Subtle changes in immune system soon after HIV infection show who may benefit from earlier treatment

Subtle changes in the immune system soon after infection with HIV have an impact on long-term prognosis, investigators from the US military report in the January 15^th edition of the Journal of Infectious Diseases. The level of cell-associated viral load was also shown to be an important prognostic marker.

“Immunologic disturbances…are established early in HIV infection and are observed even among subjects with relatively preserved CD4 cell counts”, write the investigators, who also note that “the magnitude of these disturbances correlate with progression.”

HIV is traditionally viewed as a slow and progressive illness. However, the rate of disease progression can vary between individuals.

CD4 cell count and viral load are the main measurements used to decide when a patient should start HIV treatment. Most guidelines recommend that treatment should be started when a patient has a CD4 cell count of around 350 cells/mm³.

However, there is still uncertainty about the best time to initiate antiretroviral therapy, and identifying patients most likely to benefit from earlier initiation of treatment could help reduce levels of HIV-related illness and death.

Soon after infection, HIV causes massive destruction of CD4 and CD8 memory cells. Investigators wished to see if there was a relationship between levels of such cells soon after infection with HIV and progression to AIDS or death. They also assessed the role of immune activation, levels of naive CD4 and CD8 cells, and levels of cell-associated viral load on outcome.

The study population comprised 466 US military personnel all of whom had an estimated date of HIV seroconversion. The study used archived blood samples, and the median period between estimated seroconversion and the taking of these samples was 225 days.

The patients had a median age of 26 (range, 18 to 53), most were men (94%), and were racially diverse (50% white; 39% African American; 6% Hispanic; 5% other).

At this time, median CD4 cell count was 552 cells/mm³, with median viral load being 4.2 log₁₀. The median duration of follow-up was four years, during which time 135 individuals developed an AIDS-defining illness or died.

The investigators found that there was no relationship between disease progression and either the number or proportion of CD4 and CD8 memory cells.

However, they found a number of other measures were strongly associated with disease progression.

Patients who had higher levels of naive CD8 cells were significantly less likely to progress to AIDS or die, even after taking into account CD4 cell count (p = 0.03). “These data are in agreement with findings in chronic infection and suggest that individuals capable of maintaining naive cells after the earliest stages of infection have a lower risk of AIDS”, comment the investigators.

Survival of CD8 memory cells, which was assessed by monitoring a marker called CD127, was also shown to be associated with a better prognosis (p < 0.003).

The influence of immune activation on disease progression was also assessed. This was done by monitoring the Ki-67 marker in CD4 and CD8 cells. Individuals with the highest levels of this marker in both CD4 (p = 0.009) and CD8 cells (p = 0.037) had a significantly increased risk of developing AIDS or dying. “Early levels of immune activation may set the stage for future disease”, comment the authors.

Most of the cells infected by HIV during the early stage of infection with the virus die. However, a small number of cells survive and these carry HIV’s DNA.

The investigators carried out tests to see if levels of cell-associated HIV had an impact on prognosis. Patients with higher levels of cells that carried HIV’s DNA in the period shortly after seroconversion had significantly faster disease progression. This remained the case even after adjusting for other factors associated with prognosis, such as CD4 cell count, viral load and age (p = 0.027).

“We performed a detailed evaluation of T cells and cell-associated viral load in a large, well-characterized cohort with long-term follow-up. The strength of this study is the comprehensive evaluation of T cells at early time points after seroconversion, with a large number of end points”, write the investigators.

The investigators recommend that markers of HIV proliferation and immune activation should be assessed “to identify subjects most at risk of progression and likely to benefit from early therapeutic intervention.”

HIV treatment can have a positive impact on the immunologic and virologic parameters assessed in the study. The investigators therefore conclude, “our data indirectly support early initiation of therapy.”