Abstract
The human-specific tropism of Human Immunodeficiency Virus Type 1 (HIV-1) has complicated the development of a macaque model of HIV-1 infection/AIDS that is suitable for preclinical evaluation of vaccines and novel treatment strategies. Several innate retroviral restriction factors, such as APOBEC3 family of proteins, TRIM5α, BST2, and SAMHD1, that prevent HIV-1 replication have been identified in macaque cells. Accessory proteins expressed by Simian Immunodeficiency virus (SIV) such as viral infectivity factor (Vif), viral protein X (Vpx), viral protein R (Vpr), and negative factor (Nef) have been shown to play key roles in overcoming these restriction factors in macaque cells. Thus, substituting HIV-1 accessory genes with those from SIV may enable HIV-1 replication in macaques. We and others have constructed macaque-tropic HIV-1 derivatives [also called simian-tropic HIV-1 (stHIV-1) or Human-Simian Immunodeficiency Virus (HSIV)] carrying SIV vif to overcome APOBEC3 family proteins. Additional modifications to HIV-1 gag in some of the macaque-tropic HIV-1 have also been done to overcome TRIM5α restriction in rhesus and cynomolgus macaques. Although these viruses replicate persistently in macaque species, they do not result in CD4 depletion. Thus, these studies suggest that additional blocks to HIV-1 replication exist in macaques that prevent high-level viral replication. Furthermore, serial animal-to-animal passaging of macaque-tropic HIV-1 in vivo has not resulted in pathogenic variants that cause AIDS in immunocompetent macaques. In this review, we discuss recent developments made toward developing macaque model of HIV-1 infection.
Highlights
The inefficient replication of Human Immunodeficiency Virus Type 1 (HIV-1) in macaques has complicated the development of a true HIVbased animal model of AIDS
Type 1 IFN response induced during acute infection suggests that these PTM-tropic Human-Simian Immunodeficiency Virus (HSIV)-vif viruses should overcome the effect of restrictive IFN stimulated genes (ISGs) in order to replicate to high levels and cause disease
We have previously demonstrated that the prototype PTM-tropic HSIV-vifNL4−3 is inhibited by IFNα in PTM cells
Summary
The inefficient replication of HIV-1 in macaques has complicated the development of a true HIVbased animal model of AIDS. HIV-2 viral loads are controlled and results in slow disease progression (Martinez-Steele et al, 2007; Nyamweya et al, 2013) Overall, these studies demonstrate that adaptation to the human host requires the ability of these viruses to counteract interferon-inducible restriction factors and the ability to exploit cellular dependency factors for virus replication. StHIV-1, whose genome is 88% HIV-1 derived, replicated robustly in a RM T-cell line and RM PBMCs after in vitro adaptation (Hatziioannou et al, 2006) This suggest that avoidance of capsid- and Vif-based restriction may be sufficient to allow cross-species transmission of HIV-1 to rhesus macaques. StHIV-1 carrying CCR5-tropic env from YU2, BaL, AD8, and KB9. stHIV-A18+stHIV-A19: infectious molecular clones isolated from passage 4 PTM stHIV-A19: infectious molecular clone isolated from passage 4 PTM
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