Abstract
Species-dependent variation in proteins that aid or limit virus replication determines the ability of lentiviruses to jump between host species. Identifying and overcoming these differences facilitates the development of animal models for HIV-1, including models based on chimeric SIVs that express HIV-1 envelope (Env) glycoproteins, (SHIVs) and simian-tropic HIV-1 (stHIV) strains. Here, we demonstrate that the inherently poor ability of most HIV-1 Env proteins to use macaque CD4 as a receptor is improved during adaptation by virus passage in macaques. We identify a single amino acid, A281, in HIV-1 Env that consistently changes during adaptation in macaques and affects the ability of HIV-1 Env to use macaque CD4. Importantly, mutations at A281 do not markedly affect HIV-1 Env neutralization properties. Our findings should facilitate the design of HIV-1 Env proteins for use in non-human primate models and thus expedite the development of clinically relevant reagents for testing interventions against HIV-1.
Highlights
Adaptation of primate lentiviruses to new hosts requires the acquisition of both resistance to species-specific inhibitors and ability to optimally use key host factors critical for virus replication [1]
Our data reveal how adaptation in macaques improves the ability of HIV-1 envelope glycoproteins to use macaque CD4
Our experiments show that most HIV-1 Env proteins have reduced ability to use macaque CD4 compared to human CD4, in agreement with other published studies [21, 26] and further demonstrate that
Summary
Adaptation of primate lentiviruses to new hosts requires the acquisition of both resistance to species-specific inhibitors and ability to optimally use key host factors critical for virus replication [1]. SHIVAD8-P4 sensitivity to certain antibodies, such as IgGb12, 2G12 and 2F5 was different from the parental SHIVAD8 (Fig 7), a finding that is not unexpected given that this Env clone was derived following extensive in vivo adaptation. This Env maintained the parental AD8 neutralization resistant tier 1B phenotype (S5 Fig) and bnAb neutralization properties (Fig 7). The introduction of mutation(s) at position 281 had little or no effect on the sensitivity of HIV-1 Env proteins AD8, SC31, TT29 TT31, 1051C and 1051TD to PG9 and/or PG16, antibodies that target conformational epitopes (Fig 7) This finding further supports the notion that A281V/T mutations do not affect overall Env conformation and do not alter Env sensitivity to various antibodies nor the overall neutralization phenotype
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