The importance of local mucosal HIV-specific CD8(+) cytotoxic T lymphocytes for resistance to mucosal viral transmission in mice and enhancement of resistance by local administration of IL-12.

Abstract

Although crucial to mucosal vaccine development, the mechanisms of defense against mucosal viral infection are still poorly understood. Protection, cytotoxic T lymphocytes (CTL), and neutralizing antibodies have all been observed, but cause and effect have been difficult to determine. The ability of CTL in the mucosa to mediate protection against mucosal viral transmission has never been proven. Here, we use an HIV peptide immunogen and an HIV-1 gp160-expressing recombinant vaccinia viral intrarectal murine challenge system, in which neutralizing antibodies do not play a role, to demonstrate for the first time that long-lasting immune resistance to mucosal viral transmission can be accomplished by CD8 ϩ CTL that must be present in the mucosal site of exposure. The resistance is ablated by depleting CD8 ϩ cells in vivo and requires CTL in the mucosa, whereas systemic (splenic) CTL are shown to be unable to protect against mucosal challenge. Furthermore, the resistance as well as the CTL response can be increased by local mucosal delivery of IL-12 with the vaccine. These results imply that induction of local mucosal CTL may be critical for success of a vaccine against viruses transmitted through a mucosal route, such as HIV. ( J. Clin. Invest. 1998. 102: 2072-2081.)

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

“…The possibility that genital tract CTL might play a key role in protection against sexually acquired HIV-1 infection was suggested by Belyakov et al, who showed that mucosal HIV-specific CD8 ϩ CTL conferred long-lasting immune resistance to mucosal viral transmission in mice (18), while systemic (splenic) CTL alone were unable to protect against mucosal transmission. More recently, Murphey-Corb et al have shown that MHC class I-restricted CTL directed against viral env in the jejunal lamina propria are absolutely correlated with protection from colonic SIV challenge (19).…”

“…In addition, a stepwise increase in the frequency of bulk CTL recognizing HIV-1 env has been seen with increasing levels of prior HIV exposure in HEPS prostitutes, suggesting that HIV-specific CTL may be causally associated with protection against HIV-1 infection (16). However, although CD8 ϩ lymphocytes from HEPS donors can protect against systemic HIV-1 challenge in a SCID/beige mouse model (17), other murine experiments have shown that mucosal rather than systemic (splenic) HIV-specific CTL are necessary to confer resistance to mucosal viral transmission (18). Recent work has shown that transient infection of the colonic mucosa in rhesus macaques can induce class I HLA-restricted CTL recognizing SIV env and that the presence of mucosal CTL correlates absolutely with protection against subsequent colonic viral challenge (19).…”

Intranasal HIV-1-gp160-DNA/gp41 Peptide Prime-Boost Immunization Regimen in Mice Results in Long-Term HIV-1 Neutralizing Humoral Mucosal and Systemic Immunity

“…Intrarectal immunization has been shown to induce CTL memory in Peyer's patches, lamina propia, and spleen in mice (36), and in macaques, CTL responses have also been found in mesenteric lymph nodes and PBMC (37); that protection could be enhanced by the use of IL-2 (38). Combinations of IL-1, IL-12, IL-18, and/or GM-CSF have been shown to be effective in inducing systemic and mucosal CTL-specific responses after nasal immunization (39).…”

Oral immunization of rhesus macaques with adenoviral HIV vaccines using enteric-coated capsules

“…Mucosal responses, including secretory IgA (sIgA) and mucosal-homing T cells have been shown to be important for protection of mucosal surfaces [2][3][4]. In fact, mucosal immunization is superior for generating long-lasting mucosal immunity [4][5][6].…”