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HIV infection evokes a strong CD8 + T cell response. Specific cytotoxic T lymphocytes (CTL) appear as the initial viraemia peaks and can be detected, using HLA-peptide tetramers, at levels approaching 10% of all CD8+ T cells in the peripheral blood. In macaques infected with SIV, removal of CD8+ T cells at this time results in a failure to control the early viraemia implicating CTL (1, 2). The CTL level remains high as infection progresses into the asymptomatic phase, with some virus control. The CTL response is very similar to that in Epstein Barr virus (EBV) and cytomegalovirus infection where control of the persisting infection is life-long. So why do CTL ultimately fail to control HIV infection. One reason is the evasion of the CTL response by virus variation; the effectiveness of the CTL inevitably selects escape mutants and there are several good recorded examples (reviewed in 3). For instance, in persons with HLA B27 the CTL response is focussed on a single epitope in gag and we have observed selection of the same escape mutant in four patients. In a recent study Evans et al (4) showed that in SIV infected macaques there was parallel selection of up to five escape mutants at the same time, implying that such events are commonplace for HIV/SIV, but is rare in EBV and CMV infection. Other features of HIV infection can contribute to the undermining of the CTL response, for instance nef mediated downregulation of HLA class I expression and upregulation of FasL expression on infected CD4+ T cells (reviewed in 3). The ability of the virus to integrate into host cell DNA silently must also hinder complete control by CTL. The most important difference between HIV and other persisting viruses must be the ability of HIV to infect critical cells of the immune system, CD4+ T cells and dendritic cells. It has been argued that HIV infects and often deletes HIV specific T cells (5). However this was disputed when responses were measured using antigen stimulated cytokine production (in 6 hours) rather than proliferation (over several days) (6). This study implied at least some Th1 type function in the majority of HIV infected persons, which is compatible with the rapid expansion of CTL, the cytokine response of CD8+ T cells and the antigen dependent persistence of memory CTL. All of these functions require T cell help in animal studies. However we have seen low levels of perforin in HIV specific CTL and although lytic function can be demonstrated it could be impaired. Further work is needed to characterize the relationship between T helper cell function and CTL performance in HIV infection, particularly in the context of attempts at immunotherapy and prophylactic vaccination. Recent success in creating HLA DR1 tetramers makes this feasible. |
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© 7th
Conference on Retroviruses and Opportunistic Infections, |