Our current level of knowledge suggests that simple immunological memory in the absence of activated effector cells may not be sufficient to provide vaccine protection against field strains of SIV and HIV. Once SIV and HIV establish infection in a susceptible host, they have a remarkable ability to replicate unrelentingly in the face of apparently strong host immune responses. A multiplicity of mechanisms are used by these lentiviruses to achieve continuous replication (9
). They include selection of antigenic variants that escape immune recognition within a single infected individual, destruction of CD4+
helper cell activity, and an envelope coat structure that is not easily accessible to antibodies. The failure of vaccines in animal models may be explained by a failure to blunt early, high-level replication by the virus, thus allowing the natural immune evasion strategies of the virus to take effect. Conversely, the success of live attenuated vaccine approaches in animal models may depend on the persistent, controlled nature of the infection with the attenuated strains. For an AIDS vaccine to be practically effective, we may need to develop strategies that result in persistently active immune responses that can be poised to quickly suppress the early replication of the virus.
Most vaccine approaches currently being forwarded for AIDS do not have persistence of antigen or persistent antigen expression. These include envelope subunit approaches, poxvirus recombinants, inactivated whole virus, DNA, and prime and boost regimens with combinations of these approaches. While it is theoretically possible that immunizations by such approaches could provide durable protection if the response time following live virus exposure was quick enough, they typically have not done so in animal models when challenge used pathogenic, difficult to neutralize strains of virus (15
). For influenza virus, memory CTL take at least 4 days to expand and home to the site of infection (13
). Postexposure drug studies also suggest that 4 days may be too late to block establishment of a persistent infection (24
). Herpesviruses, which persist for the lifetime of the infected host, induce humoral and cellular immune responses that also persist for life. Persisting cellular responses have been postulated to keep HSV in a latent state because decreases in cellular responses are associated with reactivation of latent HSV (45
). Thus, herpesvirus recombinant vectors may provide an alternative to live, attenuated lentivirus strains as AIDS vaccines that induce host immune responses which are persistently activated or can be rapidly induced into an active state.
What is impressive about the current results is that protection was achieved against difficult to neutralize, pathogenic SIV 5 months after the last vaccine administration. The vast majority of SIV and SHIV vaccine experiments that have used nonpersisting immunogens have scheduled the challenge at 2 to 4 weeks after the last vaccine boost, when immune responses are at or near their peak. The one exception is the study of Benson et al. (2
), in which intravenous challenge at 6 months showed no protection but rectal challenge at 9 months surprisingly showed protection in 5 of 11 monkeys despite the fact that antiviral immune responses had declined to very low or undetectable levels by that time. Further studies will be needed to determine whether a longer time interval between the last boost with a nonpersisting immunogen and challenge actually favors protection despite dramatic declines in the levels of measurable antiviral immune responses. Our results nonetheless illustrate the potential of herpesviruses as vaccine vectors for AIDS and indicate the need for development of alternate vaccine strategies that can achieve persistently active immune responses.
What is the basis for optimism if only two of seven monkeys in this study were solidly protected against challenge? Previous studies with live attenuated SIV have suggested an important role for cellular responses to core Gag-Pol antigens in protection against challenge (19
), and other studies have indicated a protective role for CTL to Tat and Rev (3
). The present study used SIV env
genes in the recombinant vaccines, but in the future it will be easily feasible to incorporate genes that express core, Tat, Rev, and other antigens. There is also reason to believe that other herpesviruses, such as other HSV strains that replicate better in rhesus monkey fibroblasts in culture (W. T. Lucas, C. G. Murphy, and D. M. Knipe, unpublished results) or the rhesus monkey rhadinovirus (11
), may elicit stronger immune responses in rhesus monkeys. We also now know that HSV strains which express much higher levels of Env protein can be constructed (Lucas et al., unpublished). Once conditions can be defined for achieving solid protection in most or all animals, herpesvirus recombinants should be an ideal means for learning the types of immune responses most important for achieving vaccine protection in the SIV/rhesus monkey system.
The basis for the comparable strength of responses to replication-competent versus replication-defective HSV is currently not understood. However, there is precedent for this type of phenomenon in poxvirus systems. Replication-defective poxviruses can elicit antiviral antibody responses comparable in strength to replication-competent counterparts (1
). There are several possible explanations for the equivalent responses to replication-competent and replication-defective strains. First, some of the primary infected cells may be the major antigen-presenting cells, and both types of strains may infect these cells. Second, even replication-competent HSV, or at least the HSV strain used in this study, may replicate so poorly in rhesus monkeys that the response to it is not detectably different from that to replication-defective HSV. Finally, there may be cells in the monkey that support replication of the mutant strain such that it is not replication defective in vivo.
Despite the potential advantages of durable immunity induced by a herpesvirus recombinant vector, preexisting immunity in the population and concern for safety could potentially limit practical application of this approach. Preexisting immunity to HSV might limit infection by the recombinant vaccine and the immune response to a new antigen expressed by the HSV vector. However, initial results in mouse models indicate that preexisting immunity to HSV does not necessarily restrict the immune response to a new antigen expressed by an HSV vector (M. Brockman and D. M. Knipe, unpublished results). With respect to safety concerns, vector replication could conceivably result in disease in immunocompromised individuals or under certain circumstances. Such safety concerns could potentially be minimized with improved vector designs (7