Functionally Inert HIV-Specific Cytotoxic T Lymphocytes Do Not Play a Major Role in Chronically Infected Adults and Children

Naturally acquired cellular immunity in individuals who have been exposed to HIV-1 but have remained uninfected may hold clues for the design of an effective HIV vaccine. To determine the presence and nature of such an HIV-1-specific immune response, we evaluated the quantity and fine specificity of HIV-1-reactive IFN-γ-secreting T cells in a group of highly exposed seronegative men having sex with men. All 46 ES reported frequent unprotected anal sex with known HIV-1-infected partners at enrollment, and high risk activities continued in at least one-half of the volunteers for up to >6 years of observation. Despite the high frequency of unprotected anal intercourse and potential HIV-1 exposure, the vast majority of individuals demonstrated no or very low numbers of HIV-1-specific, IFN-γ-secreting T cells. Even when HIV-1 epitopes were presented by peptide-pulsed autologous dendritic cells in 15 of the highest risk volunteers, HIV-1-specific T cells remained infrequent, and the proportion of responders was not significantly different from that in a lower risk seronegative control cohort. Only PBMC from two individuals who have remained uninfected to date exhibited distinctly positive responses. However, these responses rarely persisted over time, single epitope specificities were identified in only one volunteer, and HIV-1-specific memory T cell clones did not expand in vitro. HIV-1-specific, IFN-γ-secreting T cells are thus unlikely to substantially contribute to resistance against infection in most exposed seronegative men having sex with men.

Section: Discussionmentioning

confidence: 60%

Most Highly Exposed Seronegative Men Lack HIV-1-Specific, IFN-γ-Secreting T Cells

Hladik¹,

Desbien²,

Lang³

et al. 2003

“…One study of HIV infection found that Ag-specific CD8 ϩ T showed normal profiles of IFN-␥ production (48). However, there is other evidence that HIV-specific CD8 ϩ T cells may be functionally defective (49).…”

Section: Discussionmentioning

confidence: 99%

Reduced Functional Capacity of CD8+ T Cells Expanded by Post-Exposure Vaccination of γ-Herpesvirus-Infected CD4-Deficient Mice

Liu

Andreansky

Diaz

et al. 2002

Mice (I-Ab−/−) that lack CD4+ T cells remain healthy for at least three months after respiratory exposure to the murine γ-herpesvirus 68 (γHV68), then succumb with symptoms of chronic wasting disease. Postexposure challenge of γHV68-infected I-Ab+/+ and I-Ab−/− mice with a recombinant vaccinia virus (Vacc-p56) expressing an antigenic γHV68 peptide caused a massive increase in the numbers of Dbp56-specific CD8+ T cells. Previous experiments showed that, despite the large numbers of potential CTL effectors, there was little effect on the long-term survival of the CD4-deficient group and no diminution in the level of persistent virus shedding and latency. Comparison of the expanded CD8+Dbp56+ sets in the I-Ab+/+ and I-Ab−/− mice indicated that these two T cell populations were not identical. More CD69highCD8+ Dbp56+ T cells were found in the CD4-deficient mice, an effect that might be thought to reflect higher Ag load. By contrast, the mean fluorescence intensity of staining for the CD44 glycoprotein was diminished on CD8+Dbp56+ T cells from the I-Ab−/− group, the level of CTL activity was lower on a per cell basis, and the relative prevalence of IFN-γ+TNF-α+ T cells detected after in vitro stimulation with the p56 peptide was decreased. Given that this experimental system provides an accessible model for evaluating postexposure vaccination protocols that might be used in diseases like HIV/AIDS, the further need is to clarify the underlying molecular mechanisms and the relative significance of lack of CD4+ T help vs higher Ag load for these expanded CD8+ effector populations.

“…Tetramer staining of PBMC and disaggregated lymph node cells PBMC and disaggregated lymph node cells were stained with selected tetramers loaded with CD8 ϩ T cell HIV-1 epitopic peptides ( Table I) that matched subjects' HLA class I molecules. Tetramers were selected for analysis based upon prior reports in the literature (21)(22)(23)(24)(25) as well as unpublished experience within our laboratories that suggested there was a high likelihood for HIV-1-infected individuals to harbor such cells. Tetramers were obtained from the National Institute of Allergy and Infectious Diseases (NIAID) Tetramer Facility (Emory University, Atlanta, GA), except for those restricted by HLA-A*0201, which were purchased from Beckman Coulter.…”

Section: Frequencies Of Cd4mentioning

confidence: 99%

CTL Fail to Accumulate at Sites of HIV-1 Replication in Lymphoid Tissue

Connick¹,

Mattila

Folkvord³

et al. 2007

200

250

The inability of HIV-1-specific CTL to fully suppress virus replication as well as the failure of administration of exogenous CTL to lower viral loads are not understood. To evaluate the hypothesis that these phenomena are due to a failure of CTL to localize at sites of HIV-1 replication, we assessed the distribution of HIV-1 RNA and HIV-1-specific CTL identified by HIV-1 peptide/HLA class I tetrameric complexes (tetramers) within lymph nodes of 14 HIV-1-infected individuals who were not receiving antiretroviral therapy. A median of 0.04% of follicular compared with 0.001% of extrafollicular CD4+ cells were estimated to be producing HIV-1 RNA, a 40-fold difference (p = 0.0001). Tetramer-stained cells were detected by flow cytometry in disaggregated lymph node cells from 11 subjects and constituted a significantly higher fraction of CD8+ cells in lymph node (mean, 2.15%) than in PBMC (mean, 1.52%; p = 0.02). In situ tetramer staining in three subjects’ lymph nodes, in which high frequencies of tetramer-stained cells were detected, revealed that tetramer-stained cells were primarily concentrated in extrafollicular regions of lymph node and were largely absent within lymphoid follicles. These data confirm that HIV-1-specific CTL are abundant within lymphoid tissues, but fail to accumulate within lymphoid follicles where HIV-1 replication is concentrated, suggesting that lymphoid follicles may be immune-privileged sites. Mechanisms underlying the exclusion of CTL from lymphoid follicles as well as the role of lymphoid follicles in perpetuating other chronic pathogens merit further investigation.