Reduced HIV replication in CD4 T cells from elite controllers
Richard Jefferys, TAG
A number of studies have investigated whether control of HIV replication in the absence of treatment (referred to as elite control if viral load is <50 copies/mL and viraemic control if <2,000) is associated with having CD4 T cells that are intrinsically resistant to infection. Results to date have shown that elite and viraemic controllers have CD4 T cells that support viral replication just as well as those sampled from individuals with progressive disease. However, Mathias Lichterfelds laboratory at the Ragon Institute of Massachussetts General Hospital wondered if perhaps the typical conditions for measuring HIV replication in CD4 T cells in the lab – which involve the use of strong activation stimuli such as PHA – were masking subtler differences. They now report on their exploration of this possibility in the Journal of Clinical Investigation. 
The study finds that CD4 T cells from elite controllers resist HIV infection and viral replication significantly better than those from individuals with progressing disease and HIV-negative controls. The same is true for viraemic controllers, but in their case the differences are smaller. The pattern remains consistent using a variety of different approaches for measuring HIV infection and replication in vitro, and holds for both R5- and X4-tropic HIV isolates. The researchers, led jointly by Huabiao Chen, Chun Li, Jinghe Huang, and Thai Cung from the lab, go on to uncover that increased expression of a host cell protein called p21 in CD4 T cells from controllers correlates with reduced susceptibility to HIV. This is further confirmed by experiments showing that inhibition of p21 expression using a short interfering RNA substantially abrogates the apparent protective effect. In terms of the causative pathway, the researchers offer evidence that p21 blocks another host cell protein, cyclin-dependent kinase 9 (CDK9), which according to prior studies plays an important role in HIV transcription.
The discussion section of the paper points out that p21 expression has previously been connected to inhibition of HIV in macrophages and hematopoietic stem cells. The authors speculate that the reduced susceptibility of controller CD4 T cells synergises with other reported mechanisms of immunological control, noting specifically that a highly functional CD8+ T cell response against HIV-1 may only develop in the setting of a CD4+ T cell compartment that is less capable of supporting highly replicative HIV-1 infection. Broadly similar findings were also reported at the recent CROI conference in a poster by an independent group at the Institut Pasteur in France.
The discovery of p21s role in controllers may open new avenues for inhibiting HIV by targeting its interactions with host cell proteins. It also provides encouragement for strategies aiming to induce CD4 T cell resistance to the virus (such as the CCR5-deletion approach being developed by Sangamo Biosciences), because it implies that these cells would then be better able to support the function of CD8 T cells and possibly other components of the immune response against HIV.
Source: TAB Basic Science Blog. (22 Mar 2011).
- Chen H et al. CD4+ T cells from elite controllers resist HIV-1 infection by selective upregulation of p21. J Clin Invest. doi:10.1172/JCI44539.
- Saez-Cirion A et al. Low cell-associated HIV-1 DNA in HIV controllers is associated with reduced cell susceptibility to HIV-1 infection. Poster abstract 294.