A long-term latent reservoir for HIV-1: discovery and clinical implications

Despite the remarkable success of highly active antiretroviral therapy (HAART) for the treatment of HIV-1 infection, it now appears that the infection is intrinsically incurable with antiretroviral therapy alone. The major reason is that the virus can persist in a latent form in resting memory CD4 cells. These cells arise when infected CD4+ lymphoblasts carrying an integrated copy of the HIV-1 genome revert back to a resting memory state. In this resting state, CD4 cells are minimally permissive for virus gene expression, and infected memory cells can survive for many years. Following re-exposure to the relevant antigen or other activating stimuli, these cells can begin to produce virus again. The existence of a stable reservoir has altered treatment strategies in several ways. HAART is no longer given with the goal of eradication. In addition, the reservoir serves as a permanent archive for wild-type virus and for drug-resistant variants that arise during treatment. Thus, once resistance to a particular drug arises, the patient will always carry that resistance. Interruption in treatment results in the re-emergence of the original wild-type virus, which often replicates better than drug-resistant virus. Although HAART cannot eradicate the infection, current regimens do come close to stopping virus evolution. Free viruses found in the plasma at low levels in patients on HAART resemble viruses in the latent reservoir and do not contain new drug resistance mutations. Thus although HAART cannot produce eradication, lifetime control of the infection with antiretroviral drugs may be possible.