Improved capacity of a monkey-tropic HIV-1 derivative to replicate in cynomolgus monkeys with minimal modifications

Abstract

Human immunodeficiency virus type 1 (HIV-1) hardly replicates in Old World monkeys. Recently, a mutant HIV-1 clone, NL-DT5R, in which a small part of gag and the entire vif gene are replaced with SIVmac239-derived ones, was shown to be able to replicate in pigtail monkeys but not in rhesus monkeys (RM). In the present study, we found that a modified monkey-tropic HIV-1 (HIV-1mt), MN4-5S, acquired the ability to replicate efficiently in cynomolgus monkeys as compared with the NL-DT5R, while neither NL-DT5R nor MN4-5S replicated in RM cells. These results suggest that multiple determinants may be involved in the restriction of HIV-1 replication in macaques, depending on the species of macaques. The new HIV-1mt clone will be useful for studying molecular mechanisms by which anti-viral host factors regulate HIV-1 replication in macaques.

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

“…McCarthy et al reported that H4/5L and helix 6 of SIVmac239 CA also affect TRIM5␣ sensitivity (55). In the construction process for our HIV-1mt clones, we found that the CA elements involved in the interaction with RhM TRIM5␣ are the CypA-binding loop within H4/5L, H6/7L, M94L/R98S within H4/5L, and Q110D/G114Q in helix 6 (18)(19)(20)56; this study). Of the substitutions identified in this study, R98S was the primary residue to increase TRIM5␣ resistance and improve viral growth in macaque cells.…”

“…We and others have reported the construction of HIV-1 derivatives that have the ability to evade restriction factors for macaque model studies (16)(17)(18)(19)(20)(21). As a common feature, all reported macaque-tropic HIV-1 (HIV-1mt) clones have the vif gene, which can neutralize macaque APOBEC3G (e.g., SIVmac239 vif).…”

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

“…To obtain a novel class of HIV-1 that infects, replicates and finally causes AIDS in macaques, we and a research group in USA have independently initiated the work on HIV-1mt and have done macaque model studies (Hatcho et al, 2008;Hatziioannou, 2006Kamada et al, 2006Kamada et al, , 2009Kuroishi et al, 2009;Nomaguchi et al, 2008a;Saito et al, 2011;Yamashita et al, 2008). Another group has published a report on HIV-1mt derivatives very recently (Thippeshappa et al, 2011).…”

“…On the basis of this strategy, we have successfully obtained a number of new generations with increasing ability to replicate from the original prototype NL-DT5R (see below). However, so far, none of the HIV-1mt clones tested are pathogenic for macaques (pig-tailed and cynomolgus) Nomaguchi et al, manuscript in preparation;Saito et al, 2011), although they all can replicate in the monkeys. The newest clones in Fig.…”

“…We must go behind the outward form to grasp the inner meaning of the phenomenon, i.e., the species-specificity. On the collective basis of molecular and biochemical studies performed by us and others so far, we recently have constructed a series of HIV-1 derivative clones tropic for macaque cells and/or macaques (Hatcho et al, 2008;Igarashi et al, 2007;Kamada et al, 2006Kamada et al, , 2009Kuroishi et al, 2009;Nomaguchi et al, 2008a;Saito et al, 2011;Yamashita et al, 2008), and are currently further modifying them for in vivo studies (our unpublished results). The viruses we have generated carry a minimal sequence of SIVmac, and overcome at least some species barriers.…”