The possibility of a cure for HIV infection using HAART

As shown on the previous page, the combination of three drugs including a protease inhibitor can reduce the number of HIV particles to below detectable levels. This gave hope that, if HIV were not replicating in infected cells and therefore no more cells became infected, the infection might die out as the chronically-infected CD4+ T cells and macrophages turned over. In the blood, infected cells seemed to have a half life of about two weeks which would mean that all of these cells would disappear within 3 to 4 years provided that no further rounds of virus replication and infection occurred. Provided that the patient adhered strictly to the HAART regimen, this would seem to be achievable with the triple drug therapy.

However, it soon became clear that the infected short half life cells in the circulation were not the only ones in the body and other cells remained infected for much longer. Latently infected CD4+ T cells have been shown in patients that have exhibited long periods of undetectable virus in the bloodstream. It has now been shown (Finzi et al. Nat Med 5:512, 1999 and Zhang et al NEJM 1999) that these latently infected cells have a half life of 6 to 44 months and, moreover, there is a low persistent level of viral replication in patients treated with the HAART regimen. 

Memory CD4+ T cells were found to be infected at a rate of 0.1 to 1 per million and this population of cells showed an extremely slow rate of decay. The half life of these cells was calculated at 43.9 months and it was concluded that current therapy is very unlikely to have a significant effect on this cell population. In situ hybridization of lymphoid tissue of a patient with HIV levels of below 50 copies per ml blood showed scattered infected cells. Evolution of the sequence of the surface protein was also shown, demonstrating that in these cells there is actual replication even when there is no detectable virus in the blood. The conclusion was reached that it would take from 10 to 60 years to eliminate HIV from the infected patient even assuming that HAART was effective a prohibiting infection of new cells.

How can this be overcome? Clearly, it is necessary to eliminate both those few cells that are replicating virus in the HAART-treated patients and those that are latently infected and are harboring provirus but not making viral proteins; the latter are the chronically-infected unactivated memory T cells. Natural turnover of these cells is not sufficient for purging the infected patient of virus but perhaps the virus could be turned on to replicate so that either it destroyed its host cell or the expressed proteins led to immune destruction of the infected cell. This would have to occur while blocking infection of new cells. Perhaps this could be done by using the cytokine, interleukin-2, to induce the chronically-infected cells to express virus at the same time as strengthening the immune respose to viral antigens. The immune response could also be strengthened using a vaccine or brief interruption of the anti-viral treatment.