Researchers at the US Vaccine Research Center, (part of the National Institute of Allergy and Infectious Diseases, National Institute of Health) have established that HIV selectively attacks the very immune system cells designed to fight it. In a letter published in the 2 May 2002 edition of the journal Nature, the researchers suggest that taking structured treatment interruptions (STIs) from HIV therapy puts HIV-specific CD4 T cells at particular risk of attack by rebounding HIV. However the American team found a powerful response in CD8-positive T cell response during treatment breaks which they suggest could be of importance in vaccine research.
Three groups of CD4 T-cells were isolated by the American researchers from 12 people with chronic HIV infection. The CD4-positive T cells had specific responses to HIV, or a cytomegalovirus (CMV) specific response and a “mixed” response. The cells were examined for evidence of HIV infection, and in each person HIV infected a much greater percentage of HIV-specific cells than the other two groups.
Researcher Richard Koup said: “For years we have known that the immune system does not produce good CD4-positive T cell response against HIV, and we have postulated that this might be because HIV preferentially infects HIV-specific CD4-positive cells. This study is the first to show that this actually happens.” In the study CD4-positive T cells programmed to fight HIV were between two and five times more likely to be infected with HIV than CD4 cells programmed to fight other viruses.
Two possible reasons for HIV’s attack on CD4-positive T cells designed to combat it were identified by the researchers and in both cases for evidence was found of HIV infecting CD4-positive HIV-specific cells.
In the first scenario, naïve CD4-positive T-cells, which the body had generated on first identifying HIV, were found to be “exceptionally vulnerable” to invasion by HIV. The researchers stimulated naïve cells to multiply through several rounds of cell division and found that they were infected at a high rate.
Similarly in the second scenario, mature cells, previously exposed to HIV, were seen to be vulnerable to infection by HIV. The researchers postulate that because HIV-specific CD4 cells form the immune system’s “front-line” against HIV they rush to attack the virus and are exposed in much greater numbers than immune system cells programmed to fight other viruses and bacteria.
In establishing this hypothesis the American researchers established why STIs usually led to viral rebound, and explains why the hope of immune control of HIV by repeated priming of the immune system with bursts of viral replication has failed. It was once hoped that STIs would gradually generate HIV-specific responses that could control viremia for indefinite periods off treatment. Four HIV-positive people, with established HIV infection, who were taking a STI were monitored. It was found that in each case there was a significant increase in viral load and that HIV-specific CD4-positive T cells attempted to fight off the re-emergent virus, leading to their infection by HIV at a much greater rate than CD4 cells designed to attack other pathogens.
“This experiment shows that HIV continuously and preferentially infects mature HIV-specific helper T cells as they try to fight off the virus” said Koup.
Those considering STIs which allow viral rebound are being warned of the possible negative impact on the immune system, “longer regimens that permit the viral load to increase may result in long-term damage to the immune system’s ability to fight HIV” said lead researcher Dr Daniel Douek.
However, though HIV-specific CD4 T cells proved to be vulnerable to HIV, the researchers found that even during STIs the immune system generated a powerful CD8 cell response. They believe that this could have important implications for vaccine research. Dr Douek, head of the Vaccine Research Center said: “We are working on ‘prime-boost’ vaccines. These two-part vaccines first prime the immune system with a shot of HIV DNA, then boost the immune response with a harmless viral sector that contains additional HIV genes. The boost enhances the CD8-positive response.”
Reference:
D Douek et al. HIV preferentially infects HIV-specific CD4+ T cells. Nature 417:95-98, 2 May 2002.