There is consensus that effective AIDS vaccines should induce both cellular and humoral immunity. Challenge of macaques with SIV or constructs of SIV and HIV (SHIV) has been invaluable to test vaccine efficacy; however, the biological relevance of some results is uncertain. Ideally, biologically meaningful challenges should mimic human HIV-1 transmission as closely as possible and will, therefore, involve (a) R5 viruses, (b) mucosal challenge routes, (c) viruses with neutralization profiles resembling those of recently transmitted HIV-1 isolates (for testing neutralizing antibody-based vaccines), and (d) heterologous challenge viruses.
Challenge virus: route of transmission, tropism, and target cell distribution
Because approximately 90% of newly acquired human HIV-1 infections involves mucosal transmission of R5 strains, R5 viruses are preferred for primate experiments. Early-stage infections with R5 versus X4 strains differ: R5 strains preferentially infect and destroy memory CD4 T cells [1–7], because CCR5 expression is restricted to this subset. In contrast, CXCR4 is preferentially expressed on naive CD4 T cells, thus rendering these cells susceptible to elimination by X4 strains . Because tissue distribution of naive and memory CD4 T cells differs, X4 strains replicate predominantly in peripheral blood and lymph nodes, whereas R5 viruses replicate mostly within mucosal tissues [2–4,6–10]. Consequently, X4 and R5 strains interact with the immune system differently, which may affect vaccine efficacy. For instance, R5 virus-mediated destruction of vaccine-induced memory CD4 T cells may render vaccination less likely to succeed against R5 than against X4 virus challenge; the latter may, therefore, yield unrealistically favorable outcomes .
Mucosal challenges in primates: dose matters
As most human HIV-1 infections occur mucosally, developing vaccine protection against this dominant transmission mode will have the highest impact on the epidemic. Recent studies have focused on challenge virus doses. In standard protocols, high inocula ensure systemic infection in all control monkeys, permitting efficacy studies with relatively few animals. Systemic HIV-1 infection among sexually exposed humans, however, requires many exposures [12–15]; one transmission between discordant couples occurred per 122, 1429, or 357 sexual exposures, depending on the HIV-positive partner's stage of disease (acute infection, chronic stable disease, or 0.5–2 years before death, respectively) . Risk factors, such as the presence of other sexually transmitted diseases, could increase transmission rates . Nevertheless, challenge virus doses used in primates far exceed the infectious inoculum during human sexual intercourse.
Several groups have explored multiple low-dose challenges [17–21]; challenge doses were adjusted to permit infection of all control monkeys after approximately five weekly inoculations [18–21]. This infection rate still exceeds estimates obtained from HIV-1-discordant couples, although it is a step in the right direction and reflects the constraints of using costly primates. Obviously, one cannot conduct experiments where > 100 exposures are needed to ensure transmission or where low transmission rates demand large monkey groups to obtain statistical power.
Vaccine efficacy itself may be a function of the challenge virus dose: host immune defenses could be overwhelmed by unphysiologically high inocula, although lower virus doses might be withstood. For instance, vaccination completely protected three of five monkeys against low-dose challenge but none against a 10-fold higher dose, although viremia was reduced compared with controls .
A caveat of multiple ‘low-dose’ virus challenges is that subthreshold exposures may stimulate antiviral cellular immunity and protect against subsequent mucosal rechallenge [23,24]. These finding are strikingly similar to the HIV-1 resistance observed among African sex workers . Cellular immunity induced by low-dose virus exposure may complicate the interpretation of the correlates of protection in vaccinated monkeys. Additionally, repeated exposures to host-cell components contained in challenge stock virions could theoretically induce innate and/or adaptive immunity and render the animals increasingly resistant to mucosal infection. This risk could be minimized by producing virus stocks in peripheral blood mononuclear cells of the same species as that used in vaccine studies.
SHIV challenges: closer to the real thing
SHIV constructs that encode HIV-1 env are unique in that they allow direct testing of HIV-1 env-based vaccines and neutralizing antibodies isolated from HIV-1-infected individuals. Consequently, primate-tested active/passive immunization could be directly entered into clinical trials, thus accelerating development.
There are other advantages of SHIV strains compared with SIV: (a) new anti-HIV-1 neutralizing antibodies could potentially be isolated from infected animals, (b) non-clade B SHIV strains can be generated to reflect clades prevalent in different parts of the world (Table 1), and (c) HIV-1 env evolution can be studied in infected primates. If the latter follows a similar path as that in infected humans, as suggested for HIVIIIB env [26,27], primate models will be further validated.
HIV-1 clade C is the most prevalent subtype worldwide, affecting > 50% of all individuals with HIV/AIDS. Development of anti-HIV-1 clade C vaccines should, therefore, be a top priority. To date, however, most primate challenge studies have involved clade B SHIV strains. Recently, we have constructed a highly replication-competent clade C SHIV, SHIV-1157ipd3N4 , that fulfills the criteria for biological relevance: (a) R5 tropism, (b) mucosal transmissibility, and (c) susceptibility to neutralizing antibodies. Efficacy testing of anti-HIV-1 clade C vaccine candidates in primates is now feasible (Rasmussen et al., unpublished data).
Neutralization sensitivity: avoid stealth envelopes
Late-stage viruses that have undergone multiple rounds of neutralizing antibody selection followed by repeated escapes develop hard-to-neutralize envelopes. Using viruses encoding such impenetrable envelopes in primates may set the bar for achieving vaccine protection unrealistically high. Neutralization resistance has been an issue for some SIV challenge stocks, particularly SIVmac239 and primary SIVmac251 grown in rhesus monkey peripheral blood mononuclear cells. Essentially, neutralizing antibody-based vaccines cannot be evaluated for efficacy with these strains.
According to an intriguing study, recently transmitted HIV-1 clade C isolates were surprisingly neutralization sensitive . Among discordant couples, recipients harbored more neutralization-sensitive viruses compared with the strains predominant in their infected partners, suggesting that a bottleneck during or shortly after sexual transmission favored neutralization-sensitive quasispecies. In contrast, vertically transmitted pediatric HIV-1 isolates were less neutralization sensitive than maternal isolates . Therefore, the route of transmission may exert a dominant influence on the neutralization sensitivity of transmitted viruses.
To model sexual transmission in primates, SHIV constructs carrying env of recently transmitted HIV-1 isolates will be preferable over SHIV strains with env genes of late-stage viruses. However, the need to adapt new SHIV constructs to monkeys poses a dilemma: adaptation itself causes env mutations, which could be partly a result of neutralizing antibody selection. Rapid animal-to-animal passage during peak viremia before neutralizing antibodies are elicited can avoid selecting neutralizing antibody-escape variants, as we recently demonstrated .
Heterologous virus challenge: reflecting viral complexity in real life
Given the multitude of viral quasispecies and increasing divergence of HIV-1 sequences with time, there is no likelihood of human recipients of an AIDS vaccine encountering viruses exactly matched to their vaccines. Therefore, vaccine efficacy testing in primates should reflect this reality. Success with homologous virus challenges may stimulate the development of vaccine strategies inducing narrowly focused immune responses that fail to protect against divergent viruses. Clear differences in outcome of homologous versus heterologous SHIV challenge have recently been demonstrated .
Several groups have evaluated vaccine efficacy by heterologous virus challenge [31–37]. In most SHIV challenge studies, vaccine and challenge virus were only partially mismatched, usually in env, probably because all currently used SHIV constructs were built from SIVmac239 backbones. Often, vaccines designed to induce cytotoxic T lymphocyte responses incorporate Gag sequences that match those of the challenge virus. It will be important either to generate immunogens based upon SIV Gag sequences that differ from those of SIVmac239 or, to construct SHIV strains with backbones that differ from SIVmac239.
Another issue to consider is the diversity of viral inocula. In animal models, challenge inocula consisting of biological isolates with swarms of viral quasispecies and challenge inocula that are homogeneous and consist of molecularly cloned virus have different advantages. While biological isolates better reflect the inoculum involved in human HIV-1 transmission, molecularly cloned virus is well defined and is, therefore, well suited as a standard virus to evaluate different vaccine regimens. In some cases, HIV-1 transmission has been associated with substantial reductions in viral diversity [29,38,39], suggesting that only a small portion of viral quasispecies was transmitted. If a diverse virus population is reduced during the bottleneck of mucosal transmission to a founder virus in the recipient, inoculation with an already narrow, well-defined population could have the same results and consequently the diversity of viral inocula may not be as critical an aspect in animal models.
We believe that AIDS vaccine efficacy studies in primate models should involve mucosal challenge with R5 strains, preferably SHIV constructs because of the added advantage of directly testing anti-HIV-1 Env responses. To reflect the heterogeneity of the many HIV-1 quasispecies circulating in human populations, vaccine and challenge virus should not be exact matches in primate studies; ideally, AIDS vaccine efficacy studies should employ a fully heterologous challenge virus, rather than one differing only in Env. This may require the construction of SHIV strains based upon SIV backbones that differ from SIVmac239. Lastly, replacing standard single high-dose viral challenges with repeated low-dose mucosal exposures has shown promise. Ultimately, efficacy data generated in primate models through this new approach need to be compared directly with phase III clinical vaccine trials for validation.
We thank Dr Shiu-Lok Hu (University of Washington, Seattle) for critical review of this manuscript.
Sponsorship: This work was supported in part by NIH grants P01 AI48240 and R37 AI34266 to R.M.R.
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