Macaque-Tropic HIV-1 Derivatives: A Novel Experimental Approach to Understand Viral Replication and Evolution in Vivo

Nomaguchi, Masako; Doi, Naoya; Fujiwara, Sachi; Adachi, Akio

doi:10.5772/23624

Cited by 10 publications

(20 citation statements)

References 87 publications

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“…HIV-1 Vpu gains the ability to specifically counteract macaque tetherin by replacing its TM domain with the corresponding region of SIVgsn166 Vpu. Tetherin as well as TRIM5 proteins are important anti-HIV-1 factors in macaque cells (4,8,10), but the HIV-1mt clones constructed so far do not display macaque tetherin antagonism due to Vpu derived from HIV-1 NL4-3 . It has been shown that Vpu from SIVmon/mus/gsn can antagonize macaque tetherin but not human tetherin (26).…”

Section: Resultsmentioning

confidence: 99%

“…2D). Since TRIM5 proteins are potent restriction factors as species barriers (4,8,10) and can affect SIV transmission/replication in vivo (40,51), it was expected that CA mutations (M94L/R98S/ G114Q) would increase TRIM5␣ resistance as well as viral growth potential. To examine the effect of CA alterations on TRIM5␣ resistance, we carried out TRIM5␣ susceptibility assays using the recombinant SeV-TRIM5␣ expression system (36).…”

Section: Resultsmentioning

confidence: 99%

“…Nevertheless, there are significant differences between the two viruses in genome organization, the viral replication profile in vivo, and disease progression (7)(8)(9). It is therefore most preferable to generate pathogenic HIV-1 derivatives to establish AIDS macaque models (7)(8)(9). Importantly, construction of HIV-1 derivatives that overcome the species barrier would contribute much to the understanding of the molecular interaction of viral and host proteins.…”

mentioning

confidence: 99%

“…HIV-1 and SIVmac239 are mutually related primate lentiviruses and cause AIDS in their respective hosts. Nevertheless, there are significant differences between the two viruses in genome organization, the viral replication profile in vivo, and disease progression (7)(8)(9). It is therefore most preferable to generate pathogenic HIV-1 derivatives to establish AIDS macaque models (7)(8)(9).…”

mentioning

confidence: 99%

“…proteins (4,8,10). APOBEC3G is the strongest inhibitor of HIV-1 replication among APOBEC3 family proteins.…”

mentioning

confidence: 99%

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Generation of Rhesus Macaque-Tropic HIV-1 Clones That Are Resistant to Major Anti-HIV-1 Restriction Factors

Nomaguchi

Yokoyama

Kono

et al. 2013

J Virol

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h Human immunodeficiency virus type 1 (HIV-1) replication in macaque cells is restricted mainly by antiviral cellular APOBEC3, TRIM5␣/TRIM5CypA, and tetherin proteins. For basic and clinical HIV-1/AIDS studies, efforts to construct macaque-tropic HIV-1 (HIV-1mt) have been made by us and others. Although rhesus macaques are commonly and successfully used as infection models, no HIV-1 derivatives suitable for in vivo rhesus research are available to date. In this study, to obtain novel HIV-1mt clones that are resistant to major restriction factors, we altered Gag and Vpu of our best HIV-1mt clone described previously. First, by sequence-and structure-guided mutagenesis, three amino acid residues in Gag-capsid (CA) (M94L/R98S/G114Q) were found to be responsible for viral growth enhancement in a macaque cell line. Results of in vitro TRIM5␣ susceptibility testing of HIV-1mt carrying these substitutions correlated well with the increased viral replication potential in macaque peripheral blood mononuclear cells (PBMCs) with different TRIM5 alleles, suggesting that the three amino acids in HIV-1mt CA are involved in the interaction with TRIM5␣. Second, we replaced the transmembrane domain of Vpu of this clone with the corresponding region of simian immunodeficiency virus SIVgsn166 Vpu. The resultant clone, MN4/LSDQgtu, was able to antagonize macaque but not human tetherin, and its Vpu effectively functioned during viral replication in a macaque cell line. Notably, MN4/ LSDQgtu grew comparably to SIVmac239 and much better than any of our other HIV-1mt clones in rhesus macaque PBMCs. In sum, MN4/LSDQgtu is the first HIV-1 derivative that exhibits resistance to the major restriction factors in rhesus macaque cells.

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