MAb, 126-6, recognized exclusively the trimeric form of envelope glycoproteins, whereas the others recognized both trimeric and dimeric forms. Thus, a distinct trimer-specific conformation exists in the cluster II region of gp41. Analysis of soluble envelope glycoprotein mutants revealed that gp41 sequences immediately N-terminal to isoleucine 646 contribute to the formation of both the trimer and the trimer-specific conformational epitope.

show abstract

“…According to estimates from the 2007 United Nations AIDS/World Health Organization (UNAIDS/WHO) AIDS Epidemic Update, Ͼ6,800 persons become infected and Ͼ5,700 persons die from AIDS every day; in 2007, 33.2 million (30.6-36.1 million) were living with HIV, 2.5 million (1.8-4.1 million) were infected, and 2.1 million (1.9-2.4 million) have died (http://data.unaids.org/pub/ EPISlides/2007/2007 epiupdate en.pdf) despite antiretroviral therapy, which reduced AIDS-related deaths among those who received it. The efficacy of HIV therapy is significantly compromised by resistance to antiretroviral drugs (2,3). A significant percentage of patients with HIV-1 infection (Ͼ50% in the US) receiving antiretroviral therapy are infected with viruses that express resistance to at least one of the available antiretroviral drugs.…”

mentioning

confidence: 99%

Human domain antibodies to conserved sterically restricted regions on gp120 as exceptionally potent cross-reactive HIV-1 neutralizers

Chen

Zhu

Yang

et al. 2008

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

Self Cite

154

View full text Add to dashboard Cite

The antibody access to some conserved structures on the HIV-1 envelope glycoprotein (Env) is sterically restricted. We have hypothesized that the smallest independently folded antibody fragments (domains) could exhibit exceptionally potent and broadly crossreactive neutralizing activity by targeting hidden conserved epitopes that are not accessible by larger antibodies. To test this hypothesis, we constructed a large (size 2.5 ؋ 10 10 ), highly diversified library of human antibody variable domains (domain antibodies) and used it for selection of binders to conserved Env structures by panning sequentially against Envs from different isolates. The highest affinity binder, m36, neutralized all tested HIV-1 isolates from clades A-D with an activity on average higher than that of C34, a peptide similar to the fusion inhibitor T20, which is in clinical use, and that of m9, which exhibits a neutralizing activity superior to known potent crossreactive antibodies. Large-size fusion proteins of m36 exhibited diminished neutralizing activity but preincubation of virions with soluble CD4 restored it, suggesting that m36 epitope is sterically restricted and induced by CD4 (CD4i). M36 bound to gp120-CD4 complexes better than to gp120 alone and competed with CD4i antibodies. M36 is the only reported representative of a promising class of potent, broadly cross-reactive HIV-1 inhibitors based on human domain antibodies. It has potential for prevention and therapy and as an agent for exploration of the closely guarded conserved Env structures with implications for design of small molecule inhibitors and elucidation of mechanisms of virus entry and evasion of immune responses.neutralization ͉ therapeutic ͉ epitope ͉ steric restriction

show abstract

Structure and Function of the HIV Envelope Glycoprotein as Entry Mediator, Vaccine Immunogen, and Target for Inhibitors

Cited by 35 publications

References 266 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

Oligomer-Specific Conformations of the Human Immunodeficiency Virus (HIV-1) gp41 Envelope Glycoprotein Ectodomain Recognized by Human Monoclonal Antibodies

Human domain antibodies to conserved sterically restricted regions on gp120 as exceptionally potent cross-reactive HIV-1 neutralizers

Contact Info

Product

Resources

About