Abstract

Early immunological correlates of subsequent HIV progression

Presented by Mario Roederer (United States).

P. Chattopadhyay¹, Y. Mahnke¹, M. Sauer², T. Brodie¹, J. Mascola³, N. Michael⁴, E. Kallas², A. Ganesan⁴, M. Roederer¹, and the IDCRP working group

¹Vaccine Reseearch Center, NIH, ImmunoTechnology Section, Bethesda, United States, ²Universidade Federal de São Paulo, São Paulo, Brazil, ³Vaccine Reseearch Center, NIH, Bethesda, United States, ⁴Walter Reed Army Medical Center, Rockville, United States

Background: SIV studies reveal dramatic, systemic destruction of CD4+ memory T cells during acute disease; this, and early levels of central memory subsets predicted survival. In chronic HIV, activated T-cells are powerful predictors of clinical outcome. However, in early HIV, large studies that define predictors of long-term progression are lacking.
Methods: We studied retrospective samples from 466 untreated individuals (enrolled in the US military natural history study begun in 1990), and prospective samples from 51 untreated individuals (enrolled in an ongoing prospective study in Brazil) Samples represented the earliest available time points post-infection (median 225 days after seroconversion); clinical follow-up was substantial (median 4 years). The following parameters were studied: 1) T-cell differentiation, proliferation, and activation (using 13-16 color immunophenotyping panels), 2) phenotype and quality of HIV-specific T-cells (by intracellular cytokine staining), and 3) cell-associated viral load (CAVL).
Results: Central memory T cell levels at the earliest HIV+ visit did not predict long-term outcome. However, the following were associated with slower progression: high levels of long-lived cells (naïve or CD127+ memory CD8), low Ki-67 expression, and low CAVL during the first 7.5 months. Markers associated with CD8 T cell activation (CD38, CCR5, Granzyme B, CD57) were also significantly lower on T cells from slower progressors. In terms of antigen-specific T cell responses, the magnitude, phenotype, and quality showed surprisingly little predictive power. Notably however, the cytokine response profiles to HIV Gag and Env differed dramatically within individuals.
Conclusions: These results suggest: 1) early depletion of precursor cells, mediated by proliferation/differentiation, is a poor prognostic factor independent of antigen load, 2) Ki-67 measurements can inform early treatment decisions, and 3) the quality of the T-cell response to HIV early in disease impacts on progression. Our data define measurements that may identify beneficial immunogen-elicited protection in individuals with breakthrough infections in vaccine efficacy trials.