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111 Generation of Cells Within Human Nurse Macrophages and Consequences Following HIV Infection

Gartner, Suzanne; Natesan, Senthilkumar; Liu, Yiling

JAIDS Journal of Acquired Immune Deficiency Syndromes: April 2011 - Volume 56 - Issue - p 44
doi: 10.1097/01.qai.0000397301.63847.e6

Institute of Human Virology

We have observed that a subset of cultured human monocyte-derived macrophages can behave as “nurse” cells with functional capabilities that include the de novo generation, within themselves, of CD4+ T-lymphocytes and a previously unknown small cell with monocyte-macrophage characteristics. We named these novel cells “self-renewing monocytoid cells” (SRMC) because they could develop into nurse macrophages (NM) that produced another generation of SRMC. The NM/SRMC production cycle could continue in vitro for several generations. SRMC expressed CCR5, the coreceptor for macrophage-tropic HIV isolates, and unlike monocytes and mature macrophages, were highly susceptible to HIV entry leading to productive infection. Moreover, in the presence of HIV expression, infected SRMC differentiated into macrophages, including SRMC-producing NM, and the NM/SRMC cycle was maintained. We hypothesize that perpetual cycles of NM/SRMC production could maintain HIV within the body indefinitely. Because this mode of persistence does not require new rounds of infection, it would escape the effects of most antiretrovirals. HIV infection of NM decreased production of CD4+ T-lymphocytes in macrophage cultures. This was attributable to a severe, preferential loss of the CCR5+ CD4+ subpopulation. Rather than being released, the developing T-lymphocytes accumulated within infected NM, resulting in cells with the appearance of classic HIV+ multinucleated giant cells. Confocal microscopy revealed individual HIV-expressing NM simultaneously producing both virus-expressing SRMC and non-expressing T-cells, suggesting that NM might be a source of latently infected CD4+ T-lymphocytes. Real-time PCR experiments further supported this contention by showing ∼10-fold more HIV genome-positive than virus-expressing T-cells. We extend these observations to infected individuals and propose that NM play a major role in maintenance of HIV persistence via the NM/SRMC production cycle, that they are a source of latently infected T-cells, and that their infection contributes to the CD4 T-cell decline that characterizes HIV/AIDS.

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