The AIDS Beacon™

In a recent study published by Nature Medicine, researchers have found that reservoirs of HIV are found primarily in two types of T-cells and that T cell survival and proliferation allow these reservoirs to persist.

In latently infected CD4 cells (white blood cells) the HIV virus is present, but is not actively producing more viruses. Once a virus initially penetrates a CD4 cell, it will begin replicating and subsequently disperse the duplicates to other CD4 cells, thereby spreading the infection. As HIV attacks these cells, infected individuals will generally see their CD4 cell count drop, meaning that they will be less successful in fighting other infections or diseases in the future.

In latent cells, HIV does not continue the process of replication, but rather remains dormant. Presently, antiretroviral drugs do not target reservoirs that consist of latently infected CD4 cells. This prevents complete elimination of the HIV virus. The results of this study, however, indicate that HIV can potentially be eliminated by targeting T cells.

According to the study, HIV reservoirs are primarily found in special types of CD4 cells called TCM (central memory) and TTM (transitional memory) cells.

Researchers found that individuals with low CD4 cell counts had higher levels of T-cell proliferation (replication) and a larger HIV reservoir, primarily in TTM cells. In contrast, individuals with high CD4 cell counts had lower levels of cellular proliferation and a smaller HIV reservoir, mostly located in TCM cells. The larger size of the reservoirs in patients with low CD4 counts means greater difficulty in completely eliminating the HIV virus.

Additionally, results from the study suggest that T cell proliferation is responsible for sustaining the reservoir of latent HIV. Researchers found two different types of T cell proliferation, depending on CD4 count. Patients with low CD4 cell counts had high levels of TTM cell proliferation; in contrast, patients with high CD4 counts had small but steady levels of TCM cell replication. In both cases, this resulted in a stable HIV reservoir that was conserved over time, although the higher rate of proliferation with low CD4 counts led to a larger overall reservoir size.

The indication that this reservoir is maintained by T cell proliferation suggests that researchers could focus on preventing TTM and TCM cell replication as a means of eliminating these reservoirs.

Interestingly, individuals receiving highly active antiretroviral therapy (HAART) that had high CD4 counts, where the reservoir was primarily in TCM cells, showed a small decrease in these TCM reservoirs over time. This suggests that early, aggressive antiviral therapy, when patients still have high CD4 counts, could help limit the establishment of HIV reservoirs.

However, the study also confirms that active production of virus particles is not necessary to maintain a latent HIV infection, since viral DNA can be passed down by replicating T-cells even without new viruses being formed. This means complete elimination of the virus is impossible using only antiretrovirals, without also targeting the infected and proliferating T-cells containing HIV reservoirs.

Although high CD4 counts are desirable, the proliferation of these cells can lead to more reservoirs. Future drug development, therefore, will need to focus on eliminating the HIV reservoirs without significantly diminishing a patient’s CD4 cell count.

Previous studies have focused on other types of immune cells as sources of HIV. According to a study published by PLoS One, immune cells called macrophages can also serve as reservoirs of HIV and can cause tissue damage in patients who are HIV positive (related Beacon news). Both studies support targeting infected immune cells, rather than just the AIDS virus, to fully eliminate HIV.

For more information, please see the study in Nature Medicine (abstract).