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Title: AAV-Delivered Antibody Mediates Significant Protective Effects against SIVmac239 Challenge in the Absence of Neutralizing Activity}
Article:
Abstract:
Long-term delivery of potent broadly-neutralizing antibodies is a promising approach for the prevention of HIV-1 infection. We used AAV vector intramuscularly to deliver anti-SIV monoclonal antibodies( mAbs) in IgG1 form to rhesus monkeys. Persisting levels of delivered mAb as high as 270 μg/ml were achieved. However, host antibody responses to the delivered antibody were observed in 9 of the 12 monkeys and these appeared to limit the concentration of delivered antibody that could be achieved. This is reflected in the wide range of delivered mAb concentrations that were achieved: 1–270 μg/ml. Following repeated, marginal dose, intravenous challenge with the difficult-to-neutralize SIVmac239, the six monkeys in the AAV-5L7 IgG1 mAb group showed clear protective effects despite the absence of detectable neutralizing activity against the challenge virus. The protective effects included: lowering of viral load at peak height; lowering of viral load at set point; delay in the time to peak viral load from the time of the infectious virus exposure. All of these effects were statistically significant. In addition, the monkey with the highest level of delivered 5L7 mAb completely resisted six successive SIVmac239 i. v. challenges, including a final challenge with a dose of 10 i. v. infectious units. Our results demonstrate the continued promise of this approach for the prevention of HIV-1 infection in people. However, the problem of anti-antibody responses will need to be understood and overcome for the promise of this approach to be effectively realized.
Introduction:
There are good reasons for believing that development of an effective preventive vaccine against HIV-1 is going to be a very difficult task. HIV-1 has evolved a variety of immune evasion strategies that allow continuous virus replication in the face of apparently strong host immune responses, both cellular and humoral[1, 2]. For a vaccine to be effective it will likely need to either completely block the initial infection or to provide immune responses that are more effective than those resulting from infection. One promising, creative approach is to use adeno-associated virus( AAV) vector to deliver antibodies with potent and broadly neutralizing activity[3–7]. This method is an alternative to classical immunization and independent of the host immune system. Proteins delivered by AAV vector can persist at stable levels for years[8, 9], and AAV vectors have proven to be safe and effective in human gene therapy trials against a number of diseases[10–13]. More than a dozen potent broadly neutralizing anti-HIV-1 monoclonal antibodies have already been characterized; they are human-derived, they can effectively neutralize more than 90% of circulating HIV-1 strains, and they represent a range of different specificities[14–21]. In a previous pioneering study performed in monkeys, anti-SIV immunoadhesins( antibody-like molecules) were delivered by AAV vector and a reasonable percentage of the monkeys exhibited apparent sterilizing immunity against intravenous( i. v.) challenge by SIVmac316[4]. However, SIVmac316 is an easy-to-neutralize SIV strain, one third of the immunized monkeys developed antibody responses( anti-anti) to the delivered immunoadhesin, and monkeys with anti-anti responses were not protected against the challenge. It was not clear from that initial study to what extent anti-anti responses may have resulted from delivery of immunoadhesins, which do not represent an authentic IgG structure. We decided to build upon these studies by using AAV to deliver authentic IgG and to examine protection against the difficult-to-neutralize strain SIVmac239. At the time these studies were initiated, there were no monoclonal antibodies available that could neutralize SIVmac239. We thus converted the previously reported immunoadhesins 4L6 and 5L7[4] into authentic IgG versions. These anti-SIV mAbs in IgG1 form contain only authentic rhesus IgG sequences. In this study we describe the AAV-mediated delivery of these full-length immunoglobulins to rhesus macaques and the protective effects of the non-neutralizing antibody 5L7 IgG1 against SIVmac239 challenge.
Discussion:
Given the current availability of a spectacular array of human mAbs with potent broadly-neutralizing activity against HIV-1, it has become possible to envision prevention scenarios in which cocktails of such antibodies could be used to provide a sterilizing barrier to infection against the vast majority of HIV-1 strains circulating in the population. However, it is not practically feasible to consider passive delivery of purified mAbs over a period of years for prevention purposes. AAV vectors are ideally suited for this purpose. The only protein expressed from AAV vectors is derived from the inserted transgene put into it. As long as the protein is viewed as self, protein expression can continue for prolonged periods. In fact, there are already examples where proteins delivered by AAV vector have persisted at stable levels for years[4, 8, 9, 37], including animal 84–05 in our study. Since muscle cells exhibit little or no turnover, they are a preferred source for long-term delivery purposes. Little or no integration of AAV vector DNA into host genome sequences has been observed[38–40] and AAV vectors have proven safe when used in clinical settings to reverse hereditary absence of gene function[10–13]. The molecularly cloned SIVmac239 is a difficult-to-neutralize strain with many of the characteristics of a primary isolate. It has been extensively used as a challenge strain to gauge efficacy of vaccine approaches in monkeys, and it has generally proven quite difficult to achieve protection against[29, 30, 41–43]. Being a molecular clone, it avoids complications of interpretation that may arise when a heterogeneous mixture of sequences in an uncloned virus stock are used and when differences in neutralization sensitivity/resistance may exist within the mixture[44, 45]. The presence of AAV-delivered 5L7 mAb in our experiments significantly delayed the time to peak viral loads and significantly lowered SIVmac239 viral loads both at peak viremia and at viral load set point. The lowering of viral load set points in the 5L7 mAb group was also significantly different from the 4L6 mAb group, lending additional support to the significance of the protective effects. It is also likely that the lack of SIVmac239 acquisition in monkey 84–05 is also a real effect of the high concentration of 5L7 mAb in this animal. The 10x( 6th) challenge of this monkey utilized the same dose of the same stock that has been used previously in dozens of control monkeys without a failure of infection acquisition[27–35]. The protective effects in the 5L7 mAb group occurred in the absence of any detectable neutralizing activity of the 5L7 mAb against the SIVmac239 molecular clone even out to 1 mg/ml. To our knowledge, this is the first demonstration of significant protective effects of a mAb in the absence of an ability to neutralize the challenge virus[46, 47]. Recent studies have emphasized the importance of Fc-mediated effector functions in contributing to the protection afforded by mAbs capable of neutralizing the SHIV used for challenge[48–52]. These studies modulated the Fc-mediated effector functions of a neutralizing mAb up or down in order to examine the effects on protective capacity. Some vaccine studies have also found associations of ADCC activity with protective efficacy[53–57]. Effector functions potentially contributing to the protective effects of the 5L7 IgG1 observed in our current study include but are not limited to ADCC activity and complement-mediated virolysis. Along these lines, it is fascinating that the 5L7 mAb circulating in monkey 84–05 was not only present at extraordinarily high levels, it had extraordinarily high ADCC activity on a per μg basis. Because of the nature of the ADCC assay that was used, it seems likely that the extraordinarily high ADCC activity in the serum of this one animal results from differences in post-translational modifications of the 5L7 mAb. Decreased core fucosylation or terminal sialylation have been shown to dramatically increase Fc-mediated ADCC activity[58–62]. One question addressed in our current studies was whether the anti-anti responses to the immunoadhesin constructs observed in Johnson et al.[4] could be avoided by delivery of authentic IgG. The answer is a clear no. Immune responses to the delivered IgG1 antibody described here were readily detected in 9 of the 12 test monkeys and these appeared to limit the levels of delivered antibody that could be achieved. This is especially true of the 4L6 group in which the levels of delivered 4L6 IgG1 mAb dropped precipitously coincident with the appearance of the anti-anti responses. In separate studies, we have observed strong antibody responses in rhesus monkeys to AAV-delivered, rhesusized anti-HIV-1 mAbs in 24 of 24 opportunities using a ssAAV1 vector design identical to the one used for the studies described here. This contrasts strikingly with studies in humans in which 13 sequential administrations of 1g of anti-HIV mAb failed to elicit anti-anti responses to the three different antibodies that were used in each of the 12 test subjects[63, 64]. With our 5L7 and 4L6 experiments, it is possible that a lack of natural pairing of IgG heavy and light chains contributed to their immunogenicity. With our anti-HIV experiments referred to above, it is possible that the failure to rhesusize the variable regions contributed to their immunogenicity. Nonetheless, our results serve as a warning signal for the potential of immunogenicity problems when AAV is used to deliver anti-HIV mAbs in human trials.
AAV-mediated antibody delivery represents a promising alternative to classical vaccine approaches for the prevention of HIV/AIDS in humans . We used recombinant adeno-associated viral vectors ( rAAV ) as gene carrier to deliver anti-SIV ( simian immunodeficiency virus ) antibodies to monkeys . This non-classical immunization approach is independent of the host immune system and the AAV-transferred gene into muscle cells produces antibodies with known specificities . Our goal was to determine what serum levels of delivered antibodies can be achieved by using two different vector strategies , whether the delivered antibodies provoke an immune response , and to what degree the delivered non-neutralizing antibodies have the ability to protect against SIV virus challenge . This approach allowed for sustained levels of delivered antibodies in serum and exhibited significant protective effects against highly pathogenic SIVmac239 challenge . However , immune responses limited the concentration of circulating antibodies that could be achieved . This problem will need to be understood and overcome for the promise of this approach to be effectively realized .