16th International AIDS Conference Toronto, Canada - August 13 - 18, 2006

LONG-TERM NONPROGRESSOR'S JOURNEY INTO PROGRESSIVE DISEASE: ASSOCIATION WITH ESCAPE FROM CELLULAR IMMUNE CONTROL

Int Conf AIDS. 2006 Aug 13-18;16 Abstract No. WeAa0401

Kemal K.¹, Beattie T.², Dong T.², Weiser B.¹, Kuiken C.³, Sutton J.², Lang D.³, Yang H.², Yang P.², Collman R.⁴, Philpott S.¹, Rowland-Jones S.², Burger H.^1
1 Wadsworth Center, New York State Department of Health, Albany, United States, ² University of Oxford, Weatherall Institute of Molecular Medicine, Oxford, United Kingdom, ³ Los Alamos National Laboratory, Los Alamos, United States, ⁴ University of Pennsylvania, School of Medicine, Philadelphia, United States

BACKGROUND: The control of HIV-1 infection is a function of complex interactions among an individual's viral sequences, immune responses, and genetic background. A transition from long-term nonprogressive (LTNP) infection to progressive HIV-1 disease presents an opportunity to investigate the correlates of protection and disease progression in a defined immunogenetic environment.

METHODS: We studied a Caucasian homosexual male long-term nonprogressor who remained asymptomatic, viremic, and had a normal CD4+ T cell count without antiretroviral therapy for >18 years. Starting in 2003, he experienced a transition to disease progression, with a sudden and sustained decline in his CD4+ T cell count and a rise in his viral load. We analyzed his complete HIV-1 genomic RNA sequence from plasma and cellular immune responses to autologous viral peptides spanning the viral genome before and after the transition.

RESULTS: The viral sequences were subtype B and consistently utilized coreceptor CCR5; they did not appear attenuated, although insertions were found in the V2 domain of gp120. The patient displayed wildtype CCR5 and CCR2 genotypes. Longitudinal screening of all pre-defined HLA-matched autologous CD4 and CD8 epitopes found a broad, low-level T cell immune response, targeting several regions of the viral genome. The transition to disease progression was associated with newly acquired HIV-1 mutations leading to loss of recognition in two CD8+ T cell epitopes. A loss of the immunodominant HIV-1-specific CD4+ T cell response, despite an absence of immune escape in this epitope, was seen with the increasing viral burden.

CONCLUSIONS: This man's journey from LTNP to progressive infection was associated with both the acquisition of viral mutations conferring escape from CD8 mediated control and targeted depletion of HIV-1-specific CD4+ T cells. These data are relevant to the correlates of protection from disease progression.

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2006-08-13
WeAa0401

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