Tracing HIV reservoirs
Richard Jefferys, TAG
Two new papers offer differing perspectives on the reservoirs of HIV that persist despite effective antiretroviral therapy. Nicolas Chomont and colleagues demonstrate that when memory CD4 T cells containing integrated HIV proliferate (as most memory CD4 T cells do occasionally in a process known as homeostatic self-renewal), they copy the HIV provirus along with their own genomes. 
When CD4 T cell numbers decline, homeostatic proliferation occurs more frequently and Chomonts paper shows that this is associated with an increase in the number of latently infected memory CD4 T cells. The researchers describe the cells that undergo more frequent proliferation in this setting as transitional memory T cells. At earlier stages of infection when the CD4 T cell pool is relatively intact, the reservoir of infected memory CD4 T cells is found to be far smaller and integrated virus is primarily located in central memory cells that divide less frequently.
Based on these findings, the study authors suggest that anticancer drugs that interfere with memory T cell proliferation should be studied for their potential to deplete the HIV reservoir. However, given the potential toxicities associated with inhibiting T cell proliferation, the risk/benefit of such trials would need to be carefully evaluated. A more ideal therapy would be one that only targeted dividing CD4 T cells containing HIV DNA, but it is currently unclear whether such an approach is within the realm of possibility.
The second paper – by Timothy Brennan and colleagues from Bob Silicianos laboratory – uses genetic analyses of HIV sequences to show that there is a reservoir of virus that seems to be coming from a cell type other than memory CD4 T cells. 
The study finds that in most cases, the residual virus detectable in individuals on suppressive ART is genetically distinct from the virus found in memory CD4 T cells. The authors note in their conclusion: Numerous laboratories are actively pursuing various eradication strategies, most of which involve some aspect of targeting and purging the latent reservoir in resting memory CD4+ T cells. If much of the residual viremia of patients undergoing HAART comes from another reservoir or compartment as suggested here, then eradication strategies will have to include ways to target and purge this additional reservoir to be successful.
Source: TAG basic science project (24 Jun 2009).
- Chomont N et al. HIV reservoir size and persistence are driven by T cell survival and homeostatic proliferation. Nature Medicine. Published online: 21 June 2009 | doi:10.1038/nm.1972
- Brennan TP et al. Analysis of HIV-1 Viremia and Provirus in Resting CD4+ T Cells Reveals a Novel Source of Residual Viremia in Patients on Antiretroviral Therapy. JVI Accepts, published online ahead of print on 17 June 2009. J. Virol. doi:10.1128/JVI.02568-08