Blockade of HIV-1 Infection of New World Monkey Cells Occurs Primarily at the Stage of Virus Entry

Human immunodeficiency virus type 1 (HIV-1) does not replicate in primary cells of New World primates.To better understand this restriction, we expressed owl monkey (Aotus nancymaae) CD4 and CXCR4 in the owl monkey kidney cell line, OMK. An HIV-1 variant modified to evade the owl monkey restriction factor TRIM-cyp replicated efficiently in these cells but could not replicate in primary A. nancymaae CD4-positive T cells. To understand this difference, we examined APOBEC3G and tetherin orthologs from OMK cells and primary A. nancymaae cells. We observed that OMK cells expressed substantially lower levels of APOBEC3G than did A. nancymaae cells. A. nancymaae, but not marmoset (Callithrix jacchus), APOBEC3G was partially downregulated by HIV-1 vif and reduced but did not abolish HIV-1 replication when stably expressed in OMK cells. The functional difference between A. nancymaae and marmoset APOBEC3Gs mapped to residue 128, previously shown to distinguish African green monkey from human APOBEC3G. We also characterized tetherin orthologs from OMK and A. nancymaae cells. The A. nancymaae tetherin ortholog, but not OMK tetherin, prevented HIV-1 release. Alteration of threonine 181 of OMK tetherin rescued its function and its efficient N glycosylation. All alleles of Aotus lemurinus griseimembra examined, but none of A. nancymaae or Aotus vociferans, encoded this nonfunctional tetherin ortholog. Our data indicate that HIV-1 replication in owl monkeys is not restricted at entry but can be limited by APOBEC3G and tetherin. Further, A. lemurinus griseimembra does not restrict HIV-1 replication via tetherin, a property likely useful for the study of tetherin-restricted viruses.

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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A New World Primate Deficient in Tetherin-Mediated Restriction of Human Immunodeficiency Virus Type 1

Wong

Connole

Sullivan

et al. 2009

“…The susceptibility of various MuLV isolates to Fv1 restriction is largely determined by a single amino acid, residue 110, of the CA protein (34). Very recently, human cells have been shown to exhibit a similar restriction, first dubbed Ref1 activity, which blocks infection by MuLVs very early after infection, even before reverse transcription (29,36). TRIM5␣, a member of the so-called tripartite motif family, has been identified as the protein responsible for this activity (25,33,53,67,75).…”

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confidence: 99%

Interaction of Moloney Murine Leukemia Virus Capsid with Ubc9 and PIASy Mediates SUMO-1 Addition Required Early in Infection

Yueh

Leung

Bhattacharyya

et al. 2006

Yeast two-hybrid screens led to the identification of Ubc9 and PIASy, the E2 and E3 small ubiquitin-like modifier (SUMO)-conjugating enzymes, as proteins interacting with the capsid (CA) protein of the Moloney murine leukemia virus. The binding site in CA for Ubc9 was mapped by deletion and alanine-scanning mutagenesis to a consensus motif for SUMOylation at residues 202 to 220, and the binding site for PIASy was mapped to residues 114 to 176, directly centered on the major homology region. Expression of CA and a tagged SUMO-1 protein resulted in covalent transfer of SUMO-1 to CA in vivo. Mutations of lysine residues to arginines near the Ubc9 binding site and mutations at the PIASy binding site reduced or eliminated CA SUMOylation. Introduction of these mutations into the complete viral genome blocked virus replication. The mutants exhibited no defects in the late stages of viral gene expression or virion assembly. Upon infection, the mutant viruses were able to carry out reverse transcription to synthesize normal levels of linear viral DNA but were unable to produce the circular viral DNAs or integrated provirus normally found in the nucleus. The results suggest that the SUMOylation of CA mediated by an interaction with Ubc9 and PIASy is required for early events of infection, after reverse transcription and before nuclear entry and viral DNA integration.

“…However, some of these monkeys, like common marmosets, have been frequently used in animal models in other fields and are an attractive prospect for the development of a new animal model of HIV-1 infection. Previous studies have suggested that one major blockade to HIV-1 infection in New World monkeys occurs at the level of viral entry, because HIV-1 envelope glycoproteins cannot effectively bind the CD4 and CCR5 receptors of common marmosets (29). Using a directed-evolution method that takes advantage of the natural ability of the virus to mutate during replication, we were able to generate HIV-1 variants able to replicate in cells expressing the common marmoset receptors CD4 and CXCR4 (30).…”

Section: T He Main Cause Of Aids Is Chronic Infection By Human Immunomentioning

confidence: 82%

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

Fernández-Oliva

Finzi

Haim

et al. 2016

Self Cite

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...