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Journal of Virology, July 2006, p. 6801-6809, Vol. 80, No. 14
0022-538X/06/$08.00+0     doi:10.1128/JVI.00070-06

Preferential Infection Shortens the Life Span of Human Immunodeficiency Virus-Specific CD4+ T Cells In Vivo

Jason M. Brenchley,1 Laura E. Ruff,1 Joseph P. Casazza,2 Richard A. Koup,2 David A. Price,1 and Daniel C. Douek1*

Human Immunology Section,1 Immunology Laboratory, Vaccine Research Center, NIAID, NIH, Bethesda, Maryland2

Received 10 January 2006/ Accepted 1 April 2006

CD4+ T-cell help is essential for effective immune responses to viruses. In human immunodeficiency virus (HIV) infection, CD4+ T cells specific for HIV are infected by the virus at higher frequencies than other memory CD4+ T cells. Here, we demonstrate that HIV-specific CD4+ T cells are barely detectable in most infected individuals and that the corresponding CD4+ T cells exhibit an immature phenotype compared to both cytomegalovirus (CMV)-specific CD4+ T cells and other memory CD4+ T cells. However, in two individuals, we observed a rare and diametrically opposed pattern in which HIV-specific CD4+ T-cell populations of large magnitude exhibited a terminally differentiated immunophenotype; these cells were not preferentially infected in vivo. Clonotypic analysis revealed that the HIV-specific CD4+ T cells from these individuals were cross-reactive with CMV. Thus, preferential infection can be circumvented in the presence of cross-reactive CD4+ T cells driven to maturity by coinfecting viral antigens, and this physical proximity rather than activation status per se is an important determinant of preferential infection based on antigen specificity. These data demonstrate that preferential infection reduces the life span of HIV-specific CD4+ T cells in vivo and thereby compromises the generation of effective immune responses to the virus itself; further, this central feature in the pathophysiology of HIV infection can be influenced by the cross-reactivity of responding CD4+ T cells.

* Corresponding author. Mailing address: VRC, NIH, Bldg. 40, Rm. 3509, 40 Convent Drive, Bethesda, MD 20892. Phone: (301) 594-8484. Fax: (301) 480-2565. E-mail: ddouek{at}mail.nih.gov.

Journal of Virology, July 2006, p. 6801-6809, Vol. 80, No. 14
0022-538X/06/$08.00+0     doi:10.1128/JVI.00070-06




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