Generation of a neutralization-resistant CCR5 tropic simian/human immunodeficiency virus (SHIV-MK38) molecular clone, a derivative of SHIV-89.6

Ishida, Yuichi; Yoneda, Mai; Otsuki, Hiroyuki; Watanabe, Yuji; Kato, Fumihiro; Matsuura, Kiyotaka; Kikukawa, Minako; Matsushita, Shuzo; Hishiki, Takayuki; Igarashi, Tatsuhiko; Miura, Tomoyuki

doi:10.1099/jgv.0.000421

Cited by 13 publications

(23 citation statements)

References 49 publications

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Section: Neutralisation Of Mk1 (Tier 1) and #818 (Tier 2) In Mk1-and mentioning

confidence: 99%

“…First, we sought to generalise the adaptation of HIV in humans to monkeys, because neither Ishida et al nor Matsuda et al examined the neutralisation resistance of SHIV-MK1 and SHIV#818 against SHIV-infected monkey plasma (MP) [5,6]. Therefore, we assessed whether MP represented HPP by comparing the neutralisation resistance of SHIV-MK1 (tier 1B), SHIV-MK38#818 (tier 2), and the control strains HIV-1 TRO (tier 2) and HIV-1 SF162 (tier 1A) with the TZM-bl assay.…”

Section: Neutralisation Of Mk1 (Tier 1) and #818 (Tier 2) In Mk1-and mentioning

confidence: 99%

“…Three uninfected rhesus macaques (MM481, MM501, and MM502) were infected with MK38 intravenously [6]. Then, MK38#818, which was neutralisation-resistant to HIV-1-infected human plasma, like the parental SHIV-MK38, was cloned from the MK38 strain [5]. The uninfected rhesus macaque MM597 was infected by tier 2 #818 to study the pathogenesis of HIV [5].…”

Section: Isolation Of Mp From Infected Rhesus Macaquesmentioning

confidence: 99%

“…Then, MK38#818, which was neutralisation-resistant to HIV-1-infected human plasma, like the parental SHIV-MK38, was cloned from the MK38 strain [5]. The uninfected rhesus macaque MM597 was infected by tier 2 #818 to study the pathogenesis of HIV [5]. MP was collected from the infected macaques MM481 (MK1 infected macaque) and MM597 (#818 infected macaque) and stored at −80 • C.…”

Section: Isolation Of Mp From Infected Rhesus Macaquesmentioning

confidence: 99%

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Specific Substitutions in Region V2 of gp120 env confer SHIV Neutralisation Resistance

et al. 2020

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A tier 2 SHIV-MK38 strain was obtained after two in vivo passages of tier 1 SHIV-MK1. SHIV-MK38#818, cloned from the MK38 strain, was neutralisation-resistant, like the parental MK38 strain, to SHIV-infected monkey plasma (MP), HIV-1-infected human pooled plasma (HPP), and KD247 monoclonal antibody (mAb) (anti-V3 gp120 env). We investigated the mechanisms underlying the resistance of #818, specifically the amino acid substitutions that confer resistance to MK1. We introduced amino acid substitutions in the MK1 envelope by in vitro mutagenesis and then compared the neutralisation resistance to MP, HPP, and KD247 mAb with #818 in a neutralisation assay using TZM-bl cells. We selected 11 substitutions in the V1, V2, C2, V4, C4, and V5 regions based on the alignment of env of MK1 and #818. The neutralisation resistance of the mutant MK1s with 7 of 11 substitutions in the V1, C2, C4, and V5 regions did not change significantly. These substitutions did not alter any negative charges or N-glycans. The substitutions N169D and K187E, which added negative charges, and S190N in the V2 region of gp120 and A389T in V4, which created sites for N-glycan, conferred high neutralisation resistance. The combinations N169D+K187E, N169D+S190N, and N169D+A389T resulted in MK1 neutralisation resistance close to that of #818. The combinations without 169D were neutralisation-sensitive. Therefore, N169D is the most important substitution for neutralisation resistance. This study demonstrated that although the V3 region sequences of #818 and MK1 are the same, V3 binding antibodies cannot neutralise #818 pseudovirus. Instead, mutations in the V2 and V4 regions inhibit the neutralisation of anti-V3 antibodies. We hypothesised that 169D and 190N altered the MK1 Env conformation so that the V3 region is buried. Therefore, the V2 region may block KD247 from binding to the tip of the V3 region.

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Section: Neutralisation Of Mk1 (Tier 1) and #818 (Tier 2) In Mk1-and mentioning

confidence: 99%

Section: Neutralisation Of Mk1 (Tier 1) and #818 (Tier 2) In Mk1-and mentioning

confidence: 99%

Section: Isolation Of Mp From Infected Rhesus Macaquesmentioning

confidence: 99%

Section: Isolation Of Mp From Infected Rhesus Macaquesmentioning

confidence: 99%

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Specific Substitutions in Region V2 of gp120 env confer SHIV Neutralisation Resistance

et al. 2020

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“…Unlike SHIV-KS661 infection [3, 7], the reduced CD4 + T-cell depletion observed in SHIV-#64 infection might lead to better T-cell dependent help for both antibody and CD8 + T-cell responses to the virus [6, 8]. So far, we have many SHIV strains that show different pathogenesis in macaque experiments [1–7, 9, 10]. In our previous study [11], we quantified only SHIV-KS661 infection in vitro.…”

Section: Introductionmentioning

confidence: 99%

A highly pathogenic simian/human immunodeficiency virus effectively produces infectious virions compared with a less pathogenic virus in cell culture

Iwanami

Kakizoe

Morita

et al. 2017

Theor Biol Med Model

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BackgroundThe host range of human immunodeficiency virus (HIV) is quite narrow. Therefore, analyzing HIV-1 pathogenesis in vivo has been limited owing to lack of appropriate animal model systems. To overcome this, chimeric simian and human immunodeficiency viruses (SHIVs) that encode HIV-1 Env and are infectious to macaques have been developed and used to investigate the pathogenicity of HIV-1 in vivo. So far, we have many SHIV strains that show different pathogenesis in macaque experiments. However, dynamic aspects of SHIV infection have not been well understood. To fully understand the dynamic properties of SHIVs, we focused on two representative strains—the highly pathogenic SHIV, SHIV-KS661, and the less pathogenic SHIV, SHIV-#64—and measured the time-course of experimental data in cell culture.MethodsWe infected HSC-F with SHIV-KS661 and -#64 and measured the concentration of Nef-negative (target) and Nef-positive (infected) HSC-F cells, the total viral load, and the infectious viral load daily for 9 days. The experiments were repeated at two different multiplicities of infection, and a previously developed mathematical model incorporating the infectious and non-infectious viruses was fitted to the full dataset of each strain simultaneously to characterize the infection dynamics of these two strains.Results and conclusionsWe quantified virological indices including virus burst sizes and basic reproduction number of both SHIV-KS661 and -#64. Comparing the burst size of total and infectious viruses (viral RNA copies and TCID50, respectively), we found that there was a statistically significant difference between the infectious virus burst size of SHIV-KS661 and -#64, while there was no significant difference between the total virus burst size. Furthermore, our analyses showed that the fraction of infectious virus among the produced SHIV-KS661 viruses, which is defined as the infectious viral load (TCID50/ml) divided by the total viral load (RNA copies/ml), is more than 10-fold higher than that of SHIV-#64 during overall infection (i.e., for 9 days). Taken together, we conclude that the highly pathogenic SHIV produces infectious virions more effectively than the less pathogenic SHIV in cell culture.Electronic supplementary materialThe online version of this article (doi:10.1186/s12976-017-0055-8) contains supplementary material, which is available to authorized users.

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Induction of neutralizing antibodies against tier 2 human immunodeficiency virus 1 in rhesus macaques infected with tier 1B simian/human immunodeficiency virus

et al. 2019

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We previously developed CCR5-tropic neutralization-resistant simian/human immunodeficiency virus (SHIV) strains and a rhesus macaque model of infection with these SHIVs. We induced the production of neutralizing antibodies (nAbs) against HIV-1 by infecting rhesus macaques with different neutralization-resistant SHIV strains. First, SHIV-MK1 (MK1) (neutralization susceptible, tier 1B) with CCR5 tropism was generated from SHIV-KS661 using CXCR4 as the main co-receptor. nAbs against parental-lineage and heterologous tier 2 viruses were induced by tier 1B virus (MK1) infection of the rhesus macaque MM482. We analyzed viral resistance to neutralization over time in MM482 and observed that the infecting virus mutated from tier 1B to tier 2 at 36 weeks postinfection (wpi). In addition, an analysis of mutations showed that N169D, K187E, S190N, S239, T459N (T459D at 91 wpi), and V842A mutations were present after 36 wpi. This led to the appearance of neutralization-resistant viral clones. In addition, MK1 was passaged in three rhesus macaques to generate neutralization-resistant SHIV-MK38 (MK38) (tier 2). We evaluated nAb production by rhesus macaques infected with SHIV-MK38 #818 (#818) (tier 2), a molecular clone of MK38. Neutralization of the parental lineage was induced earlier than in macaques infected with tier 1B virus, and neutralization activity against heterologous tier 2 virus was beginning to develop. Therefore, CCR5-tropic neutralization-resistant SHIV-infected rhesus macaques may be useful models of anti-HIV-1 nAb production and will facilitate the development of a vaccine that elicits nAbs against HIV-1. Electronic supplementary material The online version of this article (10.1007/s00705-019-04173-5) contains supplementary material, which is available to authorized users.

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Generation of a neutralization-resistant CCR5 tropic simian/human immunodeficiency virus (SHIV-MK38) molecular clone, a derivative of SHIV-89.6

Cited by 13 publications

References 49 publications

Specific Substitutions in Region V2 of gp120 env confer SHIV Neutralisation Resistance

Specific Substitutions in Region V2 of gp120 env confer SHIV Neutralisation Resistance

A highly pathogenic simian/human immunodeficiency virus effectively produces infectious virions compared with a less pathogenic virus in cell culture

Induction of neutralizing antibodies against tier 2 human immunodeficiency virus 1 in rhesus macaques infected with tier 1B simian/human immunodeficiency virus

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