Form, function, and use of retroviral Gag proteins

Wills, John W.; Craven, Rebecca

doi:10.1097/00002030-199106000-00002

Cited by 499 publications

(502 citation statements)

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“…The resulting pseudoatomic model showed that the mature HIV-1 capsid lattice is stabilized by three different intermolecular CA-CA interfaces (Fig. 3c-e): (1) intrahexamer CA NTD -CA NTD interactions are mediated by CA helices 1-3, which associate as an 18-helix bundle in the center of the hexamer (as seen for the N-MLV CA NTD hexamer), (2) intrahexamer CA NTD -CA CTD interactions are formed by asymmetric insertion of the CA NTD helix 4 into a groove of CA CTD from an adjacent molecule within the hexamer, allowing the six CA CTD domains to form a "belt" surrounding the CA NTD core, and (3) interhexamer CA CTD -CA CTD interactions are mediated by symmetric, parallel dimerization of helix 9 from CA CTD subunits of adjacent hexamers (as seen in the side-by-side CA CTD dimer) (Fig. 2c) [68,69].…”

Section: Structure Of the Hexameric Ca Latticementioning

confidence: 99%

“…1-3) is composed of a short 3 10 helix followed by an extended strand and four α-helices (CA helices 8-11) [68,69]. The strand/turn/helix 8 element is termed the major homology region (MHR) because its sequence is highly conserved across most retroviruses and retrotransposons [2,70]. Mutations in conserved MHR residues inhibit the assembly of immature particles, indicating that the MHR plays an important role in Gag lattice formation [47,50,70,71].…”

Section: Gag-gag Lattice Interactions In the Immature Virion Are Medimentioning

confidence: 99%

“…The remarkably distinct morphologies of the immature Gag lattice and the capsid lattice presumably reflect specific requirements for organizing viral assembly in the producer cell and coordinating viral replication in the new host cell (Fig. 1a) (reviewed in [1][2][3][4]). The capsid and its contents are called the "core," and this is the object that is released into the cytoplasm of a newly infected cell to initiate a new cycle of viral replication [3][4][5][6][7][8].…”

Section: Introductionmentioning

confidence: 99%

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The structural biology of HIV assembly

Ganser‐Pornillos

Yeager

Sundquist

2008

Current Opinion in Structural Biology

412

422

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HIV assembly and replication proceed through formation of morphologically distinct immature and mature viral capsids that are organized by the Gag polyprotein (immature) and by the fully processed CA protein (mature). The Gag polyprotein is composed of three folded polypeptides (MA, CA, and NC) and three smaller peptides (SP1, SP2, and p6) that function together to coordinate membrane binding and Gag-Gag lattice interactions in immature virions. Following budding, HIV maturation is initiated by proteolytic processing of Gag, which induces conformational changes in the CA domain and results in assembly of the distinctive conical capsid. Retroviral capsids are organized following the principles of fullerene cones, and the hexagonal CA lattice is stabilized by three distinct interfaces. Recently identified inhibitors of viral maturation act by disrupting the final stage of Gag processing, or by inhibiting formation of a critical intermolecular CA-CA interface in the mature capsid. Following release into a new host cell, the capsid disassembles and host cell factors can potently restrict this stage of retroviral replication. Here, we review the structures of immature and mature HIV virions, focusing on recent studies that have defined the global organization of the immature Gag lattice, identified sites likely to undergo conformational changes during maturation, revealed the molecular structure of the mature capsid lattice, demonstrated that capsid architectures are conserved, identified the first capsid assembly inhibitors, and begun to uncover the remarkable biology of the mature capsid.

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Section: Structure Of the Hexameric Ca Latticementioning

confidence: 99%

Section: Gag-gag Lattice Interactions In the Immature Virion Are Medimentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The structural biology of HIV assembly

Ganser‐Pornillos

Yeager

Sundquist

2008

Current Opinion in Structural Biology

412

422

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“…3A, D). This peptide overlaps both the major homology region (MHR), a highly conserved 20-aa sequence in the gag protein, and a peptide that was reported as targeted by CD4 + T cells in over 50% of infected individuals [24,26,27]. It also overlaps an HLA-DRB1*1302-restricted epitope (p24 [163][164][165][166][167][168][169][170][171][172][173][174][175][176][177] ) [28].…”

Section: Fine-mapping Reveals New Epitopes Targeted By Dominant Mvahmentioning

confidence: 99%

Immunisation with recombinant modified vaccinia virus Ankara expressing HIV‐1 gag in HIV‐1‐infected subjects stimulates broad functional CD4⁺ T cell responses

et al. 2006

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Virus-specific CD4 + T cells with IL-2-secreting and/or proliferative capacity are detected readily in HIV-1-infected long-term nonprogressors and rarely in persons with untreated progressive infection. The contribution of these cells to viraemia control is uncertain, but this question might be addressed in clinical therapeutic vaccination studies. However, the quality of T helper responses induced by currently available HIV-1 vaccine candidates has not been explored in depth. We determined the effect of vaccination with modified vaccinia virus Ankara (MVA) expressing HIV-1 gag p24/p17 (MVA.HIVA) on HIV-1-specific CD4 + T cell responses in 16 chronically infected, highly active antiretroviral therapy (HAART)-treated subjects using CD8-depleted IFN-c ELISPOT assays, intracellular cytokine staining assays for IL-2 and IFN-c, and a CFSEbased proliferation assay. Gag-specific CD4 + T cell responses were significantly increased in magnitude and breadth after vaccination and targeted both known and new epitopes, several of which were also recognised by healthy HIV-uninfected volunteers immunised with the same vaccines. The frequencies of CD4 + T cells expressing IL-2 or IFN-c, alone or simultaneously, were also augmented. These findings indicate that functional virus-specific T helper cells can be boosted by vaccination in chronic HIV-1 infection. Further evaluation of their role in viraemia control is warranted. IntroductionThe rate of progression of HIV-1 infection to AIDS may be determined by the capacity for immunological recovery after early and extensive depletion of mucosal CD4 + T cells [1]. Highly active antiretroviral therapy (HAART) can restore CD4 + T cell-mediated responses to opportunistic pathogens, but maintenance of adequate CD4 + T cell counts requires lifelong antiretroviral therapy, which is associated with potentially serious adverse effects and is too costly for the majority of infected persons worldwide [2]. Furthermore, the capacity of HIV-1-specific CD4 + T cells to proliferate and secrete IL-2, characteristics which are typically preserved only in long-term nonprogressors, are not always restored after initiation of therapy, particularly when this is delayed beyond acute infection [3][4][5][6]. Loss of function may result from preferential infection of virus-specific cells by 7,8]. Enhancement of HIV-1-specific cellular responses by therapeutic vaccination in combination with fully suppressive antiretroviral therapy might be used to maintain HIV-1 control without continuous drug treatment [9]. While a critical role for virus-specific CD4 + T cells in the induction and maintenance of effective immunity against HIV-1 is inferred from animal models and other human virus infections such as hepatitis C, direct evidence for this is lacking [10][11][12][13][14]. In healthy macaques, CD4 + T cell proliferation and TNF-a secretion were induced by DNA-prime/poxvirus-boost vaccinations, and were inversely correlated with control of SIV replication following a pathogenic challenge [15]. In humans, cross-...

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“…Very early, intact Pr55 gag was shown using recombinant techniques to contain all the information necessary for viral assembly (Gheysen et al, 1989;Wills and Craven, 1991). The authentic viral RNP core shell of HTV is formed from two proteins, Pr55 Gag and Prl55 Gag-Pol, co-assembled at a ratio of approximately 20 to 1.…”

Section: H Morphogenesis and Maturation Of Hiv And Sivmentioning

confidence: 99%