Early in 1995 several scientists, including Dr David Ho, published work which changed previous ideas about the turnover of HIV replication and the replacement of CD4 T-cells by the body. The studies indicated that the time it takes for 50% of the virus in the body to enter a CD4 T-cell, replicate and spread to a new CD4 T-cell - the half-life - was about 1.2 days, of which about 0.9 days were spent inside a CD4 T-cell and 0.3 days outside CD4 T-cells. However, more recent research from estimated that HIV has a half-life of between 28 and 110 minutes. This means that HIV is cleared from the blood ten times faster than previously estimated and about half of the HIV particles in the blood die and are replaced by new virus particles every hour.

Based on data from four individuals, the research team estimated that between 2000 and 15,900 million new virus particles are produced and released into the blood every day. More than 99% of all HIV is produced from newly infected CD4 T-cells, while the remainder is from macrophages. Consequently, billions of CD4 T-cells are killed and replaced every day. If these cells were not replaced they would all be killed within several weeks.

These measurements can be interpreted along with evidence that large amounts of HIV replication and CD4 T-cell death take place in lymph nodes to indicate that an extraordinary battle between HIV and the immune system takes place with an very high capacity for lost CD4 T-cells to be replaced. Eventually, however, the immune system becomes exhausted, and is unable to match the rate at which new virus is produced and destroys CD4 T-cells.

Further investigation of the capacity for CD4 T-cell renewal has suggested that HIV causes an increased rate of CD4 T-cell proliferation and death. When antiretroviral therapy is administered, the rate of CD4 T-cell death is reduced, leading to an increase in the number of CD4 T-cells (Kovacs 2001; Mohri 2001).

Counter-arguments

The model above has been questioned by Dutch and American researchers who argue that the gradual decrease in CD4 T-cells is in part a consequence of the increased trapping of CD4 T-cells in the lymph nodes as viral infection in these sites worsens over time. This trend has been observed in macaques infected with simian immunodeficiency virus (Schenkel 1999).

The rapid rise in CD4 cell counts in the weeks after beginning potent antiretroviral therapy is a consequence of the shut-down of virus replication in the lymph nodes, and the redistribution of CD4 T-cells back into circulation. CD4 T-cell renewal could also be affected by damage to the bone marrow by destruction of precursor cell production capacity by HIV, or by a direct effect of antiretroviral drugs, by interference with CD4 T-cell production in the thymus, or by interference with cell cycling and signaling.

In early 1999 a team of researchers published a paper opposing David Ho's work on HIV and T-cell dynamics. Using their own technique for labelling immune cells, they studied the half-life and production rates of CD4 and CD8 T-cells in nine uninfected people, seven untreated HIV-positive people, and five HIV-positive people who had undergone twelve weeks of antiretroviral therapy. In the untreated HIV-positive group, the half-life of each T-cell sub-population was found to be less than a third of that of the seronegative controls.

Contrary to Ho's proposed model, the Californian researchers found that this reduced cell lifespan was not compensated for by increased cell production. Following viral suppression after twelve weeks of HIV therapy, they found a considerable increase in circulating CD4 and CD8 T-cells, but for CD4 T-cells this was due to greater production rather than a longer half-life. The authors concluded that the loss of CD4 T-cells that typically occurs in the course of HIV infection is not due to the exhaustion which follows a sustained over-production of cells, but instead to a shortened survival time and to a failure to increase the production of new CD4 T-cells (Hellerstein 1999a).

This group updated their findings in June 1999 with data comparing CD4 T-cell survival time after twelve weeks and 18 months of antiretroviral therapy. They found that after 18 months of successful viral suppression, CD4 T-cell survival times had increased until they were almost equal to those seen in a healthy uninfected control group, from 14 to 78 days. Production was elevated above normal levels during the first months of therapy but returned to normal or below average after 18 months (Hellerstein 1999b).

Complementing these findings, Professor Frank Miedema of Amsterdam University has proposed that the key mechanism leading to loss of CD4 T-cells is interference with the production of T-cell progenitors. These are produced in the bone marrow and migrate to the thymus where they are transformed into mature T-cells. In long-term non-progressors, Miedema has found that progenitor production is unchanged after six years of infection, whereas production declines in those with disease progression. Antiretroviral therapy improves T-cell progenitor production and the improvement in naive CD4 T-cell reconstitution seen on HIV therapy is correlated to the degree of improvement in progenitor production (Miedema 1998; Nielsen 1998).

Another indicator that progenitor cell production is impaired during untreated HIV infection is the observation that lymphocyte counts, white blood cell counts, neutrophil and platelet counts all increase at the same time, and at a similar rate to CD4 cell counts after commencing antiretroviral therapy (McCune).

Another theory, proposed by Haynes Sheppard, is that CD4 T-cell depletion in HIV disease is a consequence of a confused immune system. According to Sheppard's model, the immune system mistakes HIV virions for CD4 T-cells because HIV is able to mimic the CD4 receptor, and so decreases the rate of CD4 T-cell replacement in order to maintain a stable number of CD4 cells. However, this model assumes a substantial increase in viral load over time, a trend questioned by the findings of the Royal Free Hospital Haemophiliac Cohort. This study found that most people followed had viral load changes of less than 1 log₁₀ over 10 years (Sabin 1998).

Other researchers have also found that there is little difference in CD4 T-cell turnover between HIV-negative and HIV-positive asymptomatic individuals. However, CD8 T-cells cells do turn over faster in HIV-positive people. There is also evidence from a number of different studies that CD8 T-cells migrate from the lymphoid tissue in response to antiretroviral therapy, and that antiretroviral therapy stimulates proliferation of CD4 and CD8 T-cells even in the absence of HIV infection.

References

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