At the AIDS Vaccines Conference in Cape Town last fall, Louis Picker offered some solace to a chastened field when he presented encouraging results obtained with a novel vaccine strategy in the SIV/macaque model. The study has now been published online in Nature Medicine. Picker set out to design a vaccine strategy that would maintain a population of activated “effector memory” T cell responses against SIV, based on the observation that these cells traffic to mucosal tissues and may therefore offer a rapid, front-line defense against virus challenge. The rhesus cytomegalovirus (RhCMV) was selected as the vaccine vector due to its persistence and maintenance of effector memory CMV-specific T cells. Picker and colleagues report in the paper that this approach induced robust SIV-specific CD4 and CD8 T cell responses of the desired effector memory phenotype. Over a year after receipt of the vaccine, animals showed approximately equivalent CD4 and CD8 T cell responses to SIV antigens, totaling, on average, 1.5% and 2.0% of blood memory T cells, respectively. Macaques that were already infected with RhCMV developed similar responses to those that were RhCMV-naïve, suggesting that vector-specific immunity did not impact the immunogenicity of the approach.
Having established that the RhCMV vector induced SIV-specific effector memory T cell responses, the researchers went on to subject 12 immunized animals and 16 controls to a series of repeated, low-dose challenges with SIVmac239. More than half the control animals developed progressive, systemic infection after the first or second challenge, with the final control acquiring infection after 12 exposures. Immunized macaques required a median of eight exposures and, most notably, four of these animals completely resisted systemic infection. Two of these apparently protected animals briefly displayed low-level viral loads of 60-80 copies after the first exposure while the other two never had detectable virus in plasma after 13 exposures. All four of these macaques showed evidence of at least transient infection because CD8 T cell responses developed to SIV antigens (Pol and Vif) that were not included in the vaccine. Several months after the first challenge, the four protected animals were depleted of CD8 T cells using a monoclonal antibody, but virus remained undetectable in plasma and cell-associated SIV DNA or RNA was not detected in peripheral blood and lymph node CD4 T cells. Picker and colleagues write that these findings suggest “infection was effectively contained locally, before dissemination and establishment of typical systemic infection.”
Among the eight vaccinated macaques that developed systemic infection, viral loads were not significantly different from controls. The researchers state that this is not surprising because of the low proliferative capacity of effector memory T cells (TEM) compared to central memory T cells (TCM). The implication is that T cell responses that might be protective against acquisition are not necessarily synonymous with T cell responses that contribute to post-infection control of viral replication. In the conclusion of the paper, Picker and colleagues offer the following thoughts regarding the import of their findings:
“It may also be possible to engineer HIV/AIDS vaccines that generate and maintain both TEM and TCM cell components, the latter serving as a second line of defense if the initial TEM cell barrier is breached. Such TEM cell or combination TEM-TCM cell vaccines will probably not provide absolute protection against all HIV exposure (against parenteral routes, for example). However, our data suggest that vaccine-generated T cell responses are able to do more than simply lower viral replication set points. Specifically, HIV/AIDS vaccines with a TEM component may have the ability to protect against the sexual transmission of HIV.”
Thus, while previous debates about the role of TEM vs. TCM in protection have generally been framed simply in terms one or the other being more important, this new data may offer a more nuanced perspective. However, it’s probably worth bearing in mind that this perspective is based on results in four macaques. Similar examples of apparent protection against SIV are rare; to my knowledge the best result previously reported in the literature involved “clearance” of a mucosal SIVmac251 challenge by five out of 11 macaques immunized with a NYVAC regimen.
Letter
Nature Medicine
Published online: 15 February 2009 | doi:10.1038/nm.1935
Scott G Hansen1, Cassandra Vieville1, Nathan Whizin1, Lia Coyne-Johnson1, Don C Siess1, Derek D Drummond1, Alfred W Legasse1, Michael K Axthelm1, Kelli Oswald2, Charles M Trubey2, Michael Piatak, Jr2, Jeffrey D Lifson2, Jay A Nelson1, Michael A Jarvis1 & Louis J Picker1
Abstract
The rapid onset of massive, systemic viral replication during primary HIV or simian immunodeficiency virus (SIV) infection and the immune evasion capabilities of these viruses pose fundamental problems for vaccines that depend upon initial viral replication to stimulate effector T cell expansion and differentiation1, 2, 3, 4, 5. We hypothesized that vaccines designed to maintain differentiated effector memory T cell (TEM cell) responses5, 6 at viral entry sites might improve efficacy by impairing viral replication at its earliest stage2, and we have therefore developed SIV protein-encoding vectors based on rhesus cytomegalovirus (RhCMV), the prototypical inducer of life-long TEM cell responses7, 8, 9. RhCMV vectors expressing SIV Gag, Rev-Tat-Nef and Env persistently infected rhesus macaques, regardless of preexisting RhCMV immunity, and primed and maintained robust, SIV-specific CD4+ and CD8+ TEM cell responses (characterized by coordinate tumor necrosis factor, interferon- and macrophage inflammatory protein-1expression, cytotoxic degranulation and accumulation at extralymphoid sites) in the absence of neutralizing antibodies. Compared to control rhesus macaques, these vaccinated rhesus macaques showed increased resistance to acquisition of progressive SIVmac239 infection upon repeated limiting-dose intrarectal challenge, including four macaques who controlled rectal mucosal infection without progressive systemic dissemination. These data suggest a new paradigm for AIDS vaccine development—vaccines capable of generating and maintaining HIV-specific TEM cells might decrease the incidence of HIV acquisition after sexual exposure.
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