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Journal of Virology, July 1999, p. 5509-5519, Vol. 73, No. 7
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Lack of Viral Escape and Defective In Vivo Activation of Human Immunodeficiency Virus Type 1-Specific Cytotoxic T Lymphocytes in Rapidly Progressive Infection

Christine M. Hay,1 Debbie J. Ruhl,1 Nesli O. Basgoz,1 Cara C. Wilson,2 James M. Billingsley,1 Maria Pia DePasquale,1 Richard T. D'Aquila,1 Steven M. Wolinsky,3 John M. Crawford,4 David C. Montefiori,4 and Bruce D. Walker1,*

Partners AIDS Research Center and Infectious Disease Unit, Massachusetts General Hospital, Boston, Massachusetts 021141; Infectious Disease Division, University of Colorado Health Sciences Center, Denver, Colorado 802622; Infectious Disease Division, Department of Medicine, Northwestern University School of Medicine, Chicago, Illinois 606113; and Center for AIDS Research and Department of Surgery, Duke University Medical Center, Durham, North Carolina 277104

Received 21 September 1998/Accepted 19 March 1999

Human immunodeficiency virus type 1 (HIV-1)-specific immune responses over the course of rapidly progressive infection are not well defined. Detailed longitudinal analyses of neutralizing antibodies, lymphocyte proliferation, in vivo-activated and memory cytotoxic T-lymphocyte (CTL) responses, and viral sequence variation were performed on a patient who presented with acute HIV-1 infection, developed an AIDS-defining illness 13 months later, and died 45 months after presentation. Neutralizing-antibody responses remained weak throughout, and no HIV-1-specific lymphocyte proliferative responses were seen even early in the disease course. Strong in vivo-activated CTL directed against Env and Pol epitopes were present at the time of the initial drop in viremia but were quickly lost. Memory CTL against Env and Pol epitopes were detected throughout the course of infection; however, these CTL were not activated in vivo. Despite an initially narrow CTL response, new epitopes were not targeted as the disease progressed. Viral sequencing showed the emergence of variants within the two targeted CTL epitopes; however, viral variants within the immunodominant Env epitope were well recognized by CTL, and there was no evidence of viral escape from immune system detection within this epitope. These data demonstrate a narrowly directed, static CTL response in a patient with rapidly progressive disease. We also show that disease progression can occur in the presence of persistent memory CTL recognition of autologous epitopes and in the absence of detectable escape from CTL responses, consistent with an in vivo defect in activation of CTL.

* Corresponding author. Mailing address: Partners AIDS Research Center, MGH-East, 149 13th St., Room 5212D, Charlestown, MA 02129. Phone: (617) 724-8332. Fax: (617) 726-4691. E-mail: bwalker{at}helix.mgh.harvard.edu.

Journal of Virology, July 1999, p. 5509-5519, Vol. 73, No. 7
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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