HIV-1 Induces Cytotoxic T Lymphocytes in the Cervix of Infected Women

345

228

Understanding how individuals with a high degree of HIV exposure avoid persistent infection is paramount to HIV vaccine design. Evidence suggests that mucosal immunity, particularly virus-specific CTL, could be critically important in protection against sexually acquired HIV infection. Therefore, we have looked for the presence of HIV-specific CD8+ T cells in cervical mononuclear cells from a subgroup of highly HIV-exposed but persistently seronegative female sex workers in Nairobi. An enzyme-linked immunospot assay was used to measure IFN-γ release in response to known class I HLA-restricted CTL epitope peptides using effector cells from the blood and cervix of HIV-1-resistant and -infected sex workers and from lower-risk uninfected controls. Eleven of 16 resistant sex workers had HIV-specific CD8+ T cells in the cervix, and a similar number had detectable responses in blood. Where both blood and cervical responses were detected in the same individual, the specificity of the responses was similar. Neither cervical nor blood responses were detected in lower-risk control donors. HIV-specific CD8+ T cell frequencies in the cervix of HIV-resistant sex workers were slightly higher than in blood, while in HIV-infected donor cervical response frequencies were markedly lower than blood, so that there was relative enrichment of cervical responses in HIV-resistant compared with HIV-infected donors. HIV-specific CD8+ T cell responses in the absence of detectable HIV infection in the genital mucosa of HIV-1-resistant sex workers may be playing an important part in protective immunity against heterosexual HIV-1 transmission.

Section: Discussionmentioning

confidence: 99%

Section: T Is Now Recognized That There Is Variability In Susceptibmentioning

confidence: 98%

HIV-1-Specific Mucosal CD8+ Lymphocyte Responses in the Cervix of HIV-1-Resistant Prostitutes in Nairobi

Kaul

Plummer

Kimani

et al. 2000

345

228

“…Only limited information is available on mucosal vaccine induction of CTL responses in mucosal tissues themselves, by using either peptidebased vaccines (19), live viruses (20,21,55), DNA vaccination (56), or targeted lymph node immunization (13,57). The development of vaccines capable of inducing CTL in mucosal sites, however, is becoming more critical with the emergence of recent evidence that natural genital infection with HIV-1 leads to the development of MHC class I-restricted cytotoxic T cells in the cervix (17) and that mucosal administration of live attenuated SIV, which protects against subsequent infection with virulent virus, elicits a CTL response in gut-associated lymph nodes (18).…”

Section: Discussionmentioning

confidence: 99%

“…Studies of candidate HIV vaccines that are designed to elicit mucosal immune responses have so far focused mainly on HIV-induced B cell (IgA) and Th cell responses (13)(14)(15) or CTLs in the spleen (16). While recent findings underscore the need for vaccines capable of inducing CTL in mucosal sites (17)(18)(19)(20)(21)(22), the knowledge necessary to create them remains scarce. Only a few vaccine approaches for HIV have been shown to induce a CTL response in the mucosa (19 -22).…”

mentioning

confidence: 99%

The Induction of HIV Gag-Specific CD8+ T Cells in the Spleen and Gut-Associated Lymphoid Tissue by Parenteral or Mucosal Immunization with RecombinantListeria monocytogenesHIV Gag

Peters

Peng

Douven

et al. 2003

The induction of mucosal immunity is crucial in controlling viral replication during HIV infection. In this study we compare the ability of a recombinant Listeria monocytogenes that expresses and secretes the HIV Ag Gag to induce CD8+ T cells against this Ag in the spleen, mesenteric lymph nodes, and Peyer’s patches and the ability to provide effector Gag-specific CD8+ T cells to the lamina propria after i.v., oral, or rectal administration of the vaccine. The levels of Ag-specific CD8+-activated T cells were measured ex vivo using intracellular cytokine staining for IFN-γ and H-2Kd Gag peptide tetramer staining. We found that all routes of immunization induced Gag-specific CD8+ T cells in the spleen. After secondary infection, we observed substantial increases in splenic levels of CD8+ T cells, and levels of Gag-specific cells were similar to those against listeriolysin O, the immunodominant Ag of L. monocytogenes. Both primary and secondary oral immunization resulted in abundant Gag-specific CD8+-activated T cells in the lamina propria that constituted ∼35% of the CD8 compartment. However, significant levels of Gag and listeriolysin O-specific CD8+ T cells were observed in mucosal lymphoid tissue only after two immunizations, perhaps because they had already entered the lamina propria compartment after a single immunization. In the context of HIV, a mucosally administered vaccine seems best calculated to prompt an immune response that is capable of preventing infection. The data presented in this report demonstrate that mucosally administered Listeria can prompt such a response and that booster doses can maintain this response.

“…Although it would be difficult to obtain suitable T cell samples, HLA class I tetramers could greatly facilitate attempts to characterize the Ag specificity of intraepithelial and submucosal T lymphocytes that are present in the cervix of Ct-infected women. It is encouraging in this respect that cervical T cells obtained from HIV-1-infected women have been successfully used to establish a functional role for HLA-restricted T cells in cervical infections and that the HLA restriction elements and epitope specificities of peripheral and cervical CTLs were similar in given individuals (45).…”

Section: Discussionmentioning

confidence: 99%

Direct Detection and Magnetic Isolation ofChlamydia trachomatisMajor Outer Membrane Protein-Specific CD8+ CTLs with HLA Class I Tetramers

Kim

Devine

Angevine

et al. 2000

We recently identified HLA class I-presented epitopes in the major outer membrane protein (MOMP) of Chlamydia trachomatis that elicit CTL responses in human genital tract infections. T cells possessing cytolytic activities specific for these epitopes could be detected following in vitro stimulation of peripheral blood CD8+ T cells with peptides. In the present study we used HLA-A2 tetramers for detailed characterization of MOMP-specific CTL responses. Ex vivo tetramer analysis detected MOMP-specific T cells in the peripheral blood of infected individuals at significant frequencies (0.01–0.20% of CD8+ T cells). After in vitro stimulation with peptides, the frequencies of MOMP peptide-specific T cells increased up to 2.34% of CD8+ T cells in bulk cultures. In contrast, HLA-A2/MOMP tetramer-binding T cells were virtually undetectable in the peripheral blood from uninfected individuals, either ex vivo or after 3 wk of in vitro peptide stimulation of their T cells. Magnetically sorted, tetramer-bound T cells specifically lysed peptide-pulsed targets as well as C. trachomatis-infected epithelial cells with nearly 50-fold greater per cell efficiency than that of unsorted populations. This study provides conclusive evidence of in vivo induction of HLA class I-restricted CD8+ CTL responses to C. trachomatis MOMP. Direct detection of these cells with tetramers will allow their further characterization without prior manipulation and facilitate monitoring of CTL responses during infections and in immunization trials with MOMP-based vaccines.