Feline Immunodeficiency Virus Envelope Glycoproteins Antagonize Tetherin through a Distinctive Mechanism That Requires Virion Incorporation

Morrison, James H.; Guevara, Rebekah B.; Marcano, Adriana C.; Saenz, Dyana T.; Fadel, Hind J.; Rogstad, Daniel K.; Poeschla, Eric M.

doi:10.1128/jvi.03814-13

Cited by 33 publications

(57 citation statements)

References 96 publications

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“…While HIV-2 does have a nef gene, it does not use Nef to antagonize BST-2 but has found yet another way by using its Env protein (8,16,18). Finally, FIV and EIAV acquired Env-dependent strategies similar to those of HIV-2 (39,40). Thus, there are at least three lentiviral proteins with the demonstrated capacity to target and antagonize BST-2.…”

Section: Discussionmentioning

confidence: 99%

Antagonism of BST-2/Tetherin Is a Conserved Function of the Env Glycoprotein of Primary HIV-2 Isolates

Chen

Shingai

Welbourn

et al. 2016

J Virol

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Although HIV-2 does not encode a vpu gene, the ability to antagonize bone marrow stromal antigen 2 (BST-2) is conserved in some HIV-2 isolates, where it is controlled by the Env glycoprotein. We previously reported that a single-amino-acid difference between the laboratory-adapted ROD10 and ROD14 Envs controlled the enhancement of virus release (referred to here as Vpulike) activity. Here, we investigated how conserved the Vpu-like activity is in primary HIV-2 isolates. We found that half of the 34 tested primary HIV-2 Env isolates obtained from 7 different patients enhanced virus release. Interestingly, most HIV-2 patients harbored a mixed population of viruses containing or lacking Vpu-like activity. Vpu-like activity and Envelope functionality varied significantly among Env isolates; however, there was no direct correlation between these two functions, suggesting they evolved independently. In comparing the Env sequences from one HIV-2 patient, we found that similar to the ROD10/ROD14 Envs, a single-amino-acid change (T568I) in the ectodomain of the TM subunit was sufficient to confer Vpu-like activity to an inactive Env variant. Surprisingly, however, absence of Vpu-like activity was not correlated with absence of BST-2 interaction. Taken together, our data suggest that maintaining the ability to antagonize BST-2 is of functional relevance not only to HIV-1 but also to HIV-2 as well. Our data show that as with Vpu, binding of HIV-2 Env to BST-2 is important but not sufficient for antagonism. Finally, as observed previously, the Vpu-like activity in HIV-2 Env can be controlled by single-residue changes in the TM subunit. IMPORTANCE Lentiviruses such as HIV-1 and HIV-2 encode accessory proteins whose function is to overcome host restriction mechanisms.Vpu is a well-studied HIV-1 accessory protein that enhances virus release by antagonizing the host restriction factor BST-2. HIV-2 does not encode a vpu gene. Instead, the HIV-2 Env glycoprotein was found to antagonize BST-2 in some isolates. Here, we cloned multiple Env sequences from 7 HIV-2-infected patients and found that about half were able to antagonize BST-2. Importantly, most HIV-2 patients harbored a mixed population of viruses containing or lacking the ability to antagonize BST-2. In fact, in comparing Env sequences from one patient combined with site-directed mutagenesis, we were able to restore BST-2 antagonism to an inactive Env protein by a single-amino-acid change. Our data suggest that targeting BST-2 by HIV-2 Env is a dynamic process that can be regulated by simple changes in the Env sequence.

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Section: Discussionmentioning

confidence: 99%

Antagonism of BST-2/Tetherin Is a Conserved Function of the Env Glycoprotein of Primary HIV-2 Isolates

Chen

Shingai

Welbourn

et al. 2016

J Virol

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“…Titers are calculated as GFP-transducing units per ml. Virion reverse transcriptase activities were determined as previously described using a 32 P-based assay with an oligo(dT) template (53). Experiments were performed in triplicate, and values are reported as means Ϯ SD.…”

Section: Methodsmentioning

confidence: 99%

“…HIV-1 NL4-3 was produced by transfection of 293T cells in 175-cm 2 flasks with 10 g of pNL4-3 plasmid DNA using PEI. Particle inputs were normalized by reverse transcriptase (RT) activity or p24 antigen as described previously (53). p24 antigen was measured using a Zeptometrix enzyme-linked immunosorbent assay (ELISA).…”

Section: Methodsmentioning

confidence: 99%

TALEN Knockout of the PSIP1 Gene in Human Cells: Analyses of HIV-1 Replication and Allosteric Integrase Inhibitor Mechanism

Fadel

Morrison

Saenz

et al. 2014

J Virol

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“…5). A recent publication has shown that canine BST2 (dogBST2) is able to block HIV-1 particle release (60). HIV-1 is able to replicate efficiently in Cf2Th cells if they are engineered to express a functional CD4 and CXCR4 or CCR5.…”

Section: Discussionmentioning

confidence: 99%

HIV-1 Adapts To Replicate in Cells Expressing Common Marmoset APOBEC3G and BST2

Fernández-Oliva

Finzi

Haim

et al. 2016

J Virol

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Previous studies have shown that a major block to HIV-1 replication in common marmosets operates at the level of viral entry and that this block can be overcome by adaptation of the virus in tissue-cultured cells. However, our current studies indicate that HIV-1 encounters additional postentry blocks in common marmoset peripheral blood mononuclear cells. Here, we show that the common marmoset APOBEC3G (A3G) and BST2 proteins block HIV-1 in cell cultures. Using a directed-evolution method that takes advantage of the natural ability of HIV-1 to mutate during replication, we have been able to overcome these blocks in tissue-cultured cells. In the adapted viruses, specific changes were observed in gag, vif, env, and nef. The contribution of these changes to virus replication in the presence of the A3G and BST2 restriction factors was studied. We found that certain amino acid changes in Vif and Env that arise during adaptation to marmoset A3G and BST2 allow the virus to replicate in the presence of these restriction factors. The changes in Vif reduce expression levels and encapsidation of marmoset APOBEC3G, while the changes in Env increase viral fitness and discretely favor cell-to-cell transmission of the virus, allowing viral escape from these restriction factors. T he main cause of AIDS is chronic infection by human immunodeficiency virus type 1 (HIV-1). Without treatment, HIV-1 infection results in a progressive depletion of CD4 ϩ T cells that leads to severe immunodeficiency, characterized by opportunistic infections and certain types of cancer that are the leading causes of death in HIV-1-positive patients.The presence of several barriers to HIV-1 replication in cells of many species narrows the viral tropism to humans and chimpanzees. The limited species tropism of HIV-1 is due to two types of host factors: (i) factors that are required for HIV-1 replication but that exhibit species-specific changes that do not allow efficient use by HIV-1 and (ii) dominant-acting factors that block replication in many species. The latter, also known as restriction factors, are part of so-called intrinsic antiviral immunity. Altogether, intracellular restriction factors can act as powerful barriers to viral replication. However, viruses have developed mechanisms that can antagonize restriction factors in an equally successful way. These viral countermeasures are often proteins encoded by accessory genes that are not needed for viral replication in the absence of restriction factors. The main restriction factors that block HIV-1 and other lentivirus infections at different stages of the viral life cycle are TRIM5␣ (1), APOBEC3G (A3G) (2), BST2 (3, 4), SAMHD1 (5,6), and the recently discovered Mx2 (7-9).BST2, also known as tetherin, CD317, or HM1.24, tethers viral particles to the plasma membrane of the cell, blocking their release (3, 4). BST2 is able to block the release of a broad range of enveloped viruses (10, 11). To escape from the action of BST2, viruses have developed a variety of strategies. In HIV-1, the acce...

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Feline Immunodeficiency Virus Envelope Glycoproteins Antagonize Tetherin through a Distinctive Mechanism That Requires Virion Incorporation

Cited by 33 publications

References 96 publications

Antagonism of BST-2/Tetherin Is a Conserved Function of the Env Glycoprotein of Primary HIV-2 Isolates

Antagonism of BST-2/Tetherin Is a Conserved Function of the Env Glycoprotein of Primary HIV-2 Isolates

TALEN Knockout of the PSIP1 Gene in Human Cells: Analyses of HIV-1 Replication and Allosteric Integrase Inhibitor Mechanism

HIV-1 Adapts To Replicate in Cells Expressing Common Marmoset APOBEC3G and BST2

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