Eliminating viral reservoirs key to curing HIV

A cure for HIV infection will require identifying and eliminating reservoirs of silent HIV in the body, in addition to using highly active antiretroviral therapy to stop viral replication.

“It’s 11 years since the introduction of HAART”. The dramatic reductions in viremia seen in patients on HAART initially (fueled) hopes that the infection could be cured with 2-3 years of continuous treatment. But to date, not a single patient has been cured as said in a plenary session at the International AIDS Conference.

Typically, when patients begin antiretroviral therapy, they experience a sharp drop in plasma HIV viral load, below the limits of detection of clinical assays, because the infected cells that produce most of the virus are short lived and the therapy stops new cells from becoming infected.

However, more sensitive assays show that instead of continued reduction of viral load with eventual cure, patients still have a very low level viremia because of the “unique mechanism of viral persistence that exploits the fundamental physiology of CD4-positive T cells.

In particular, HIV occasionally infects and replicates in activated T cells that revert to a resting state in which they can survive for decades. “This gives you a stably integrated form of the viral genome in a long-lived memory T cell,” and in addition, the cell undergo molecular changes during the reversion that turn off HIV viral gene expression, as per a professor of medicine at John Hopkins University, Baltimore.

This is almost a perfect recipe for persistence because it allows the virus essentially to persist just as information, and in this form, it is unaffected by immune responses and antiretroviral drugs.

However, if these cells become activated again, as some of them likely do everyday, viral replication will resume.

Research data show that all HIV-infected patients who were tested had these latently infected, resting CD4 cells, the longevity of which has been confirmed. The number of these cells decrease extremely slowly in patients who are on antiretroviral therapy and who have had viral levels below the clinical limits of detection for years. At this rate of decay, it would take over 70 years to clear this reservoir.

There are two main hypotheses on the persistent, very low level of viremia seen in HAART patients who have clinically undetectable viral levels.

One scenario is that viral replication continues despite the therapy. That would be of concern, because it would enable viral evolution leading to resistance and eventual treatment failure.

Another hypothesis is that antiretroviral therapy stops ongoing viral replication, and the residual viremia that patients experience is a reflection of the release of virus from stable reservoirs — that is, cells that were infected before the therapy was initiated, such as those long-lived memory T cells.

The second hypothesis has a number of testable predictions. First, the virus in the blood should genetically resemble that in the reservoir. Indeed, phylogenetic testing supports this prediction, showing that at least some of the circulating virus in such patients is similar and even identical to that in the resting cells.

Second, the residual viremia should not be accompanied by evolution (that is, change in the viral genome), which requires replications. Here, too, phylogenetic testing shows no evidence of the emergence of evolution in the form of new resistance mutations in the residual virus.

Third, and most important, is that intensifying HAART by adding another drug should not reduce the residual viremia, because there is no ongoing replication to inhibit. Intensification studies have found no additional reduction in viral load.

We cannot exclude a small contribution from ongoing replication, but it is clear at this point that the major problem is the release of virus from stable reservoirs.

To identify these reservoirs, colleagues have been focusing on the residual virus in the plasma released from the reservoirs. In about half of the patients in the study, this viral population is dominated by just a few viral clones, which suggests that there is a common source. However, the researchers have not been able to identify the clones in the resting CD4 cells, suggesting that there is another source.

Our current hypothesis is that this represents the rare infection of a stem cell or progenitor cell, and that this cell can divide after infection. The idea is that there is a second major source of residual viremia, perhaps in a cell that has some capacity for self-renewal. It is certainly a disturbing (idea) and will require much further research.