Induction by Human Immunodeficiency Viruses Types 1 and 2 of Degradation of CD4 But Not of a CD4 Mutant Unable to Bind Viral Envelope Glycoproteins

The occurrence of human immunodeficiency virus type 1 (HIV-1) recombinant genomes belonging to different subtypes is a common event in regions where more than two subtypes cocirculate. Although there are accumulating data toward an increase in the number of intersubtype recombinants, little has been addressed about the biological behavior of such mosaic genomes. This work reports the biological characterization of engineered in vitro HIV-1 intersubtype recombinants in the gp120 region. The recombinants possess the entire gp120 of B or F Brazilian isolates in the Z6 (subtype D) backbone. Here we show that this type of recombinant structure results in profound impairment to the establishment of productive infections in CD4-positive cells. The characterization of biological properties of those recombinant viruses demonstrated viral production occurring only during a transient peak early on infection and that they are not able to down-regulate the expression of CD4 receptor on the cell surface. We also report the phenotype reversion of one recombinant virus studied here, after 62 days in culture. Two amino acid substitutions in highly constant gp120 regions (C1 and C4) were identified in the revertant virus. The mutation occurring in the C4 region is localized near two amino acid residues critical for gp120/CD4 interaction. Based on these data, we suggest that failure in CD4 down-modulation by recombinant viruses can be due to a structural dysfunction of gp160 protein unable to block CD4 at the endoplasmic reticule. The possibilities that the establishment of latent infections can be directly related to the continuous expression of CD4 on the infected cell surface and that the occurrence of mutations in amino acid nearby residues critical for gp120/CD4 interaction can restore the fully productive infectious process are discussed.

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Generation of Intersubtype Human Immunodeficiency Virus Type 1 Recombinants in env Gene In Vitro: Influences in the Biological Behavior and in the Establishment of Productive Infections

Costa

Munerato

Diaz

et al. 2000

Virology

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Function of ubiquitin (Ub) specific protease 15 (USP15) in HIV-1 replication and viral protein degradation

et al. 2016

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HIV-1 Nef is necessary and may be sufficient for HIV-1-associated AIDS pathogenicity, in that knockout of Nef alone can protect HIV-infected patients from AIDS. We therefore investigated the feasibility of physical knockout of Nef, using the host ubiquitin proteasome system in HIV-1-infected cells. Our co-immunoprecipitation analysis demonstrated that Nef interacted with ubiquitin specific protease 15 (USP15), and that USP15, which is known to stabilize cellular proteins, degraded Nef. Nef could also cause decay of USP15, although Nef-mediated degradation of USP15 was weaker than USP15-mediated Nef degradation. Direct interaction between Nef and USP15 was essential for the observed reciprocal decay of the proteins. Further, USP15 degraded not only Nef but also HIV-1 structural protein, Gag, thereby substantially inhibiting HIV-1 replication. However, Gag did not degrade USP15, indicating that the Nef and USP15 complex, in distinction to other viral proteins, play an integral role in coordinating viral protein degradation and hence HIV-1 replication. Moreover, Nef and USP15 globally suppressed ubiquitylation of cellular proteins, indicating that these proteins are major determinants for the stability of cellular as well as viral proteins. Taken together, these data indicate that Nef and USP15 are vital in regulating degradation of viral and cellular proteins and thus HIV-1 replication, and specific degradation of viral, not cellular proteins, by USP15 points to USP15 as a candidate therapeutic agent to combat AIDS by eliminating viral proteins from the infected cells via USP15-mediated proteosomal degradation.

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T Cells Chronically Infected With HIV Do Not Contain Sufficient Nef to Promote CD4 Downmodulation in the Absence of Envelope-Mediated Effects

Cucchiarini

Barcellini-Couget

Lefébvre

et al. 1998

Journal of Acquired Immune Deficiency Syndromes and Human Retro

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Among HIV viral proteins, envelope glycoproteins and Nef have been both suggested to participate in CD4 downregulation during the course of HIV infection. In a previous study, we provided evidence that a mutant form of CD4 that does not bind gp120 was never downregulated in chronically HIV-1- and HIV-2-infected CEM cells. To further investigate the relative effects of Nef or glycoproteins in CD4 downregulation, recombinant vaccinia virus (VV) vectors were used to express high levels of HIV-1 viral proteins in cells expressing both wild-type and mutant CD4. It was demonstrated that during HIV infection, overexpression of Nef, achieved through the VV expression system, was necessary to induce CD4 downregulation in the mutant CD4-expressing cell model. These results are consistent with the hypothesis that Nef-mediated CD4 downregulation depends on the cellular levels of Nef expression. We concluded that during the late stage of viral replication, CD4 downregulation is mostly due to gp120 and not to Nef because of a low level of Nef expression.

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Induction by Human Immunodeficiency Viruses Types 1 and 2 of Degradation of CD4 But Not of a CD4 Mutant Unable to Bind Viral Envelope Glycoproteins

Cited by 5 publications

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Generation of Intersubtype Human Immunodeficiency Virus Type 1 Recombinants in env Gene In Vitro: Influences in the Biological Behavior and in the Establishment of Productive Infections

Generation of Intersubtype Human Immunodeficiency Virus Type 1 Recombinants in env Gene In Vitro: Influences in the Biological Behavior and in the Establishment of Productive Infections

Function of ubiquitin (Ub) specific protease 15 (USP15) in HIV-1 replication and viral protein degradation

T Cells Chronically Infected With HIV Do Not Contain Sufficient Nef to Promote CD4 Downmodulation in the Absence of Envelope-Mediated Effects

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