Abstract
Long-term survival of human immunodeficiency virus type 1 (HIV-1) infection has been noted in rare cohorts of individuals infected with nef-deleted virus. Enhanced macrophage tropism and cytopathicity contribute to pathogenicity of wild type HIV-1. To better understand the pathogenesis of nef-deleted HIV-1, we analyzed the replication capacity and macrophage cytopathicity of nef-deleted HIV-1 isolated sequentially from a long-term survivor during progression to AIDS (n=6 isolates). Compared with controls, all nef-deleted viruses replicated to low levels in peripheral blood mononu-clear cells and monocyte-derived macrophages (MDM). One nef-deleted virus that was isolated on the development of AIDS caused high levels of syncytia in MDM similar to control viruses, but five viruses isolated from earlier times prior to AIDS onset caused only minimal cytopathicity. Together, these results suggest that enhanced cytopathicity of nef-deleted HIV-1 for MDM can occur independently of replication capacity, and may contribute to the pathogenesis of nef-deleted HIV-1 infection.
Highlights
Infection with human immunodeficiency virus type 1 (HIV-1) causes depletion of CD4+ T-cells, and without highly active antiretroviral therapy (HAART) results in acquired immunodeficiency syndrome (AIDS)
HIV-associated dementia (HIVD) was the subjects first and only AIDS defining illness, and coincided with the CD4+ T-cell count falling below 200 cells/l and plasma viral load steadily increasing to approximately 20,000 RNA copies/ml
Replication in monocyte-derived macrophages (MDM): all the D36 isolates are phenotypically R5X4 (Table 1 and [31]), we recently showed that certain R5X4 viruses isolated from blood of a subject with HIVD were highly M-tropic, and that efficient macrophage entry by these viruses occurred via CXCR4 [22]
Summary
Infection with human immunodeficiency virus type 1 (HIV-1) causes depletion of CD4+ T-cells, and without highly active antiretroviral therapy (HAART) results in acquired immunodeficiency syndrome (AIDS). Whether enhanced M-tropism and enhanced macrophage cytopathicity are properties of nef-deleted HIV-1 strains isolated from subjects who experienced slowly progressive infection is unknown. To better understand M-tropism and macrophage cytopathicity of nef-deleted viruses, and to determine whether these properties are linked to pathogenicity of nef-deleted HIV-1, we characterized 6 sequentially isolated nef-deleted HIV-1 variants from the SBBC “donor”, subject D36, during progression to AIDS.
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