CD4 T cells specific for different pathogens vary in susceptibility to HIV infection

Richard Jefferys, TAG

When it comes to susceptibility to HIV infection, not all CD4 T cells are created equal.

There are a variety of factors that have been shown to influence how readily HIV gains entry and replicates, with the best-described distinction being between activated CD4 T cells, which are highly susceptible, and resting CD4 T cells, which are relatively resistant. The particular types of cytokines and chemokines that a CD4 T-cell makes have also been shown to influence the efficiency of HIV infection.

Less well understood is the influence of antigen specificity – the pathogen being targeted by the CD4 T cell. Evidence has been published showing that TB-specific CD4 T cells are highly susceptible [1], whereas those responding to the viral infection CMV are relatively resistant [2] (with this resistance being associated with the release of beta-chemokines capable of binding the CCR5 receptor and blocking HIV entry). A study by Haitao Hu and colleagues from the US Military HIV Research Program has now explored this issue further by looking at the susceptibility of various pathogen-specific CD4 T cells and the relationship with the genes that the different cells express. [3]

The results confirm that CMV-specific CD4 T cells are highly resistant to HIV, but not just due to release of beta-chemokines: gene expression analyses revealed that the cells also upregulate several innate antiviral factors such as IFIT1 (a protein that recognises a particular form of viral RNA). Because of these factors, CMV-specific CD4 T cells displayed reduced susceptibility to HIV infection even when the researchers used antibodies to neutralise any effect of beta-chemokines. In contrast, CD4 T cells specific for Tetanus Toxoid (TT) and Candida exhibited a pro-inflammatory Th17-type profile and were highly permissive to HIV infection. The researchers suggest that these differences in susceptibility may contribute to the well-documented relationship between differing levels of immune deficiency and risk of specific opportunistic infections; i.e. candidiasis is typically an early sign of immune deficiency whereas active CMV disease almost exclusively occurs at extremely low CD4 T cell levels.

Another important implication of the study is that HIV vaccines should aim to induce HIV-specific CD4 T cells with a profile that resembles CMV-specific responses. The researchers speculate that there may be a connection between their observations and the fact that the best results obtained to date in the stringent SIV/macaque model of vaccination have involved a CMV-based vaccine vector. [4]

Several research groups – including those of Louis Picker at the Oregon Health & Science University and Rafick-Pierre Sekaly at the Vaccine & Gene Therapy Institute in Florida – are now working to develop CMV-based HIV vaccine vectors with the aim of conducting human studies in both the therapeutic and preventive contexts.


TAG Web Blog. CD4 T cells specific for different pathogens vary in susceptibility to HIV infection. TAG web Blog. (6 February 2013).


  1. Geldmacher C et al. Preferential infection and depletion of Mycobacterium tuberculosis–specific CD4 T cells after HIV-1 infection. J Exp Med. 2010, December 20; 207(13): 2869–2881. doi: 10.1084/jem.20100090.
  2. Casazza JP et al. Autocrine production of Beta-chemokines protects CMV-specific CD4+ T cells from HIV infection. PLoS Pathog. 30 October 2009; 5(10): e1000646. doi: 10.1371/journal.ppat.1000646.
  3. Hu H et al. Distinct gene expression profiles associated with the susceptibility of pathogen-specific CD4 T cells to HIV-1 infection. Blood, Early online 20 December 2012, doi: 10.1182/blood-2012-07-446278.
  4. Hansen SG. Profound early control of highly pathogenic SIV by an effector-memory T cell vaccine. Nature. 2011 May 26; 473(7348): 523–527. Published online 2011 May 11. doi: 10.1038/nature10003.

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