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Genetic diversity of the envelope glycoprotein from human immunodeficiency virus type 1 isolates of African origin.

ABSTRACT: The genetic diversity of the envelope glycoprotein of human immunodeficiency virus type 1 (HIV-1) isolates was studied. HIV-1 isolates were obtained from eight countries in Africa: Djibouti, Gabon, Kenya, Senegal, Somalia, Uganda, Zaire, and Zambia. The DNA sequences encoding the complete HIV-1 envelope protein were PCR amplified and sequenced. Phylogenetic relationships among the 21 sequences from this study and the 32 previously published full-length env HIV-1 sequences were determined. Twenty of the newly sequenced African isolates could be assigned to envelope subtypes A, C, D, and G. One isolate, collected in Zambia, did not belong to any of the eight previously described subtypes and may represent a prototype sequence of its envelope subtype. The phylogenetic classification of these isolates was strongly supported by bootstrapping and the congruence of trees generated by either distance methods or maximum parsimony analysis. The data presented in this study confirm the existence of several genetic subtypes within the global HIV epidemic and broaden the genetic variability previously observed for envelope subtypes. The geographic spread of different subtypes was shown to be substantial, and the notion of cocirculation of subtypes was reinforced.

SUBMITTER: Louwagie J

PROVIDER: S-EPMC188572 | biostudies-other | 1995 Jan

REPOSITORIES: biostudies-other

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Genetic diversity of the envelope glycoprotein from human immunodeficiency virus type 1 isolates of African origin.

Louwagie J J Janssens W W Mascola J J Heyndrickx L L Hegerich P P van der Groen G G McCutchan F E FE Burke D S DS

Journal of virology 19950101 1

The genetic diversity of the envelope glycoprotein of human immunodeficiency virus type 1 (HIV-1) isolates was studied. HIV-1 isolates were obtained from eight countries in Africa: Djibouti, Gabon, Kenya, Senegal, Somalia, Uganda, Zaire, and Zambia. The DNA sequences encoding the complete HIV-1 envelope protein were PCR amplified and sequenced. Phylogenetic relationships among the 21 sequences from this study and the 32 previously published full-length env HIV-1 sequences were determined. Twenty ...[more]

PMID: 7983718

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Project description:Membrane-associated RING-CH-type 8 (MARCH8) strongly blocks human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein (Env) incorporation into virions by downregulating its cell surface expression, but the mechanism is still unclear. We now report that MARCH8 also blocks the Ebola virus (EBOV) glycoprotein (GP) incorporation via surface downregulation. To understand how these viral fusion proteins are downregulated, we investigated the effects of MARCH8 on EBOV GP maturation and externalization via the conventional secretion pathway. MARCH8 interacted with EBOV GP and furin when detected by immunoprecipitation and retained the GP/furin complex in the Golgi when their location was tracked by a bimolecular fluorescence complementation (BiFC) assay. MARCH8 did not reduce the GP expression or affect the GP modification by high-mannose N-glycans in the endoplasmic reticulum (ER), but it inhibited the formation of complex N-glycans on the GP in the Golgi. Additionally, the GP O-glycosylation and furin-mediated proteolytic cleavage were also inhibited. Moreover, we identified a novel furin cleavage site on EBOV GP and found that only those fully glycosylated GPs were processed by furin and incorporated into virions. Furthermore, the GP shedding and secretion were all blocked by MARCH8. MARCH8 also blocked the furin-mediated cleavage of HIV-1 Env (gp160) and the highly pathogenic avian influenza virus H5N1 hemagglutinin (HA). We conclude that MARCH8 has a very broad antiviral activity by prohibiting different viral fusion proteins from glycosylation and proteolytic cleavage in the Golgi, which inhibits their transport from the Golgi to the plasma membrane and incorporation into virions.IMPORTANCE Enveloped viruses express three classes of fusion proteins that are required for their entry into host cells via mediating virus and cell membrane fusion. Class I fusion proteins are produced from influenza viruses, retroviruses, Ebola viruses, and coronaviruses. They are first synthesized as a type I transmembrane polypeptide precursor that is subsequently glycosylated and oligomerized. Most of these precursors are cleaved en route to the plasma membrane by a cellular protease furin in the late secretory pathway, generating the trimeric N-terminal receptor-binding and C-terminal fusion subunits. Here, we show that a cellular protein, MARCH8, specifically inhibits the furin-mediated cleavage of EBOV GP, HIV-1 Env, and H5N1 HA. Further analyses uncovered that MARCH8 blocked the EBOV GP glycosylation in the Golgi and inhibited its transport from the Golgi to the plasma membrane. Thus, MARCH8 has a very broad antiviral activity by specifically inactivating different viral fusion proteins.

Project description:BackgroundThe HIV envelope (Env) promotes viral entry in the host cell. During this process, Env undergoes several conformational changes to ensure its function. At the same time, the gp120 component of Env is the protein of the virus presenting the largest genetic diversity. Understanding how the virus maintains the balance between the competing requirements for maintenance of functionality and antigenic variation of this protein is central for the comprehension of its strategies of evolution and can highlight vulnerable aspects of its replication cycle. We focused on the variable domains V1 and V2 of the HIV-1 gp120 that are involved in conformational changes and are critical for viral escape from antibody neutralization.ResultsDespite the extensive sequence diversity found in the epidemic for these regions and their location on the external face of the protein, we observed that replacing V1V2 of one primary isolate with that of another severely interferes with Env functionality in more than half of the cases studied. Similar results were obtained for intra- and intersubtype chimeras. These observations are indicative of an interference of genetic diversity in these regions with Env functionality. Therefore, despite the extensive sequence diversity that characterizes these regions in the epidemic, our results show that functional constraints seem to limit their genetic variation. Defects in the V1V2 chimeras were not relieved by the insertion of the V3 region from the same isolate, suggesting that the decrease in functionality is not due to perturbation of potential coevolution networks between V1V2 and V3. Within the V1V2 domain, the sequence of the hypervariable loop of the V1 domain seems to be crucial for the functionality of the protein.ConclusionsBesides the well-documented role of V1V2 in the interplay with the immune response, this work shows that V1 is also involved in the selection of functional envelopes. By documenting a compromise between the opposing forces of sequence diversification and retention of functionality, these observations improve our understanding of the evolutionary trajectories of the HIV-1 envelope gene.

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Genetic diversity of the envelope glycoprotein from human immunodeficiency virus type 1 isolates of African origin.

Publications

Genetic diversity of the envelope glycoprotein from human immunodeficiency virus type 1 isolates of African origin.

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