Viral load is a poor predictor of CD4 decline at the individual level
Richard Jefferys, Treatment Action Group
One of the more notorious quotes in the history of HIV research came from David Ho at an International AIDS Conference in 1994. During a presentation on the factors driving HIV pathogenesis, Ho put up a slide with the line its the virus, stupid! A study published in the journal Science in 1996 showing that viral load levels are a strong predictor of disease progression further solidified the view that there is a very direct connection between viral replication (as inferred by counting copies of HIVs genetic material using viral load assays) and the development of immunodeficiency. 
However, a number researchers – particularly the late Janis Giorgi from UCLA – continued to investigate the effects of HIV on the immune system and published papers showing that the degree of immune activation associated with HIV infection is also a very strong predictor of immune system decline.  Over recent years, researchers focused on studying HIV pathogenesis have reached a consensus that Giorgi was on the right track; the accumulated evidence strongly suggests that immune activation is a (perhaps the) major driver of HIV pathogenesis.
On Sept 27, a new study was published in JAMA that offers additional support for this viewpoint. The authors, led by Benigno Rodriguez from Mike Ledermans immunology research group at Case Western Reserve in Cleveland, looked at the ability of viral load measurements to predict future CD4 declines in individuals with HIV infection (the data were obtained from three large cohorts over a 12 year period). 
The researchers first confirmed that, on average, people with higher viral loads lose CD4 T cells from the peripheral blood faster than people with lower viral loads. For example, people with viral loads less than 500 copies/mL had an average loss of CD4 cells of -20 cells/mm3 per year whereas those with viral loads over 40,000 copies/mL had an average loss of -78 cells/mm3 a year). These data were completely consistent with the Science study from 1996.
However, the researchers also conducted a complex statistical analysis to try and unearth how much of an individuals CD4 T cell decline over a six month period could be accounted for by their initial viral load measurement. This analysis showed that only 5-6% of the inter-individual variation in CD4 T cell decline could be explained by the initial viral load level. So while it held true that higher viral loads are associated with faster CD4 decline and vice versa, the data showed that you cannot use the viral load to accurately predict the actual specific number of CD4 T cells that will be lost from the peripheral blood in a given individual over a six month period.
In the discussion section of the JAMA paper, the authors note that immune activation may be a key factor explaining the observed variation in CD4 T cell decline between individuals. As a hypothetical example, if two individuals have the same viral load but one loses CD4 T cells faster (as the JAMA study suggests can often happen), its possible that differences in the levels of immune activation would explain – at least in part – the divergent outcomes. This would be consistent with previous studies that have reported stronger associations between immune activation and disease progression than those seen between viral load levels and disease progression. There are also a number of complex factors that might impact how much immune activation occurs in the setting of HIV infection (e.g. co-infections, the functionality of the HIV-specific memory T cell response, the genetic make-up – particularly the HLA genes – of the individual, antigen-presenting cell function & turnover, the genetic make-up of the virus, etc.). There may also be additional factors that have yet to be uncovered. The authors close their discussion by noting:
In humans, the predictive value of immune activation level on HIV disease course, independent of plasma HIV RNA levels, can be demonstrated even when measured during early infection or before actual seroconversion. [5, 6] Thus, immune activation may be a major determinant of T-cell turnover and CD4 cell depletion in chronic HIV infection both in human and animal hosts. Our results provide further support for additional studies exploring the relative contribution of immune activation to the pathogenesis of immune deterioration in treatment naive, HIV-infected persons.
A couple of news articles have also reported on these findings. Erika Check profiled the immunology researchers behind the JAMA paper in Nature News and Jon Cohen wrote a piece in Science which interviewed John Mellors (author of the 1996 Science paper on viral load);  Mellors simply refuses to accept that that the JAMA paper is accurate. David Ho offers an uninterpretable defense of his view of the primacy of viral replication. Conversely, leading immunologists note that these data fit perfectly with understanding of HIV pathogenesis that has emerged over recent years based on studies of T cell turnover and immune activation markers. Key goals for future research will include analyzing the predictive value of immune activation markers in more detail, delineating the precise mechanisms by which HIV causes immune activation and investigating whether its possible to develop novel & safe approaches to diminishing activation (potentially ameliorating its apparently harmful immunological consequences) in people with HIV.
Treatment Action Group http://tagbasicscienceproject.typepad.com
- Mellors JW, Rinaldo CR Jr, Gupta P et al. Prognosis in HIV-1 infection predicted by the quantity of virus in plasma. Science. 1996 May 24;272(5265):1167-70.
- Giorgi JV, Liu Z, Hultin LE et al. Elevated levels of CD38+ CD8+ T cells in HIV infection add to the prognostic value of low CD4+ T cell levels: results of 6 years of follow-up. The Los Angeles Center, Multicenter AIDS Cohort Study. J Acquir Immune Defic Syndr. 1993 Aug;6(8):904-12.
- Rodrguez B, Sethi AK, Cheruvu VK et al. Predictive Value of Plasma HIV RNA Level on Rate of CD4 T-Cell Decline in Untreated HIV Infection. JAMA. 2006;296:1498-1506.
- Leng Q, Borkow G, Weisman Z et al. Immune activation correlates better than HIV plasma viral load with CD4 T-cell decline during HIV infection. J AIDS. 2001 Aug 1;27(4):389-97.
- Deeks SG, Kitchen CM, Liu L et al. Immune activation set point during early HIV infection predicts subsequent CD4+ T-cell changes independent of viral load. Blood. 2004 Aug 15;104(4):942-7. Epub 2004 Apr 29.
- Hazenberg MD, Otto SA, van Benthem BH et al. Persistent immune activation in HIV-1 infection is associated with progression to AIDS. AIDS. 2003 Sep 5;17(13):1881-8.
- Cohen J. Study says HIV blood levels dont predict immune decline. Science 29 September 2006.