Beta-chemokine and CD8+ T-cell noncytotoxic anti-HIV/SIV activity

Abstract

A small number of individuals remain uninfected despite repeated exposure to HIV. A number of viral and host factors are thought to account for this resistance. The cell-mediated immune response is likely to be important in controlling HIV/SIV infections. Two types of anti-viral responses, cytolytic and non-cytolytic have been associated with CD8+ T cells.

Non-cytolytic host responses to HIV include still unknown CD8+ T cell antiviral factor (CAF) and β-chemokines. These factors have been correlated to protection against HIV-1 infection and associated with asymptomatic HIV-1 infection and decreased disease progression. Different HIV isolates use different co-receptors, in addition to CD4, for cell entry. Macrophage tropic viruses (R5) use CCR5, also ligand for the β-chemokines RANTES, MIP-1α and MIP-1β, as co-receptors for fusion with the cells. T cell tropic viruses (X4) use the β-chemokine receptor CXCR4 to enter the cells.

In some our earlier HIV vaccine studies in macaques some animals have been protected against the infectious challenge virus, whereas some monkeys have become infected but have been able to control the virus infection. We investigated the role of β-chemokines and CD8+ T cell non-cytotoxic antiviral activity in protection against HIV/SIV infection and to disease progression in macaques and also in HIV-2 infected humans.

We showed that the protected and partially protected animals presented in this thesis had higher CD8+ T cell non-cytolytic antiviral response and β-chemokine production compared to the infected animals. Interestingly, the completely protected animals had higher β-chemokine production already before vaccination and without any pre-selection of the animals. β-chemokine secretion is associated with a Th1-type response with secretion of IL-2 and IFN-γ and CTL activity.

In one of the studies the two completely protected animals had also higher numbers of IFN-γ producing CD8+ cells compared to the non-protected animals and in an other study HIV-2 exposed animals protected against infection and SIV-induced disease developed SIV specific CTL. We also showed a strong correlation between antigen specific β-chemokine production and the absolute number of CD4+ cells in HIV-2 infected individuals. Furthermore, non-cytotoxic CD8+ cells from HIV-1 and HIV-2 infected individuals suppressed R5 virus replication in vitro in a similar manner. Interestingly, the suppression of X4 virus replication by CD8+ cells seemed to be more frequent and of higher magnitude among HIV-2 infected patients as compared to HIV-1 infected individuals.

These findings indicate that the anti-viral defence in individuals infected with the less pathogenic HIV-2 seems to control the virus replication better than that in HIV-1 infected individuals. The production of β-chemokines and CD8+ T cell non-cytotoxic antiviral activity seems to be part of the overall set of antiviral defence mechanisms and play a role in protective immunity. Furthermore, the genetic background of the host or environmental factors may influence their production.