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Unformatted text preview: Persistent HIV-1 infection of natural killer cells in patients receiving highly active antiretroviral therapy Antonio Valentin*, Margherita Rosati*, Daniel J. Patenaude*, Angelos Hatzakis , Leondios G. Kostrikis , Marios Lazanas , Kathleen M. Wyvill , Robert Yarchoan , and George N. Pavlakis* *Human Retrovirus Section, Basic Research Laboratory, National Cancer Institute, Frederick, MD 21702; School of Medicine, University of Athens, 11527 Athens, Greece; Red Cross General Hospital, 11527 Athens, Greece; and HIV and AIDS Malignancy Branch, National Cancer Institute, Bethesda, MD 20892 Edited by Robert C. Gallo, Institute of Human Virology, Baltimore, MD, and approved March 11, 2002 (received for review December 17, 2001) We have identified a subset of CD56 1 CD3 2 human natural killer (NK) cells that express CD4 and the HIV coreceptors CCR5 and CXCR4. These cells can be productively infected in vitro by both CCR5- and CXCR4-using molecular clones of HIV-1 in a CD4-depen- dent manner. Analysis of HIV-infected persons showed that viral DNA is present in purified NK cells, and virus could be rescued from these cells after in vitro cultivation. Longitudinal analysis of the HIV-1 DNA levels in NK cells from patients after 12 years of highly active antiretroviral therapy indicated that NK cells remain persis- tently infected and account for a substantial amount of the viral DNA in peripheral blood mononuclear cells. These results demon- strate that a subset of non-T cells with NK markers are persistently infected and suggest that HIV infection of NK cells is important for virus persistence. The properties of the virus reservoir in these cells should be considered in attempts to further optimize antiretroviral therapies. H ighly active antiretroviral therapy (HAART) is very ef- fective in controlling HIV-1 as reflected by the dramatic decrease (100- to 1,000-fold) in plasma viral load that follows the initiation of treatment in most HIV-1 patients (15). Despite this effectiveness, virus is never eradicated. The presence of a pool of latently infected cells (6, 7) that appears to be established early during primary HIV-1 infection (8, 9) provides a mechanism for HIV-1 persistence even in patients receiving HAART. It has been established that quiescent CD4 1 T lymphocytes harbor replication-competent HIV-1 in a latent form (69). This pool of long-living, latently infected CD4 1 T cells represents a major obstacle for the eradication of HIV-infected cells in patients receiving HAART. Some reports have indicated a lack of correlation between the estimated frequency of resting CD4 1 T cells harboring infec- tious virus and the kinetics of viral rebound upon cessation of antiretroviral therapy (10). In addition, lack of genetic identity between the rapidly rebounding virus after therapy interrup- tion and the virus present in the T cell latent reservoir was noticed in several patients (11, 12). This finding suggested thatnoticed in several patients (11, 12)....
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