nitiation of antiretroviral therapy is often associated with a reduced size of the HIV reservoir.

HIV reservoir size and persistence are driven by T cell survival and homeostatic proliferation. Nat Med. 2009;15:893-900.

HIV persists in a reservoir of latently infected CD4(+) T cells in individuals treated with highly active antiretroviral therapy (HAART). Here Chomont and colleagues identify central memory (T(CM)) and transitional memory (T(TM)) CD4(+) T cells as the major cellular reservoirs for HIV and find that viral persistence is ensured by two different mechanisms. HIV primarily persists in T(CM) cells in subjects showing reconstitution of the CD4(+) compartment upon HAART. This T-cell central memory reservoir is maintained through T cell survival and low-level antigen-driven proliferation and is slowly depleted with time. In contrast, proviral DNA is preferentially detected in transitional memory t-cells from aviremic individuals with low CD4(+) counts and higher amounts of interleukin-7-mediated homeostatic proliferation, a mechanism that ensures the persistence of these cells. The authors conclude that their results suggest that viral eradication might be achieved through the combined use of strategic interventions targeting viral replication and, as in cancer, drugs that interfere with the self renewal and persistence of proliferating memory T cells.

initiation of antiretroviral therapy is often associated with a reduced size of the HIV reservoir.

Conversely, CD4 T-cell depletion associated with high levels of immune activation and increased proliferation tends to increase the size of the reservoir. The mechanisms underlying this have perplexed basic scientists for years. Chomont and colleagues have shed light on this by showing that there are two distinct HIV reservoirs. One is a long-lasting genetically stable reservoir found in immune responders to antiretroviral therapy that decays slowly and is regulated by antigen-driven proliferation. The second reservoir is genetically variable, predominates in people with low CD4 counts and persistent immune activation, and is regulated by homeostatic proliferation. The size of this second reservoir is reduced in individuals treated early in infection, supporting the concept of early initiation of antiretroviral treatment. The findings suggest that, beyond antiretroviral treatment, eradication of HIV in people with undetectable viral loads will require new therapies that target pathways downstream of proliferation such as those developed for treatment of leukaemia and cancer.