Immune recovery on antiretroviral therapy
Richard Jefferys, TAG
A free access paper and accompanying commentary in Clinical Infectious Diseases address the issue of long-term immune recovery on antiretroviral therapy (ART). [1, 2]
The paper describes results from ACTG384, the largest and most detailed evaluation of the effects of ART on CD4 T cell counts and other immune parameters. The commentary by Elvin Geng and Steve Deeks provides an excellent overview of the findings.
ACTG 384 stratified participants using baseline CD4 count, and the most striking consequence of being below 50 cells/mm3 was the depletion of naive CD4 T cells and the consequent skewing of the naive-memory ratio. The strata used in the study were <50, 51200, 201350, 351500, and >500 cells/mm3, and the median baseline CD4+ naive-memory cell ratio for individuals starting with a CD4 cell count <50 cells was 0.21 at baseline and increased to only 0.43 at week 144 this was still lower than the median pre-treatment ratio for the higher CD4 strata.
The lower CD4 strata also had the poorest improvement in CD4/CD8 ratio, and as Geng & Deeks note in their commentary These two trendsa low naive-memory cell ratio and a low CD4:CD8 ratiohave been seen both in those with untreated HIV infection and in the elderly (>75 years of age). Conversely, individuals who started ART with CD4 counts >350 attained immune profiles that overlapped with HIV-negative individuals.
The ACTG 384 data complement the findings recently reported by Rita Effros and colleagues regarding the premature aging of the immune system in HIV infection. 
Geng & Deeks also offer some intriguing thoughts as to how the results may relate to the elevated risk of clinical disease that has been reported in individuals with a poor CD4 T cell recovery on ART: We believe that the conclusions reached by Robbins et al. might provide a mechanistic explanation for why some patients who receive HAART remain at risk of disease. Naive T cells are critical in both mounting an effective adaptive immune response against novel antigens and maintaining normal T cell homeostasis. Those naive T cells that survive untreated HIV infection are at least partially dysfunctional and have impaired proliferative capacity. It has recently been shown that chronic inflammation contributes to failure of naive T cell homeostasis, either by causing too much proliferation or by causing failure of naive T cells to proliferate in response to either homeostatic signals (which leads to lack of robust peripheral CD4 gains) or to novel antigens (which leads to disease). Tying this together, it is possible to construct a testable model in which those patients who initiate HAART late in their disease course have residual inflammation, suboptimal CD4+ T cell gains, skewed immunophenotypic profiles, persistent T cell dysfunction, and increased risk of all-cause morbidity and mortality.
Among the studies cited in support of this model is the recent Christine Bourgeois paper suggesting that naive T cell depletion can lead to microbial translocation, which in turn contributes to ongoing immune activation and naive T cell depletion. 
However, the commentary also cautions that: determining the causal association among these factors will be a challenge, given the complexity of the human immune system and the lack of therapeutic interventions. One important implication of the data is that the few therapies that might have the potential to increase naive T cell levels (currently, IL-7 and human growth hormone derivatives) deserve urgent and careful evaluation in people with suboptimal immune recovery on ART, as there may be the potential for these approaches to offer significant clinical benefits.
Source: TAG Basic Science Weblog. (4 Feb 2009)
- Robbins GK et al. Incomplete Reconstitution of T Cell Subsets on Combination Antiretroviral Therapy in the AIDS Clinical Trials Group Protocol 384. Clinical Infectious Diseases 2009;48:350361
- Elvin H. Geng and Steven G. Deeks. CD4+ T Cell Recovery with Antiretroviral Therapy: More Than the Sum of the Parts. Editorial Commentary. Clinical Infectious Diseases 2009;48:362364.
- http://tag basicscienceproject.typepad.com/tags_basic_science_vaccin/2009/01/accelerated-aging-of-the-immune-system-in-hiv-infection.html
- http://tagbasicscienceproject.typepad.com/tags_bas ic_science_vaccin/2008/07/naive-cd4-t-cel.html