HAART during primary HIV infection restores interferon production

Levels of the antiviral factor type I interferon are dramatically reduced during primary HIV infection, but can be restored by early anti-HIV therapy, according to the results of a small test tube study presented in the 15^th July edition of The Journal of Infectious Diseases. These results suggest that HIV treatment early in infection, or use of artificial interferon therapy, may help the body to keep HIV under control.

In the first few weeks after HIV infection, the body attempts to attack the virus by producing antiviral factors as part of the ‘innate’ immune response. Immune cells called ‘plasmocytoid dendritic cells’ (PDCs) are responsible for the production of factors such as type I interferon, which co-ordinate the immune system’s attack on HIV.

Levels of type I interferon and PDCs are known to be reduced during long-term HIV infection, as the body loses the ability to keep HIV under control. However, few studies have examined innate immunity during the early stages of HIV infection, when a balance between the virus and the body’s anti-HIV defences is set up.

Accordingly, investigators from the PRIMO cohort examined levels of type I interferon and PDCs in 26 recently infected patients. The patients were enrolled a median of 51 days after the presumed date of infection.

“The present study shows – for the first time to our knowledge – that in vitro production of type I interferon in HIV-infected patients is profoundly impaired during primary infection,” the researchers conclude. “It also confirms that PDC counts are low during this stage of the disease.

“Our data suggest that initiating highly active antiretroviral therapy (HAART) at the time of diagnosis of primary infection may favour recovery of antiviral innate immunity,” they write.

The investigators examined the levels of type I interferon produced in samples of the patients’ blood by stimulating the samples with herpes simplex virus type 1 in the test tube. At the time of inclusion in the study, the 26 patients had lower levels of interferon production than samples from 31 HIV-negative controls (median 180 vs. 800IU/ml; p

Fifteen of the HIV-positive patients were treated with HAART during early infection. These patients showed a significant increase in the production of type I interferon over twelve months of treatment (median 425IU/ml; p = 0.02). In contrast, the eight patients who did not receive any anti-HIV therapy showed no significant change in interferon production over the same period.

“These data indicate that HAART may help to restore type I interferon production after the profound impairment that results from HIV primary infection,” the investigators explain.

A similar recovery in PDC levels was observed in the patients taking HAART, increasing from 5900 to 10,100 cells/ml (p = 0.048), but there was no increase in the untreated patients. “This indicates that HAART may help PDC counts to recover after the profound initial loss at the onset of primary infection,” the researchers conclude.

Pharmaceutical versions of type I interferon, known as interferon alfa, are available for use in the treatment of viral infections such as hepatitis C infection. The investigators of this study speculate that interferon alfa treatment may be beneficial in helping the body to maintain its anti-HIV activity during primary HIV infection.

“Defective interferon production during primary infection should perhaps be supplemented. It will be important to assess whether peginterferon alfa treatment, which has already given promising results in preliminary studies, helps to control viral replication during primary infection and whether it acts on PDC cell numbers and function,” they suggest.

Their results also suggest that early initiation of HAART could help the body to control HIV levels, rather than waiting for CD4 cell counts to fall to between 200 and 350 cells/mm³, as advised in current guidelines. However, the possible benefits of early HAART must be considered alongside the risks of the development of drug resistance, side-effects and reductions in treatment adherence that may compromise the long-term efficacy of anti-HIV therapy.

However, this study was not randomised, with patients being selected for anti-HIV therapy by their HIV doctors based on their higher viral loads (median 126,000 vs. 20,000 copies/ml) and lower CD4 cell counts (median 370 vs. 700 cells/mm³) at the time of diagnosis. While these results suggest that HAART may be of benefit, it is not possible to eliminate the potential effect of the baseline differences between the treated and untreated groups in determining their response to treatment.

In addition, the small number of analysed patients limits the confidence of the study’s conclusions, which require confirmation in future, prospective randomised trials.