Abstract
Most myeloid lineage cells express the receptor and coreceptors that make them susceptible to infection by primate lentiviruses (SIVs and HIVs). However, macrophages are the only myeloid lineage cell commonly infected by SIVs and/or HIVs. The frequency of infected macrophages varies greatly across specific host and virus combinations as well as disease states, with infection rates being greatest in pathogenic SIV infections of non-natural hosts (i.e., Asian nonhuman primates (Asian NHPs)) and late in untreated HIV-1 infection. In contrast, macrophages from natural SIV hosts (i.e., African NHPs) are largely resistant to infection due to entry and/or post-entry restriction mechanisms. These highly variable rates of macrophage infection may stem from differences in the host immune environment, entry and post-entry restriction mechanisms, the ability of a virus to adapt to efficiently infect macrophages, and the pleiotropic effects of macrophage-tropism including the ability to infect cells lacking CD4 and increased neutralization sensitivity. Questions remain about the relationship between rates of macrophage infection and viral pathogenesis, with some evidence suggesting that elevated levels of macrophage infection may contribute to greater pathogenesis in non-natural SIV hosts. Alternatively, extensive infection of macrophages may only emerge in the context of high viral loads and immunodeficiency, making it a symptom of highly pathogenic infections, not a primary driver of pathogenesis.
Highlights
Human immunodeficiency viruses (HIV-1 and HIV-2) and simian immunodeficiency viruses are primate lentiviruses capable of generating chronic disease in humans and in nonhuman primates (NHPs)
The resulting tissue-culture-adapted variants have been observed to have an enhanced ability to infect cells lacking CD4 and an open Env conformation that greatly increases their neutralization sensitivity, which likely explains why they are not observed in vivo [100,101]. These results indicate that it is possible for HIV-1 to evolve the ability to efficiently infect cells lacking CD4, but that natural selection does not favor this phenotype in humans
While many of the most commonly studied macrophage-tropic SIVs are capable of CD4independent entry (Table 2), in vitro analyses of SIVsmE543-3, which was derived from a macaque with SIV-induced encephalitis, indicate that this variant is macrophage-tropic but retains the need for
Summary
Human immunodeficiency viruses (HIV-1 and HIV-2) and simian immunodeficiency viruses (various SIVs) are primate lentiviruses capable of generating chronic disease in humans and in nonhuman primates (NHPs). The preferential infection of CD4+ T-cells is clearly supported by studies of infected humans and NHPs in which the frequency of CD4+ T-cells containing viral DNA, RNA, or protein is high relative to the low frequency found in monocytes in the blood [21,22] or myeloid cells in tissues [48,49,50] This is supported by in vitro studies showing that most HIV-1 and SIV variants enter and replicate more efficiently in CD4+ T-cells relative to macrophages [14,48,51,52]. These data indicate that CD4+ T-cells are the primary target cells in SIV and HIV-1 infections
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