CD8 T-cells only kill a fifth of the HIV-infected CD4 T-cells

CD8 T-cells may be responsible for only a fifth of the death of CD4 T-cells infected with HIV, according to a mathematical modelling study published on 14^th March in the freely available online journal, PLoS Biology. This may have implications for the design of vaccines for the prevention and treatment of HIV infection.

CD8 T-cells or ‘cytotoxic T-lymphocytes’ are white blood cells that find and kill infected cells in the body. Until now, experts have believed that these cells are responsible for most of the death of CD4 T-cells that are infected with HIV, but it is difficult to measure their contribution accurately. Around half of the CD4 T-cells that are infected with HIV die every twelve hours, with each infected cell having a lifespan of around one day.

To estimate the contribution of CD8 T-cells more precisely, investigators developed a new mathematical model using previously published data from twelve patients with HIV.

The model revealed that CD8 T-cells kill up to ten million infected CD4 T-cells a day in a patient with HIV. However, this is equivalent to a maximum of only 20% of the death of CD4 T-cells, with other factors mediating the majority of the cell death.

“We suggest that although cytotoxic T-lymphocyte-mediated lysis plays an important role in controlling HIV-1 infection, cytotoxic T-lymphocytes may not be responsible for the majority of infected cell death,” the investigators conclude.

Since most current vaccine strategies are focusing on stimulating CD8 T-cells to clear away HIV, this result means that any vaccine-induced responses will need to be much stronger than those that occur naturally in the body.

“Unless the cytotoxic T-lymphocyte response elicited by vaccines is several-fold more efficient than the natural response, vaccines relying on the lytic pathway are unlikely to prevent infection or to mediate complete viral clearance,” they explain, "but ... they may well reduce viral load and lengthen the asymptomatic period."

When HIV infects a CD4 T-cell, its protein components are broken into small pieces that are displayed on the cell’s outer surface. These ‘epitopes’, which are attached to human leukocyte antigen (HLA) class I molecules, act as a signal to the CD8 T-cells, indicating that the cell is infected and needs to be destroyed or ‘lysed’.

HIV manages to get around this immune response by developing mutations that enable it to avoid being displayed on the cell surface. These ‘escape mutants’ are then free to replicate and can eventually become the dominant HIV strain in the body.

In this study, the investigators used data describing the rate of emergence of 21 different escape mutants from twelve HIV-infected patients, plus measures of the reduction in the virus’s ability to replicate, to calculate the rate at which the CD8 T-cells killed the infected CD4 T-cells.

They found that the rate of escape was very low, with a median of 0.01 escapes per day. Despite being from studies spanning 14 years of research, the calculations all gave similar results, with 95% of the values being below 0.1 escapes per day.

With each patient averaging between 14 and 19 CD8 T-cell responses to HIV epitopes, the researchers calculated that this was equivalent to a maximum of 20% of CD4 T-cell death being due to CD8 T-cells.

Although this value is lower than expected, it does clear up one paradox in understanding how HIV is controlled by the immune system. It is known that variations in the HLA molecules can determine how quickly an HIV-positive patient will progress to AIDS. This is the best evidence that CD8 T-cell responses are important in controlling HIV levels.

However, other studies tell us that an impaired CD8 T-cell response late in HIV disease does not seem to result in slower rates of CD4 T-cell death. This seems to contradict the evidence that CD8 T-cells are crucial in determining the speed of disease progression.

“We resolve this issue by suggesting that cytotoxic T-lymphocyte lysis is small relative to other factors contributing to cell death,” the researchers explain. “Therefore between-individual differences in cytotoxic T-lymphocyte lysis rates (e.g. with disease stage) are unlikely to be detectable by measuring total infected cell clearance rates.”

This was supported by the investigators’ observation that the rate of killing by CD8 T-cells was significantly higher in the early stages of HIV infection than in ‘chronic infection’, when the viral load had reached a steady level (p = 0.004).

“As we have shown, these small differences can be detected if the death rate attributable to cytotoxic T-lymphocytes is measured directly,” they write.

The investigators do not suggest what is responsible for the remainder of the death of infected CD4 T-cells, although this could include antibody-mediated mechanisms. However, the investigators do point out that their model only takes into account the direct cell-killing properties of CD8 T-cells and not their secretion of virus-killing factors into the blood.

“Our study of the role of cytotoxic T-lymphocytes therefore only relates to cytotoxic T-lymphocyte killing and will not encompass cytotoxic T-lymphocyte secretion of anti-viral factors which may be of considerable significance,” they explain.