Abstract
An effective vaccine remains the best solution to stop the spread of human immunodeficiency virus (HIV). Cellular immune responses have been repeatedly associated with control of viral replication and thus may be an important element of the immune response that must be evoked by an efficacious vaccine. Recombinant viral vectors can induce potent T-cell responses. Although several viral vectors have been developed to deliver HIV genes, only a few have been advanced for clinical trials. The live-attenuated yellow fever vaccine virus 17D (YF17D) has many properties that make it an attractive vector for AIDS vaccine regimens. YF17D is well tolerated in humans and vaccination induces robust T-cell responses that persist for years. Additionally, methods to manipulate the YF17D genome have been established, enabling the generation of recombinant (r)YF17D vectors carrying genes from unrelated pathogens. Here, we report the generation of seven new rYF17D viruses expressing fragments of simian immunodeficiency virus (SIV)mac239 Gag, Nef, and Vif. Studies in Indian rhesus macaques demonstrated that these live-attenuated vectors replicated in vivo, but only elicited low levels of SIV-specific cellular responses. Boosting with recombinant Adenovirus type-5 (rAd5) vectors resulted in robust expansion of SIV-specific CD8+ T-cell responses, particularly those targeting Vif. Priming with rYF17D also increased the frequency of CD4+ cellular responses in rYF17D/rAd5-immunized macaques compared to animals that received rAd5 only. The effect of the rYF17D prime on the breadth of SIV-specific T-cell responses was limited and we also found evidence that some rYF17D vectors were more effective than others at priming SIV-specific T-cell responses. Together, our data suggest that YF17D – a clinically relevant vaccine vector – can be used to prime AIDS virus-specific T-cell responses in heterologous prime boost regimens. However, it will be important to optimize rYF17D-based vaccine regimens to ensure maximum delivery of all immunogens in a multivalent vaccine.
Highlights
The human immunodeficiency virus (HIV) epidemic is one of the worst public health tragedies in human history
To check the presence of all simian immunodeficiency virus (SIV) inserts in their corresponding rYF17D viruses, we extracted viral RNA (vRNA) from all rYF17D/SIV stocks and carried out RT-PCR using primers flanking the E/non-structural protein 1 (NS1) intergenic region
In the case of rYF17D/Nef(45–210), we noticed a dim PCR fragment of approximately 700 kilobases (Fig. 1C). Since this might be a sign of mixed viral quasi-species, we sequenced the E/NS1 intergenic region of the rYF17D/Nef(45–210) stock – and the other rYF17D/SIV stocks as well – and confirmed that all SIV inserts were intact
Summary
The HIV epidemic is one of the worst public health tragedies in human history. More than 25 million human lives have been lost due to Acquired Immune Deficiency Syndrome (AIDS)-related causes since the first description of the disease in 1981 [1,2]. A myriad of vaccination platforms have been developed to induce HIV-specific cellular responses. Non-replicating adenoviruses and poxviruses, for instance, have been heavily exploited as potential HIV vector systems due to their good preclinical immunogenicity and safety profiles [15,16,17,18]. The high prevalence worldwide of preexisting immunity to Ad5 and the safety concerns raised by the rAd5-vectored HIV vaccine tested in STEP study have dampened the enthusiasm toward this vector platform [19,20,21,22]. Modified vaccinia virus Ankara (MVA)- and canarypox (ALVAC) expressing HIV immunogens have elicited low levels of cellular immunity in most human clinical trials conducted so far [23,24,25]. Novel viral vectors capable of safely inducing robust Tcell responses in humans are needed to advance HIV vaccine design
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