Christine A. Jansen

Functional restoration of human immunodeficiency virus and Epstein-Barr virus-specific CD8 + T cells during highly active antiretroviral therapy is associated with an increase in CD4 + T cells

To investigate the effect of highly active antiretroviral therapy (HAART) on HIV‐ and Epstein‐Barr virus (EBV)‐specific CD8+ T cells, total number and function of these cells was determined in 16 HIV‐infected individuals using tetrameric HLA‐peptide complexes and IFN‐γ ELISPOT assays after peptide stimulation, respectively. HAART induced a significant decrease in HIV‐specific tetramer+ T cells, whereas EBV‐specific tetramer+ T cells did not change. In addition, individuals who temporarily failed on therapy showed a temporary increase in the number of HIV‐specific T cells, suggesting that differences in the pool size of antigen‐specific T cells was determined by the presence of antigen. Interestingly, there was an increase in the ratio of IFNγ‐producing T cells per total number of both HIV‐ and EBV‐specific T cells in the majority of individuals, suggesting that the function of virus‐specific T cells is improved in individuals successfully treated with HAART. Despite this relative functional improvement of EBV‐specific T cells, no significant changes were observed in EBV load. In four subjects who temporarily failed on HAART, the percentage of IFN‐γ‐producing T cells, both for HIV and EBV, paralleled CD4+ T cell kinetics, suggesting that function seems to be related to differences in CD4+ T cell numbers. Overall, these data indicate that HAART improves the antigen responsiveness of both HIV‐ and EBV‐specific T cells, which is associated with an increase in CD4+ T cells.

Abundance of early functional HIV-specific CD8+ T cells does not predict AIDS-free survival time

Background T-cell immunity is thought to play an important role in controlling HIV infection, and is a main target for HIV vaccine development. HIV-specific central memory CD8+ and CD4+ T cells producing IFNγ and IL-2 have been associated with control of viremia and are therefore hypothesized to be truly protective and determine subsequent clinical outcome. However, the cause-effect relationship between HIV-specific cellular immunity and disease progression is unknown. We investigated in a large prospective cohort study involving 96 individuals of the Amsterdam Cohort Studies with a known date of seroconversion whether the presence of cytokine-producing HIV-specific CD8+ T cells early in infection was associated with AIDS-free survival time. Methods and Findings The number and percentage of IFNγ and IL-2 producing CD8+ T cells was measured after in vitro stimulation with an overlapping Gag-peptide pool in T cells sampled approximately one year after seroconversion. Kaplan-Meier survival analysis and Cox proportional hazard models showed that frequencies of cytokine-producing Gag-specific CD8+ T cells (IFNγ, IL-2 or both) shortly after seroconversion were neither associated with time to AIDS nor with the rate of CD4+ T-cell decline. Conclusions These data show that high numbers of functional HIV-specific CD8+ T cells can be found early in HIV infection, irrespective of subsequent clinical outcome. The fact that both progressors and long-term non-progressors have abundant T cell immunity of the specificity associated with low viral load shortly after seroconversion suggests that the more rapid loss of T cell immunity observed in progressors may be a consequence rather than a cause of disease progression.

High responsiveness of HLA‐B57‐restricted Gag‐specific CD8+ T cells in vitro may contribute to the protective effect of HLA‐B57 in HIV‐infection

HLA‐B57 has been shown to be associated with long‐term asymptomatic HIV‐1 infection. To investigate the biological mechanism by which the HLA‐B57 allele could protect from HIV‐1 disease, we studied both the number of CD8+ T cells as well as CD8+ T cell responsiveness directed to different HIV‐1 Gag peptides presented by HLA‐A2, ‐B8 or ‐B57. T cells specific for the HLA‐B57 peptide KAFSPEVIPMF responded more readily and to a higher extend to antigenic stimulation in vitro than T cells specific for the HLA‐A2 peptide SLYNTVATL or the HLA‐B8 peptide EIYKRWII. This phenomenon was reproducible with T cells from individuals expressing HLA‐B57 in combination with one or both of the other alleles and was persistent during long‐term follow‐up. Lower reactivity of A2‐ and B8‐restricted T cells was not explained by mutations in the B8‐ or A2‐restricted Gag‐peptides. Moreover, no correlation between peptide mutation frequency and IFN‐γ production by the corresponding Gag‐specific T cells was observed. In conclusion, functional differences were observed between T cells specific for HIV epitopes derived from the same protein presented by different HLA molecules. B57‐restricted KAFSPEVIPMF‐specific CD8+ T cells have relatively high responsiveness, which could contribute to the protective effect of HLA‐B57 in HIV infection.

Reconstitution of EBV Latent but Not Lytic Antigen-Specific CD4+ and CD8+ T Cells after HIV Treatment with Highly Active Antiretroviral Therapy

The incidence of (EBV-related) malignancies in HIV-infected subjects has declined since the introduction of highly active antiretroviral therapy (HAART). To investigate the effect of HAART on EBV infection, we performed a longitudinal analysis of the T cell response to both a latent and a lytic Ag and EBV viral load in 10 subjects from early in HIV infection up to 5 years after HAART. All individuals responded to HAART by a decline in HIV viral load, a restoration of total CD4+ T cell numbers, and a decline in T cell immune activation. Despite this, EBV load remained unaltered, even after 5 years of therapy, although a decline in both CD4+ and CD8+ T cells specific for the lytic EBV protein BZLF1 suggested a decreased EBV reactivation rate. In contrast, latent EBV Ag EBNA1-specific CD4+ and CD8+ T cell responses were restored after 5 years of treatment to levels comparable to healthy individuals. In two individuals who were treated by HAART late during HIV progression, a lymphoma developed shortly after initiation of HAART, despite restoration of EBV-specific CD4+ and CD8+ T cells. In conclusion, long-term HAART does not alter the EBV DNA load, but does lead to a restoration of EBNA1-specific T cell responses, which might allow better control of EBV-infected cells when applied early enough during HIV infection.