Exposing HIV-1 Env: Implications for therapeutic strategies

Finzi, Andrés

doi:10.25011/cim.v42i4.33109

Cited by 4 publications

(3 citation statements)

References 32 publications

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“…Taken together, these data suggest that SERINC5 and IFITM 3 stabilize more "open" Env conformations that result in the exposure of certain CD4i-epitopes such as the coreceptor binding site. This provides an opportunity to sensitize HIV-1 to the inhibition by SERINC5 by targeting the gp120 Phe43 cavity using small CD4mc (38,39).…”

Section: Resultsmentioning

confidence: 99%

Differential Pressures of SERINC5 and IFITM3 on HIV-1 Envelope Glycoprotein over the Course of HIV-1 Infection

Beitari

Pan

Finzi

et al. 2020

J Virol

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Infection of human immunodeficiency virus type 1 (HIV-1) is subject to restriction by cellular factors. Serine incorporator 5 (SERINC5) and interferon inducible transmembrane 3 (IFITM3) proteins represent two of these restriction factors, which inhibit HIV-1 entry into target cells. Both proteins impede fusion of the viral membrane with the cellular membrane and the formation of a viral fusion pore, and both are countered by the HIV-1 envelope glycoprotein (Env). Given the immense and lasting pressure which Env endures from host adaptive immune responses, it is important to understand whether and how HIV-1 Env is able to maintain the resistance to SERINC5 and IFITM3 throughout the course of infection. We have thus examined a panel of HIV-1 Env clones that were isolated at different stages of viral infection: transmission, acute and chronic. While HIV-1 Env clones from the transmission stage are resistant to both SERINC5 and IFITM3, as infection progresses into the acute and chronic stages, the resistance to IFITM3 but not to SERINC5 is gradually lost. We further discovered a significant correlation between the resistance of HIV-1 Env to soluble CD4 inhibition and the resistance to SERINC5 but not to IFITM3. Interestingly, the miniprotein CD4 mimetic M48U1 sensitizes HIV-1 Env to the inhibition by SERINC5 but not IFITM3. Together, these data indicate that SERINC5 and IFITM3 exert differential inhibitory pressures on HIV-1 Env over different stages of HIV-1 infection, and that HIV-1 Env uses varied strategies to resist these two restriction factors. IMPORTANCE HIV-1 Env protein is exposed to the inhibition not only by humoral response, but also by host restriction factors, including SERINC5 and IFITM3. This study investigates how HIV-1 Env manages to overcome the pressures from all these different host inhibition mechanisms over the long course of viral infection. While HIV-1 Env preserves the resistance to SERINC5, but becomes sensitive to IFITM3 when infection progresses into the chronic stage. Our study also supports the possibility of using CD4 mimetic compounds to sensitize HIV-1 Env to the inhibition by SERINC5, as a potential therapeutic strategy.

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Section: Resultsmentioning

confidence: 99%

Differential Pressures of SERINC5 and IFITM3 on HIV-1 Envelope Glycoprotein over the Course of HIV-1 Infection

Beitari

Pan

Finzi

et al. 2020

J Virol

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“…Amino acid mutations in the receptor binding site on the surface of mutable viruses can affect antibody binding efficiency, leading to immune escape that ultimately impairs vaccine efficacy. Taking HIV-1 as an example, the env protein of HIV-1 contains important antigenic epitopes [ 78 , 79 ], and the mutations that occur have invariably reduced the efficacy of existing vaccines [ 80 , 81 ]. BnaAbs, which recognize conserved regions on the surface of the virus, can circumvent the escape brought about by a large fraction of mutations.…”

Section: Broad-spectrum Vaccine Design To Induce Bnabsmentioning

confidence: 99%

The Mechanism of bnAb Production and Its Application in Mutable Virus Broad-Spectrum Vaccines: Inspiration from HIV-1 Broad Neutralization Research

Zhang,

Zhou

2023

Vaccines

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Elite controllers among HIV-1-infected individuals have demonstrated a stronger ability to control the viral load in their bodies. Scientists have isolated antibodies with strong neutralizing ability from these individuals, which can neutralize HIV-1 variations; these are known as broadly neutralizing antibodies. The nucleic acid of some viruses will constantly mutate during replication (such as SARS-CoV-2), which will reduce the protective ability of the corresponding vaccines. The immune escape caused by this mutation is the most severe challenge faced by humans in the battle against the virus. Therefore, developing broad-spectrum vaccines that can induce broadly neutralizing antibodies against various viruses and their mutated strains is the best way to combat virus mutations. Exploring the mechanism by which the human immune system produces broadly neutralizing antibodies and its induction strategies is crucial in the design process of broad-spectrum vaccines.

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“…Strikingly, the same non-neutralizing gp120-elicited Abs combined with CD4mc protected monkeys from multiple heterologous SHIV challenges [21]. We recently reported that CD4mc in combination with two types of CD4i anti-gp120 antibodies stabilize a new Env conformation, state 2A, that is vulnerable to antibody attack [26,27]. Specifically, this conformation is stabilized by CD4mc in combination with anti-co-receptor binding site (CoRBS) and anti-cluster A antibodies [26,28].…”

Section: Introductionmentioning

confidence: 99%

Elicitation of Cluster A and Co-Receptor Binding Site Antibodies Are Required to Eliminate HIV-1 Infected Cells

et al. 2020

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HIV-1-infected individuals raise a polyclonal antibody response targeting multiple envelope glycoprotein (Env) epitopes. Interestingly, two classes of non-neutralizing CD4-induced (CD4i) antibodies, present in the majority of HIV-1-infected individuals have been described to mediate antibody-dependent cellular cytotoxicity (ADCC) in the presence of small CD4 mimetic compounds (CD4mc). These antibodies recognize the coreceptor binding site (CoRBS) and the constant region one and two (C1C2 or inner domain cluster A) of the gp120. In combination with CD4mc they have been shown to stabilize an antibody-vulnerable Env conformation, known as State 2A. Here we evaluated the importance of these two families of Abs in ADCC responses by immunizing guinea pigs with gp120 immunogens that have been modified to elicit or not these types of antibodies. Underlying the importance of anti-CoRBS and anti-cluster A Abs in stabilizing State 2A, ADCC responses were only observed in the presence of these two types of CD4i antibodies. Altogether, our results suggest that these two families of CD4i antibodies must be taken into account when considering future strategies relying on the use of CD4mc to eliminate HIV-1-infected cells in vivo.

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Exposing HIV-1 Env: Implications for therapeutic strategies

Cited by 4 publications

References 32 publications

Differential Pressures of SERINC5 and IFITM3 on HIV-1 Envelope Glycoprotein over the Course of HIV-1 Infection

Differential Pressures of SERINC5 and IFITM3 on HIV-1 Envelope Glycoprotein over the Course of HIV-1 Infection

The Mechanism of bnAb Production and Its Application in Mutable Virus Broad-Spectrum Vaccines: Inspiration from HIV-1 Broad Neutralization Research

Elicitation of Cluster A and Co-Receptor Binding Site Antibodies Are Required to Eliminate HIV-1 Infected Cells

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