Immune Activation Correlates with CD4 T cell Declines in HIV Controllers

A new study just published online in the Journal of Infectious Diseases (authored by Peter Hunt from UCSF and colleagues) reports that levels of CD4 and CD8 T cell activation correlate with declines in peripheral blood CD4 T cell counts, even in individuals who consistently maintain viral loads below 75 copies/mL (dubbed "controllers"). It has been reported previously that maintenance of a low viral load does not confer absolute protection against disease progression; for example, an individual in the Sydney Blood Bank Cohort who was infected with a partially attenuated HIV eventually developed immune deficiency despite a persistently low viral load. A prior study also found that CD4 T cell declines in HIV-2-infected individuals can occur despite very low or undetectable viremia; these declines correlated with immune activation levels, echoing the findings of Hunt et al.

The JID paper also notes that LPS levels - a potential indicator of the translocation of microbial products from the gut - were elevated compared to HIV-negative individuals and correlated with CD8 (but not CD4) T cell activation levels in the controllers. However, the authors do not state whether a similar correlation was seen in the HIV-infected individuals with detectable viral loads (as has been reported previously by Jason Brenchley, one of the co-authors of this paper).

This study further highlights the critical role of immune activation in the pathogenesis of HIV/AIDS. Critical issues that remain to be addressed include the specificity of the activated T cells (a question that may be complicated by the fact that activated T cells can transiently downregulate their T cell-receptor), the phenotype of the T cells at the time of activation (naive, central memory, effector memory), the factors driving immune activation (HIV antigens, non-HIV antigens such as translocated microbial products, cytokines, stimulation through toll-like receptors or some combination of these or other factors) and whether novel therapeutic approaches can beneficially ameliorate immune activation in HIV infection. Studies such as this one may also suggest that immune activation levels should be measured (in addition to viral loads and CD4 T cell counts) in trials of vaccines intended to prevent or slow progression of HIV infection in immunized individuals.

The Journal of Infectious Diseases 2008;197:000–000
DOI: 10.1086/524143

MAJOR ARTICLE

Relationship between T Cell Activation and CD4+ T Cell Count in HIV-Seropositive Individuals with Undetectable Plasma HIV RNA Levels in the Absence of Therapy

Peter W. Hunt,1 Jason Brenchley,7 Elizabeth Sinclair,3 Joseph M. McCune,1,3 Michelle Roland,1 Kimberly Page‐Shafer,4 Priscilla Hsue,2 Brinda Emu,1 Melissa Krone,4,5 Harry Lampiris,6 Daniel Douek,7 Jeffrey N. Martin,4,5 and Steven G. Deeks1

1Positive Health Program and 2Division of Cardiology, San Francisco General Hospital, 3Division of Experimental Medicine, Department of Medicine, 4Center for AIDS Prevention Studies, 5Department of Epidemiology and Biostatistics, and 6San Francisco Veterans Administration Medical Center, University of California, San Francisco; 7Human Immunology Section, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland

Background.  Although untreated human immunodeficiency virus (HIV)–infected patients maintaining undetectable plasma HIV RNA levels (elite controllers) have high HIV‐specific immune responses, it is unclear whether they experience abnormal levels of T cell activation, potentially contributing to immunodeficiency.

Methods.  We compared percentages of activated (CD38+HLA-DR+) T cells between 30 elite controllers, 47 HIV-uninfected individuals, 187 HIV-infected individuals with undetectable viremia receiving antiretroviral therapy (antiretroviral therapy suppressed), and 66 untreated HIV-infected individuals with detectable viremia. Because mucosal translocation of bacterial products may contribute to T cell activation in HIV infection, we also measured plasma lipopolysaccharide (LPS) levels.

Results.  Although the median CD4+ cell count in controllers was 727 cells/mm3, 3 (10%) had CD4+ cell counts <350 cells/mm3 and 2 (7%) had acquired immunodeficiency syndrome. Controllers had higher CD4+ and CD8+ cell activation levels (p=<.001 for both) than HIV-negative subjects and higher CD8+ cell activation levels than the antiretroviral therapy suppressed (p=.048). In controllers, higher CD4+ and CD8+ T cell activation was associated with lower CD4+ cell counts (p=.009 and p=.047). Controllers had higher LPS levels than HIV-negative subjects (p=<.001), and in controllers higher LPS level was associated with higher CD8+ T cell activation (p=.039).

Conclusion.  HIV controllers have abnormally high T cell activation levels, which may contribute to progressive CD4+ T cell loss even without measurable viremia.

Comments

[Ian]

Potentially very relevant to the recent adenovirus vaccine/enhancement of disease phenomenon, right?

[Richard Jefferys]

I think very possibly, particularly given some recent evidence that Ad5 vectors may persist longer than had been thought. My understanding is that Juliana McElrath's group is undertaking a detailed investigation of this possibility. A big part of the conundrum with immune activation seems to be separating the good from the bad; controllers also typically have HIV-specific memory T cell responses (and are enriched for certain HLA types, particularly B*57, which is associated not just with viral control but better clinical outcomes) and so the activation of some HIV-specific T cell responses is presumably good. But perhaps being exposed before a memory response has rested down is bad? Or if the particular vaccine vector also potently activates pre-existing vector-specific CD4 T cell responses, then an activation-related impact on susceptibility seems distinctly possible.

[Ian]

enriched for certain HLA types, particularly B*57, which is associated not just with viral control but better clinical outcomes

Although note the recent study that hinted the resistance associated with B57 may actually be linked to an endogenous retrovirus linked to the allele:
"A Whole-Genome Association Study of Major Determinants for Host Control of HIV-1" (DOI: 10.1126/science.1143767) (I talked about it at www.iayork.com/MysteryRays/2007/08/20/, a while ago.)

[Richard Jefferys]

Bit late catching up with this, I think that the possibility is interesting, there's been a lot of intriguing information about HERVs appearing recently. The New Yorker just published a long article by Michael Specter which is now available online:

http://www.newyorker.com/reporting/2007/12/03/071203fa_fact_specter