Identification and characterization of a macrophage-tropic SIV envelope glycoprotein variant in blood from early infection in SIVmac251-infected macaques

Abstract

Macrophages play an important role in HIV/SIV pathogenesis by serving as a reservoir for viral persistence in brain and other tissues. Infected macrophages have been detected in brain early after infection, but macrophage-tropic viruses are rarely isolated until late-stage infection. Little is known about early variants that establish persistent infection in brain. Here, we characterize a unique macrophage-tropic SIV envelope glycoprotein (Env) variant from two weeks post-infection in blood of an SIVmac251-infected macaque that is closely related to sequences in brain from animals with neurological disease. SIVmac251 clones expressing this Env are highly fusogenic, and replicate efficiently in T cells and macrophages. N173 and N481 were identified as novel determinants of macrophage tropism and neutralization sensitivity. These results imply that macrophage-tropic SIV capable of establishing viral reservoirs in brain can be present in blood during early infection. Furthermore, these SIVmac251 clones will be useful for studies on pathogenesis, eradication, and vaccines.

Derivation and Characterization of a CD4-Independent, Non-CD4-Tropic Simian Immunodeficiency Virus

“…However, an Env containing only the iMac239 gp120 changes, while CD4 independent, remained highly neutralization resistant, similar to parental SIVmac239. Similar findings were reported by Yen and coworkers, in which the loss of a glycosylation site in the SIVmac239 V2 loop (Asn-173) conferred the ability to infect macrophages in the context of cell-to-cell transmission while retaining the neutralization-resistant phenotype of SIVmac239 (59,60). In addition to indicating that CD4 independence and enhanced neutralization sensitivity can be dissociated, our findings also suggest that changes in the gp41 ectodomain that arose with iMac239's CD4 independence contribute to its neutralization sensitivity.…”

“…Because CD4-independent viruses are characteristically neutralization sensitive, it is likely that they are strongly selected against during typical pathogenic infection (32,48,49,97). Recent publications by Yen et al have suggested that CD4-independent entry serves as a mechanism of cell-cell viral spread in tissue macrophages, which is more efficient and can shield virus from neutralizing antibodies than cell-free transmission, thereby allowing CD4-independent variants to circulate in compartments such as the brain (59,60). Interestingly, primary isolates of HIV-2, which is less pathogenic than HIV-1 (reviewed in reference 98), have been reported to exhibit CD4 independence in vitro (61,99).…”

“…For one neuropathic SIV isolate, its ability to cause AIDS encephalopathy in macaques correlated with the infection of brain-derived endothelial cells that expressed CCR5 but not CD4 (58). In addition, CD4-independent infection has been proposed to contribute to SIV infection of macrophages in the context of cell-to-cell transmission (59,60). Of note, viruses that are CD4 independent typically retain their CD4 binding site and the ability to engage CD4, if present (30,34,58,61,62), and have been shown to exhibit faster fusion kinetics in the presence of CD4 than CD4-dependent viruses (63).…”

Non-human primate models of SIV infection and CNS neuropathology

“…Historically early models used rhesus macaques (RM) or pigtail macaques (PM) and different viral clones or swarms that resulted in immune suppression (AIDS) macrophage tropism for CNS infection, and SIV encephalitis (SIVE) in approximately 30 percent of the animals in RM and higher percentages of PM [8](Table 1). More recently, immune modulation (depletion) of CD4 and CD8 T lymphocytes, and/or serial passage of virus through monkeys for enhanced macrophage replication and neurotropism have been used [6,9–11] (Table 1). One model uses mAb depletion of CD8 lymphocytes and infection with the viral swarm SIVmac251.…”

“…Hirsch and colleagues used a serially passaged SIVSmE543 and obtained SIVsm804E that established infection of the CNS early and resulted in a high incidence of SIVE. Gabuzda and collaborators similarly identified a macrophage tropic SIV env glycoprotein variant also found in the blood early in infection found in early infection of SIV251 infected animals, and made a molecular clones that enters the CNS early after inoculation and results in a high degree of SIVE [10,11](Table 1). The viral sequence data from these two models are discussed below.…”