More on the links between the CD4/CD8 ratio, immunological perturbations, and risk of illness and death

Richard Jefferys, TAG

Since the review in the last issue of HTB of studies investigating the relevance of the CD4/CD8 ratio in the antiretroviral therapy era, [1] several new papers and presentations have provided more information on the topic.

In the open access journal PLoS Pathogens, Sergio Serrano-Villar and colleagues reported evidence that a low CD4/CD8 ratio (less than or equal to 0.4) – despite CD4 T cell recovery to a count above 500 on ART – is associated with low naïve CD8 T cells, elevated levels of activated and senescent CD8 T cells, increased innate immune activation, and a greater risk of non-AIDS events. [2]

After controlling for age, gender, ART duration and both nadir and proximal CD4 count, each 10% decrease in the CD4/CD8 ratio was associated with 48% higher odds of serious non-AIDS events.

In a separate cohort that started ART with advanced disease, a significant correlation between the CD4/CD8 ratio and the risk of mortality was documented. In this analysis, the researchers report that for each 10% increase in the CD4/CD8 ratio on ART there was a 15% decrease in the risk of death. Individuals initiating ART earlier in the course of HIV infection exhibited greater and more rapid improvements in the CD4/CD8 ratio compared to those starting late.

A poster at CROI 2014 presented similar findings. Cristina Mussini and colleagues assessed whether the CD4/CD8 ratio predicted clinical progression in the Icona cohort in Italy. The CD4/CD8 ratio was a significant predictor of the risk of serious non-AIDS events and death, independent of CD4 T cell counts. Normalization of the CD4/CD8 ratio (to greater than or equal to 1) only occurred in a minority of participants, and was more common among younger individuals, those with higher CD4/CD8 ratios at ART initiation, and those starting ART in more recent periods at higher CD4 T cell counts. [3]

Another poster at CROI from Talia Sainz et al described the role of CMV infection in lowering CD4/CD8 ratios in HIV-positive people, as is also known to occur in the HIV negative elderly. [4]

Lastly, a recent paper in PLoS One published by Willard Tinago and colleagues from the laboratory of Paddy Mallon in Dublin looked at the links between the CD4/CD8 ratio and other immunological perturbations, with results that appear consistent with those reported by Sergio Serrano-Villar’s group. [5]

The discussion section of the Serrano-Villar paper notes that the data imply that the CD4/CD8 ratio could be useful for monitoring responses to therapies that aim to reduce residual immune activation.

Additionally, HIV positive individuals on suppressive ART who do not experience an increase in the CD4/CD8 ratio “might benefit from screening programmes or aggressive management of concomitant risk factors for ageing-associated disease.”


TAG Basic Science Blog. Update published on the first Berlin patient. (21 May 2014).


  1. Jefferys R. The relevance of the CD4/CD8 ratio in the ART era. HIV Treatment Bulletin (HTB) March/April 2014.
  2. Serrano-Villar S et al. HIV-infected individuals with low CD4/CD8 ratio despite effective antiretroviral therapy exhibit altered T cell subsets, heightened CD8+ T cell activation, and increased risk of non-AIDS morbidity and mortality.PLoS Pathog. 2014 May 15;10(5):e1004078. doi: 10.1371/journal.ppat.1004078.
  3. Mussini C et al. Incidence of CD4/CD8 ratio normalization and its role in the onset of non-AIDS-related events. Conference on Retroviruses and Opportunistic Infections, March 3-6 2014, Boston, MA CROI 2014. Poster abstract 753. (PDF)
  4. Sainz T et al. CMV and HIV: A Double Hit On the CD4/CD8 Ratio. Conference on Retroviruses and Opportunistic Infections, March 3-6 2014, Boston, MA CROI 2014. Postar abstract 243. (PDF)
  5. Tinago W et al. Clinical, immunological and treatment-related factors associated with normalised CD4+/CD8+ T-cell ratio: effect of naïve and memory T-cell subsets. PLoS One. 2014 May 9;9(5):e97011. doi: 10.1371/journal.pone.0097011.

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