Early predictors of disease progression
Richard Jefferys, TAG
Recent research involving SIV-infected macaques has suggested that the early loss of a particular type of memory CD4 T cell (known as a “central memory” T cell or Tcm) may be a key predictor of the subsequent pace of disease progression.
Tcm are a long-lived subset of memory T cells that can proliferate robustly in response to antigen. Tcm proliferation generates a fleet of T cells belonging to a shorter-lived subset called “effector memory” (Tem) cells. Tem are generally viewed as first-responders that can rapidly execute anti-pathogen functions, while Tcm provide a stem-cell like renewal source for new Tem if their numbers need to be bolstered. Studies in HIV-infected people have consistently shown a loss of Tcm and increase in Tem (which equates to a decrease in long-lived resting T cells and an increase in short-lived activated T cells), but whether changes in the numbers of different T cell subsets during early infection can predict disease progression has not been thoroughly evaluated.
A new study published in the Journal of Infectious Diseases set out to answer the question of whether quantifying Tcm in early infection provides prognostic information. To provide sufficient statistical power to ensure confidence in the findings, a total of 466 individuals were studied, among whom 101 progression events occurred.
It turned out that the proportion or absolute number of Tcm did not correlate with subsequent disease progression (defined as the time to AIDS or death), but several other parameters did. These included the proportion of naïve CD8 T cells, with a greater proportion being strongly associated with slower disease progression (p<0.001); this correlation remained significant after adjustment for CD4 T cell count. The numbers of CD8 T cells expressing the IL-7 receptor (CD127) were also linked to the rate of progression; having fewer of these cells correlated with a faster disease course.
Immune activation was assessed by measuring the proportion of CD4 and CD8 T cells expressing the proliferation marker Ki67. In both subsets, higher proportions of Ki67-expressing cells equated to faster progression, and for CD8 T cells this relationship held up after adjustment for baseline CD4 T cell count, age, and viral load. The median time to AIDS or death among subjects with the highest levels of Ki67-expressing CD8 T cells (based on dividing participants into quartiles) was 4 years for those in the top quartile compared to 10 years for those in the lowest.
Finally, measures of cell-associated viral load (CAVL: the proportion of CD4 T cells containing HIV DNA) were correlated significantly with progression in those participants sampled within 225 days of their estimated date of seroconversion (225 days was the median time after the estimated date of seroconversion that samples were obtained). Among participants sampled later, CAVL was not significantly correlated with rate of progression, suggesting an important impact of the early spread of HIV among CD4 T cells on subsequent disease course. The researchers also evaluated CAVL in different CD4 T cell subsets: naïve, central memory, transitional memory and effector memory. To their surprise, naïve CD4 T cells showed relatively high rates of infection, albeit around 10-fold lower than the memory subsets. Because resting naïve CD4 T cells are known to be very resistant to HIV, the researchers speculate that the infected naïve cells may have been rendered susceptible by immune activation (naïve CD4 T cells have been shown to become susceptible to R5-using HIV after they receive activation signals).
The authors conclude by stating: “we ﬁnd that quantiﬁcation of Tcm cells in early infection does not provide predictive power for progression. However, measures of homeostasis and activation, including CD127 expression and Ki-67, do provide such information and should be studied further to determine their role in clinical monitoring of HIV-1 progression…Future efforts to identify markers of subsequent progression should focus on measures of activation and homeostasis during the earliest stages of infection.”
Ganesa A et al. Immunologic and Virologic Events in Early HIV Infection Predict Subsequent Rate of Progression. The Journal of Infectious Diseases 2010;201:272284. DOI: 10.1086/649430.