title: A variant macaque-tropic human immunodeficiency virus type 1 is resistant to alpha interferon-induced restriction in pig-tailed macaque CD4+ T cells.
abstract: Human immunodeficiency virus type 1 (HIV-1) antagonizes innate restriction factors in order to infect and persistently replicate in a host. In a previous study, we demonstrated that HIV-1 NL4-3 with a simian immunodeficiency virus mne (SIVmne) vif gene substitution (HSIV-vif-NL4-3) could infect and replicate in pig-tailed macaques (PTM), indicating that APOBEC3 proteins are primary barriers to transmission. Because viral replication was persistent but low, we hypothesized that HSIV-vif-NL4-3 may be suppressed by type I interferons (IFN-I), which are known to upregulate the expression of innate restriction factors. Here, we demonstrate that IFN-α more potently suppresses HSIV-vif-NL4-3 in PTM CD4(+) T cells than it does pathogenic SIVmne027. Importantly, we identify a variant (HSIV-vif-Yu2) that is resistant to IFN-α, indicating that the IFN-α-induced barrier can be overcome by HSIV-vif chimeras in PTM CD4(+) T cells. Interestingly, HSIV-vif-Yu2 and HSIV-vif-NL4-3 are similarly restricted by PTM BST2/Tetherin, and neither virus downregulates it from the surface of infected PTM CD4(+) T cells. Resistance to IFN-α-induced restriction appears to be conferred by a determinant in HSIV-vif-Yu2 that includes env su. Finally, we show that the Yu-2 env su allele may overcome an IFN-α-induced barrier to entry. Together, our data demonstrate that the prototype macaque-tropic HIV-1 clones based on NL4-3 may not sufficiently antagonize innate restriction in PTM cells. However, variants with resistance to IFN-α-induced restriction factors in PTM CD4(+) T cells may enhance viral replication by overcoming a barrier early in the viral replication cycle.
authors.affiliation: Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Rajesh
authors.initials: R
authors.lastname: Thippeshappa
authors.forename: Hongmei
authors.initials: H
authors.lastname: Ruan
authors.forename: Weiming
authors.initials: W
authors.lastname: Wang
authors.forename: Paul
authors.initials: P
authors.lastname: Zhou
authors.forename: Jason T
authors.initials: JT
authors.lastname: Kimata
mesh_terms: D000818:Animals; D018791:CD4 Lymphocyte Count; D015496:CD4-Positive T-Lymphocytes / Q000821:virology*; D024882:Drug Resistance, Viral / Q000276:immunology; D057809:HEK293 Cells; D015497:HIV-1 / Q000235:genetics* / Q000502:physiology*; D006367:HeLa Cells; D054884:Host-Pathogen Interactions / Q000276:immunology*; D006801:Humans; D016898:Interferon-alpha / Q000276:immunology* / Q000494:pharmacology; D008254:Macaca nemestrina / Q000276:immunology / Q000821:virology*; D014779:Virus Replication
chemical_list: D016898:Interferon-alpha
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