Test tube study shows how resting CD4 T-cells avoid infection with HIV

A team of scientists has discovered how resting, inactive CD4 T-cells avoid infection with HIV. Their discovery, reported on 13^th April in the online version of Nature, could pave the way for new strategies to control the spread of HIV through the body.

CD4 T-cells, the main target for HIV, exist in two forms. Active, dividing CD4 T-cells are susceptible to infection with HIV. In contrast, the resting, inactive CD4 T-cells that form around 95% of the total CD4 population are highly resistant to infection with the virus, .

Investigators from San Francisco wished to determine whether the resistance of the resting cells to infection was due to the lack of a key factor necessary for infection, or the presence of an efficient mechanism for defence against the virus. Their study, carried out in cell culture, revealed that the activity of a potent antiviral factor called APOBEC3G is the key to these cells’ resistance to infection.

“Until now, the prevailing belief has been that HIV failed to infect resting T-cells due to a simple lack of some essential factor or nutrient,” said the lead investigator. “This study now shifts the paradigm, showing that resting CD4 T-cells actively repel HIV infection through the action of the small, enzymatically active form of APOBEC3G, which stops the virus in its tracks.”

The research team found that APOBEC3G exists in two forms: a large, inactive form, and a smaller, active form. In resting T-cells, the inactive form is predominant. However, in active CD4 T-cells, APOBEC3G is found in the smaller, active form that binds to and mutates HIV’s genetic material.

By blocking the production of the small, inactive form of APOBEC3G using small interfering RNA (siRNA), they managed to make resting CD4 T-cells susceptible to HIV infection, confirming the importance of this enzyme in resistance to infection.

They also found that stimulation of resting CD4 T-cells with cytokines, which converts them to active cells, caused APOBEC3G to be converted into the large, inactive form. This reduced the enzyme’s anti-HIV activity, allowing them to be infected with the virus.

The investigators speculate that their findings could be translated into future treatments for HIV. By preventing the conversion of APOBEC3G into the large, inactive form, drugs could help active CD4 T-cells to repel HIV infection.

An alternative approach would be to create therapies that release the small form of APOBEC3G from the larger complex. However, both strategies would need to be thoroughly investigated to ensure that affecting the activity of APOBEC3G does not produce any deleterious effects, such as early death of the cells or creation of mutations in the human cells’ DNA.

“The possibility of exploiting the natural and potent antiviral properties of APOBEC3G to control HIV infection is very exciting,” they said. “We have learned a great deal from our studies of how the resting CD4 T-cell resists HIV. Now, the challenge is for scientists … to translate these basic discoveries into novel treatments that could benefit HIV-infected patients around the world.”

The action of APOBEC3G was discovered around four years ago. It was previously believed only to have anti-HIV activity when it managed to get into new HIV particles. However, this study shows that it acts within the human cell itself to prevent HIV replication in resting CD4 T-cells.

However, when they examined the HIV's genetic material (RNA) found in the resting CD4 T-cells, the investigators found unexpectedly low levels of ‘hypermutated’ RNA. This suggested that APOBEC3G may not only work by mutating HIV’s RNA, as previously thought. They speculate that it may also act by binding to the RNA, preventing it from gaining access to the reverse transcriptase enzyme.

The enzyme Vif, which is produced by HIV, can counteract the antiviral effects of APOBEC3G, by instructing the cell to destroy APOBEC3G and to reduce its production. However, Vif is ineffective in resting CD4 T-cells as there is little Vif in incoming HIV particles and the virus cannot progress far enough through its life cycle to make new copies of the enzyme.