Immune activation correlates with CD4 T cell declines in HIV controllers

Richard Jefferys, TAG

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”). [1]

It has been reported previously that maintenance of a low viral load does not confer absolute protection against disease progression; [2] 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. [3]

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). [4]

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 immunised individuals.

Source: TAG Basic Science Blog (05 Dec 2007)


  1. Hunt PW, Brenchley J, Sinclair E et al. 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. JID 2008;197:000–000. DOI: 10.1086/524143 
  2. Greenough TC et al. Declining CD4 T-cell counts in a person infected with nef-deleted HIV-1. NEJM 1999 Jan 21;340(3):236-7. 
  3. Sousa A et al. CD4 T Cell Depletion Is Linked Directly to Immune Activation in the Pathogenesis of HIV-1 and HIV-2 but Only Indirectly to the Viral Load. Journal of Immunology, 2002, 169: 3400-3406. 
  4. Leaking Bacteria & HIV Pathogenesis.

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