Immunologic and virologic events in early HIV infection predict subsequent rate of progression

Abstract

Background: Variability in human immunodeficiency virus (HIV) disease progression cannot be fully predicted by CD4(+) T cell counts or viral load (VL). Because central memory T (T(CM)) cells play a critical role in the pathogenesis of simian immunodeficiency virus disease, we hypothesized that quantifying these cells in early HIV infection could provide prognostic information.

Methods: We measured expression of CD45RO, chemokine (C-C motif) receptor (CCR) 5, CCR7, CD27, and CD28 to enumerate naive and memory subsets in samples from recently infected individuals. We also quantified proliferation, CD127 expression, and cell-associated VL. Disease progression was compared across subgroups defined by these measurements, using Kaplan-Meier survival curves and multivariate Cox proportional hazards regression.

Results: Four hundred sixty-six subjects contributed 101 events. The proportion or absolute count of T(CM) cells did not correlate with disease progression, defined as the time to AIDS or death. However, significant associations were observed for proliferation within CD4(+) or CD8(+) T cells, loss of naive or CD127(+) memory CD8(+) T cells, and CD4(+) T cell-associated VL.

Conclusions: Our results demonstrate that the extent of the immunopathogenesis established early in HIV infection predicts the course of future disease. Because antiretroviral drug treatment reverses such defects in part, our study provides mechanistic clues to why early use of antiretrovirals may prove beneficial.

Figure 1. Representation of T cell subsets in early infection

(A) Immunophenotypic characteristics of T-cell subsets. Graphs illustrate the sequential gating to identify pure populations. The first gate eliminates doublets; the second restricts analysis to live, CD3+ T cells; within those, CD4 or CD8 T cells are identified. (B) Naïve cells were defined by defining gates within the total CD4⁺ or CD8⁺ T-cell populations, and then combining these gates with the Boolean function indicated. The resulting naïve cell population was CD45RO⁻CD28⁺CD27⁺CCR7⁺. (C) Subsets of memory CD4⁺ and CD8⁺ T cells were identified utilizing various combinations of cell-surface markers, as follows: Central memory cells (T_CM) = CD45RO⁺ CD28⁺ CCR7⁺ CCR5⁻; transitional memory cells (T_TM) = CD45RO⁺ CD28⁺ CCR7⁻ CCR5⁺; effector memory cells (T_EM) = CD45RO⁻ CD28⁻ CCR7⁻ CCR5⁺. (D) Distribution of naïve and memory cell subsets in the CD4 and CD8 compartments. The box and whisker plot represents the relative frequencies of naïve, central, transitional, and effector memory cells in the CD4 (left panel) and CD8 (right panel) compartments. Interquartile ranges are shown.

Figure 2. Relationship between T cell phenotypes and time to AIDS or death

Subjects were grouped into three groups based on the relative proportion of any given T cell subset. Kaplan-Meier survival curves are shown for the groups. The red lines show data for those individuals with the lowest levels of a particular subset (<25^th percentile), green lines for those with intermediate levels (25^th–75^th percentile), and blue lines for those with the highest levels (>75^th percentile). (A) Disease progression according to baseline CD4 (left) or CD8 (right) T_CM levels. (B) Disease progression according to baseline naïve CD8 T cell levels, for individuals measured within 225 days of imputed seroconversion (left) or after 225 days (right). (C) Disease progression according to baseline expression of CD127 on total CD8 T cells (left) or on memory CD8 T cells (right).

Figure 3. Association of cell associated viral load and disease progression

(A) Distribution of gag DNA within CD4+ T-cell subsets. This box and whisker plot depicts number of HIV gag DNA molecules per cell in each of the four sorted T-cell subsets. Interquartile ranges are shown. (B) Kaplan-Meier curves comparing the time to AIDS/death with levels of cell-associated DNA, for subjects identified within 225 days of imputed seroconversion.

Figure 4. Immune activation a marker of disease free survival

Kaplan-Meier curves comparing the time to AIDS/death among subjects with differing levels of Ki-67 expression in the CD4 compartment (left) or the CD8 compartment (right).