Higher immune system activation prior to seroconversion leads to faster CD4 T-cell loss

Patients with a history of high immune system activation before HIV infection experience faster declines in CD4 cell counts, according to a prospective cohort study of Dutch injecting drug users published in the September 24^th edition of AIDS. The study also found that high CD4 cell counts before seroconversion were associated with larger initial falls in CD4 cell count after HIV infection, confirming similar findings in a recent study of gay men.

Although higher levels of immune activation prior to HIV infection are expected to increase the speed of progression of HIV disease, it has been difficult to test this hypothesis, as stored blood samples are usually not available for patients before their HIV diagnosis. This study examined blood samples from participants of the Amsterdam Cohort Study among Drug Users, which recruits HIV-negative or asymptomatic HIV-positive drug users in the Amsterdam area. Cohort participants give a blood sample every four months, and are asked about their health and drug use. The blood samples are then tested for evidence of viral infections before being frozen and stored.

The research group examined the blood samples of the 51 injecting drug users from the cohort who became HIV positive between April 1989 and October 2002. “Access to stored serum samples from injecting drug users … have [sic] provided a unique opportunity to study how the rate of CD4 cell decline during HIV infection depends on the immune status of an individual prior to HIV infection,” state the authors.

At seroconversion, the median age of the patients was 32 years and 67% were male. Most of the patients had been injecting heroin and cocaine (55%), heroin alone (18%) or cocaine alone (18%), for a median of 9.8 years and at an average frequency of 2.2 injections a day. Each patient was followed up for a median of 6.9 years after seroconversion, until the initiation of antiretroviral therapy, an AIDS diagnosis or death.

The investigators used antibody-based staining techniques and DNA analysis to measure the following values from each patient’s last blood sample before seroconversion:

• The total number of CD4 T-cells (CD4 cell count).
• The number of ‘naïve’ CD4 T-cells, new T-cells that have not been activated by a particular ‘antigen’ (foreign substance).
• The number of 'memory' CD4 T-cells, long-lived cells that remain in the body awaiting the reappearance of their target antigen.
• The number of CD4 T-cells expressing Ki67, a marker of cells dividing at the time the blood sample was taken.
• The number of ‘CD4 T-cell receptor division circles’ (TRECs) per CD4 T-cell, a marker of the total amount of immune system activation the patient has experienced during their lifetime.

When they compared these values with CD4 cell counts after seroconversion, the investigators saw that patients with low TREC values (less than 0.029 per cell) lost CD4 T-cells at a higher rate than those with higher TREC values (p

In contrast, there was no clear relationship between Ki67 expression, which is related to the degree of immune stimulation only at the moment of when the blood sample was taken, and the rate of CD4 T-cell loss.

The investigators also found that patients with a higher CD4 cell count before seroconversion (above 896 cells/mm³) had a quicker CD4 T-cell decline in the first three months of HIV infection (p = 0.05). They argue that this is “most likely related to increased HIV replication in those with higher CD4 T cell numbers.”

However, these patients’ CD4 cell counts remained above those with lower initial CD4 cell counts throughout the follow-up period, “supporting the previous observation that high pre-seroconversion CD4 T cell counts are associated with slower progression to AIDS in homosexual men.” A similar link was seen between the number of naïve CD4 T-cells and post-infection CD4 cell counts, but there was no clear effect of the number of memory CD4 T-cells on the progression of HIV disease.

Surprisingly, the investigators found a correlation between high rates of drug injection (more than 3 times a day) prior to seroconversion and a slower decline in CD4 cell counts. However, the intensity of drug use was not linked to the level of immune activation. The authors do not offer an explanation for this unexpected observation.

The authors conclude: “The data suggest that immune status prior to HIV infection affects the course of HIV infection in a well-defined cohort of injecting drug user seroconverters and confirmed findings in homosexual men.” However, “because the number of patients analyzed was small, these results warrant further research in larger groups of patients and other risk groups.”