Abstract
The initial step in target cell infection by human, and the closely related simian immunodeficiency viruses (HIV and SIV, respectively) occurs with the binding of trimeric envelope glycoproteins (Env), composed of heterodimers of the viral transmembrane glycoprotein (gp41) and surface glycoprotein (gp120) to target T-cells. Knowledge of the molecular structure of trimeric Env on intact viruses is important both for understanding the molecular mechanisms underlying virus-cell interactions and for the design of effective immunogen-based vaccines to combat HIV/AIDS. Previous analyses of intact HIV-1 BaL virions have already resulted in structures of trimeric Env in unliganded and CD4-liganded states at ∼20 Å resolution. Here, we show that the molecular architectures of trimeric Env from SIVmneE11S, SIVmac239 and HIV-1 R3A strains are closely comparable to that previously determined for HIV-1 BaL, with the V1 and V2 variable loops located at the apex of the spike, close to the contact zone between virus and cell. The location of the V1/V2 loops in trimeric Env was definitively confirmed by structural analysis of HIV-1 R3A virions engineered to express Env with deletion of these loops. Strikingly, in SIV CP-MAC, a CD4-independent strain, trimeric Env is in a constitutively “open” conformation with gp120 trimers splayed out in a conformation similar to that seen for HIV-1 BaL Env when it is complexed with sCD4 and the CD4i antibody 17b. Our findings suggest a structural explanation for the molecular mechanism of CD4-independent viral entry and further establish that cryo-electron tomography can be used to discover distinct, functionally relevant quaternary structures of Env displayed on intact viruses.
Highlights
About 2.5 million individuals are newly infected with human immunodeficiency virus (HIV) each year, and over 2 million deaths result annually from HIV/AIDS
The gp120 density profiles obtained from the coordinates of the sCD4/17b complex (Figure S4a) and the b12 complex (Figure S4b) are rather similar when viewed at,20 Aresolution, even though there are important differences in their atomic resolution structures. Both of these HIV-1 gp120 structures differ significantly from the conformation reported for monomeric, unliganded, simian immunodeficiency virus (SIV) gp120 (Figure S4c). When each of these coordinates are fitted into the SIVmneE11S map we present here, it is the HIV-1 gp120 coordinates determined for the complexes with sCD4/17b (Figures S4d, S4g) or b12 (Figures S4e, S4h) that show a visually better fit rather than the coordinates reported for the unliganded SIV gp120 core (Figures S4f, S4i)
Knowledge of the structure and functionally relevant conformational changes of trimeric envelope glycoprotein spikes (Env) remains an important challenge in HIV structural biology
Summary
About 2.5 million individuals are newly infected with human immunodeficiency virus (HIV) each year, and over 2 million deaths result annually from HIV/AIDS (http://www.unaids.org). HIV-1 and the closely related simian immunodeficiency virus (SIV) bind to target cells by the interaction of trimeric envelope glycoprotein spikes (Env), a heterodimer of a transmembrane glycoprotein (gp41) and a surface glycoprotein (gp120) [1], with CD4 and a co-receptor (CCR5 or CXCR4) [2]. Understanding of the molecular structure of trimeric Env on infectious virus particles before and after contact with the T-cell surface is fundamental to the informed design of immunogens to elicit broadly neutralizing antibodies and for deciphering the detailed molecular mechanisms underlying HIV infection [3,4]. By extracting subvolumes corresponding to each trimeric spike, and accounting properly for the missing wedge [10] of data that is inherent to electron tomography, 3D classification and averaging can be used to obtain density maps at signal-to-noise ratios that are sufficiently high for molecular interpretation [9,10,11,12]
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