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

Abstract

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...

<p>Bone Marrow Stromal Antigen 2 is a Potential Unfavorable Prognostic Factor for High-Grade Glioma</p>

“…BST2 had been initially reported to act as an effective nuclear factor kappa binding (NF-кB) activator and participates in DNA transcription. 24,25 Besides, BST2 participates in cell-cell interactions due to its role on regulating the adhesion of monocytes to endothelial cells. 26,27 Both NF-кB activation and cell-cell adhesion are important regulators of tumor progression.…”

Characterization of two distinct early post-entry blocks to HIV-1 in common marmoset lymphocytes

“…Common marmosets are resistant to HIV-1 infection due to the presence of several barriers1314. To investigate the presence of additional early blocks to HIV-1 infection in primary lymphocytes of common marmosets, we prepared single-cycle luciferase reporter viruses pseudotyped with the vesicular stomatitis virus G (VSV-G) envelope glycoprotein in 293T cells.…”

“…The earliest block to HIV-1 infection of common marmoset cells occurs at the level of virus entry, due to an inefficient recognition of common marmoset CD4 and CCR5 by the HIV-1 envelope glycoproteins13. Common marmoset A3G and BST2 also block HIV-1 replication14. Using a directed evolution method that takes advantage of the natural ability of the virus to mutate during replication, we have generated HIV-1 variants able to replicate in cells expressing common marmoset CD4 and CXCR415, A3G or BST214.…”

“…Common marmoset A3G and BST2 also block HIV-1 replication14. Using a directed evolution method that takes advantage of the natural ability of the virus to mutate during replication, we have generated HIV-1 variants able to replicate in cells expressing common marmoset CD4 and CXCR415, A3G or BST214.…”

Faecal transplantation for the treatment of Clostridium difficile infection in a marmoset

“…Here, we present a report of successful recovery from severe chronic diarrhoea after FMT in a male common marmoset ( Callithrix jacchus ). This species of small New World monkey has been used as an experimental animal for various purposes, including medical [ 7 ], neuroscientific [ 8 ], and cognitive studies [ 9 ], and the recent establishment of genetically modified animals [ 10 ] has enhanced the use of this species in additional research areas. Because their average weight ranges from 250 to 500 g, weight loss quickly becomes critical for sick animals.…”