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Journal of Virology, August 2008, p. 7886-7896, Vol. 82, No. 16
0022-538X/08/$08.00+0     doi:10.1128/JVI.00245-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Dendritic Cells Preferentially Transfer CXCR4-Using Human Immunodeficiency Virus Type 1 Variants to CD4+ T Lymphocytes in trans{triangledown}

Thijs van Montfort,1 Adri A. M. Thomas,2 Georgios Pollakis,1 and William A. Paxton1*

Laboratory of Experimental Virology, Department of Medical Microbiology, Center for Infection and Immunity Amsterdam, Academic Medical Center of the University of Amsterdam, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands,1 Laboratory of Developmental Biology, Department of Biology, Faculty Betascience, University Utrecht, Padualaan 8, 3584 CH Utrecht, The Netherlands2

Received 4 February 2008/ Accepted 23 May 2008

Human immunodeficiency virus type 1 (HIV-1) preferentially utilizes the CCR5 coreceptor for target cell entry in the acute phase of infection, while later in disease progression the virus switches to the CXCR4 coreceptor in approximately 50% of patients. In response to HIV-1 the adaptive immune response is triggered, and antibody (Ab) production is elicited to block HIV-1 entry. We recently determined that dendritic cells (DCs) can efficiently capture Ab-neutralized HIV-1, restore infectivity, and transmit infectious virus to target cells. Here, we tested the effect of Abs on trans transmission of CCR5 or CXCR4 HIV-1 variants. We observed that transmission of HIV-1 by immature as well as mature DCs was significantly higher for CXCR4- than CCR5-tropic viral strains. Additionally, neutralizing Abs directed against either the gp41 or gp120 region of the envelope such as 2F5, 4E10, and V3-directed Abs inhibited transmission of CCR5-tropic HIV-1, whereas Ab-treated CXCR4-tropic virus demonstrated unaltered or increased transmission. To further study the effects of coreceptor usage we tested molecularly cloned HIV-1 variants with modifications in the envelope that were based on longitudinal gp120 V1 and V3 variable loop sequences from a patient progressing to AIDS. We observed that DCs preferentially facilitated infection of CD4+ T lymphocytes of viral strains with an envelope phenotype found late in disease. Taken together, our results illustrate that DCs transmit CXCR4-tropic HIV-1 much more efficiently than CCR5 strains; we hypothesize that this discrimination could contribute to the in vivo coreceptor switch after seroconversion and could be responsible for the increase in viral load.

* Corresponding author. Mailing address: Laboratory of Experimental Virology, Department of Medical Microbiology, Center for Infection and Immunity Amsterdam, Academic Medical Center of the University of Amsterdam, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands. Phone: 31 2056 64739. Fax: 31 2069 16531. E-mail: w.a.paxton{at}amc.uva.nl

{triangledown} Published ahead of print on 4 June 2008.

Journal of Virology, August 2008, p. 7886-7896, Vol. 82, No. 16
0022-538X/08/$08.00+0     doi:10.1128/JVI.00245-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.





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