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

Abstract

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.

Interplay of Cytokines and Adjuvants in the Regulation of Mucosal and Systemic HIV-Specific CTL

“…This observation accords with the facts that protection against rectal SIV challenge strongly correlates with the activity of MHC class I-restricted env-specific CTLs in the gut lamina propria (2) and, in addition, that HIV-1-specific CD8 ϩ lymphocytes were detected in the cervical mucosa of HIV-exposed, seronegative prostitutes in Nairobi (3). These findings suggest that while HIV-specific CTL are important in mediating protective immunity against HIV-1 infection (4 -8), the CTL may need to be present in the genital and gastrointestinal mucosa to prevent natural HIV transmission, which typically occurs through a mucosal barrier (9,10).…”

“…3 Therefore, we asked whether the vaccine-induced mucosal CTL response is similarly enhanced synergistically by IL-12 and GM-CSF when the vaccine and cytokines are given together by IR administration. Accordingly, we immunized BALB/c mice IR twice (on days 0 and 7) with the HIV-peptide construct PCLUS3-18IIIB and CT with or without GM-CSF plus recombinant murine (rm) IL-12, all together in DOTAP.…”

RNA interference: The molecular immune system

“…These individuals are regularly exposed to various HIV-1 strains due to unprotected sex (reviewed by Kaul et al 2002). Numerous additional reports indicate that certain individuals or groups are immune to HIV-1 altogether (Baur et al 1989, Bryson et al 1995, Deacon et al 1995, Roques et al 1995, Paxton et al 1996, Kaul et al 2000, Kulkarni et al 2003, while others remain AIDS free for extensive periods of time . In order to develop sufficient human protection against HIV-1 variants, a number of homologous sequences will be required in the endogenous repertoire (Hiroshika et al 2000, Donze & Picard 2002, Hohjoh 2002, Jeong et al 2002, Leirdal & Sioud 2002, Miyagishi & Taira 2002, Paddison et al 2002, Paul et al 2002, Sui et al 2002, Yu et al 2002.…”

Engineering RENTA, a DNA prime-MVA boost HIV vaccine tailored for Eastern and Central Africa

“…37 In addition, the HLA-A*6802-restricted CTL epitope DTVLEDINL from HIV pol was inserted, which was associated with long-term nonprogression. 38 Also incorporated were a Plasmodium berghei-derived epitope SYIPSAEKI, Amino-acid sequence of the RENTA polyprotein was compared with proteins in the available databases. With the exception of sequences derived from exo-and endogenous retroviruses, no homologies to human proteins greater than 27% over 175 amino acids (hepatocyte nuclear factor 3-b HNF-3B) were found.…”