Elite Control, Gut CD4 T Cell Sparing, and Enhanced Mucosal T Cell Responses in Macaca nemestrina Infected by a Simian Immunodeficiency Virus Lacking a gp41 Trafficking Motif

Abstract

Deletion of Gly-720 and Tyr-721 from a highly conserved GYxxØ trafficking signal in the SIVmac239 envelope glycoprotein cytoplasmic domain, producing a virus termed ⌬GY, leads to a striking perturbation in pathogenesis in rhesus macaques (Macaca mulatta). Infected macaques develop immune activation and progress to AIDS, but with only limited and transient infection of intestinal CD4؉ T cells and an absence of microbial translocation. Here we evaluated ⌬GY in pig-tailed macaques (Macaca nemestrina), a species in which SIVmac239 infection typically leads to increased immune activation and more rapid progression to AIDS than in rhesus macaques. In pig-tailed macaques, ⌬GY also replicated acutely to high peak plasma RNA levels identical to those for SIVmac239 and caused only transient infection of CD4 ؉ T cells in the gut lamina propria and no microbial translocation. However, in marked contrast to rhesus macaques, 19 of 21 pig-tailed macaques controlled ⌬GY replication with plasma viral loads of <15 to 50 RNA copies/ml. CD4 ؉ T cells were preserved in blood and gut for up to 100 weeks with no immune activation or disease progression. Robust antiviral CD4 ؉ T cell responses were seen, particularly in the gut. Anti-CD8 antibody depletion demonstrated CD8؉ cellular control of viral replication. Two pig-tailed macaques progressed to disease with persisting viremia and possible compensatory mutations in the cytoplasmic tail. These studies demonstrate a marked perturbation in pathogenesis caused by ⌬GY's ablation of the GYxxØ trafficking motif and reveal, paradoxically, that viral control is enhanced in a macaque species typically predisposed to more pathogenic manifestations of simian immunodeficiency virus (SIV) infection. IMPORTANCE The pathogenesis of human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) reflects a balance between viral replication, host innate and adaptive antiviral immune responses, and sustained immune activation that in humans andAsian macaques is associated with persistent viremia, immune escape, and AIDS. Among nonhuman primates, pig-tailed macaques following SIV infection are predisposed to more rapid disease progression than are rhesus macaques. Here, we show that disruption of a conserved tyrosine-based cellular trafficking motif in the viral transmembrane envelope glycoprotein cytoplasmic tail leads in pig-tailed macaques to a unique phenotype in which high levels of acute viral replication are followed by elite control, robust cellular responses in mucosal tissues, and no disease. Paradoxically, control of this virus in rhesus macaques is only partial, and progression to AIDS occurs. This novel model should provide a powerful tool to help identify host-specific determinants for viral control with potential relevance for vaccine development.

Mechanisms of reactivation of latent tuberculosis infection due to SIV coinfection

“…Although CD4 + T cells were massively depleted in both experimental groups of NHPs, it was vital SIVΔGY replicated to comparable levels in the acute phase and established similar set points ( Figure 1K). Although significantly lower peripheral viremia was observed at peak in our SIVΔGY-coinfected NHPs compared with SIVmac239-coinfected reactivators and nonreactivators, this is not unexpected as rhesus macaques infected with SIVΔGY often have variable viremia (8,9).…”

“…SIVΔGY-coinfected and CD4R1-administered NHPs had lower numbers of viable Mtb in their bronchoalveolar lavage (BAL) fluid throughout infection (Supplemental Figure 1B), and significantly lower viable Mtb in their BAL at endpoint ( Figure 1F). Similarly, both experimental groups harbored low lung ( Figure 1G), bronchial but to spare gut mucosal tissues (7,8).…”

Increased surface expression of HIV-1 envelope is associated with improved antibody response in vaccinia prime/protein boost immunization

“…This highly conserved motif binds to cellular adaptor protein complex 2 (AP-2) and recruits Env that is not incorporated into virions into clathrin-coated pits, thereby mediating internalization and clearance from the cell surface ( Boge et al, 1998 , Rowell et al, 1995 , Bowers et al, 2000 , Egan et al, 1996 ). GYxxΦ has also been shown to mediate directional budding of virus in polarized cell types ( Lodge et al, 1997 , Deschambeault et al, 1999 ) and to contribute to pathogenesis in SIV infection of pigtail macaques ( Fultz et al, 2001 , Breed et al, 2013 , Breed et al, 2015 ). Additional but less well characterized internalization signals are present in the more distal CT ( Wyss et al, 2001 , Byland et al, 2007 ), consistent with the view that a low steady-state expression of Env on infected cells is an important and conserved viral property.…”

New Connections: Cell-to-Cell HIV-1 Transmission, Resistance to Broadly Neutralizing Antibodies, and an Envelope Sorting Motif

“…Nevertheless, ΔGY-infected animals exhibited immune activation and progressed to AIDS-like disease. In a recent study using a different nonhuman primate host, the pig-tailed macaque, infection with the ΔGY virus again resulted in preservation of mucosal CD4 T cells; however, in contrast to the results seen with rhesus macaques, viral replication of the ΔGY virus was controlled to elite levels, and the pig-tailed macaques did not develop immune activation or progress to disease (58). Thus, disruption of this motif appears to alter the course of SIVmac239 pathogenesis in a manner that is specific to the macaque species.…”