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AIDS:
doi: 10.1097/QAD.0b013e328340fefc
Editorial Comment

HIV vaccines: sin boldly!

Cohen, George B

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Department of Biochemistry and Volen Center for Complex Systems, Brandeis University, Waltham, Massachusetts, USA.

Received 13 September, 2010

Accepted 22 September, 2010

Correspondence to George B. Cohen, PhD, Department of Biochemistry and Volen Center for Complex Systems, Brandeis, University, 415 South Street, Waltham, MA 02454, USA. E-mail: gcohen@brandeis.edu

In this issue of AIDS, Matano and colleagues present another chapter in their ongoing efforts to understand protective immunity in Burmese macaques carrying the protective 90-120-Ia+ major histocompatibility complex (MHC) haplotype [1]. The study touches upon many areas of interest to HIV vaccine researchers with perhaps the most interesting experiments still to come.

Previously, the authors demonstrated that vaccination of 90-120-Ia+ macaques with a relatively simple vaccine (SHIV-DNA prime, followed by a single Sendai virus boost expressing SIVmac239 Gag alone) lead to cytotoxic T lymphocyte (CTL) responses targeting multiple Gag epitopes and protection from wild-type SIVmac239 challenge, but not protection from an SIVmac239 variant, SIV-G64723-mt, containing five Gag-immune-escape mutations [2]. More surprisingly, a vaccine expressing only a single simian immunodeficiency virus (SIV) Gag epitope (as part of a GFP-fusion protein), also protected the macaques from wild-type SIV challenge [3]. Neither vaccine provided sterilizing protection, but during chronicity viral loads were controlled to below detection limits. However, in some animals, Gag CTL escape variants subsequently arose and control was lost.

In the current manuscript the authors now show that those vaccinated 90-120-Ia+ macaques that retain control over SIVmac239 expand their immune responses beyond Gag and now resist ‘superchallenge’ with SIV-G64723-mt. The authors also present evidence that protection against SIV-G64723-mt correlated with the presence of anti-Vif CTLs (that claim, however, requires further study as the regression analysis seems to rest largely on two time points taken from the same animal and not independent animals).

What is particularly striking about their system is how easily protection was elicited. This suggests that humans with protective MHC alleles [e.g. human leukocyte antigen (HLA) B57] might similarly benefit from vaccination and constitute ‘low hanging fruit’ for vaccine researchers. Indeed, the term ‘protective MHC allele’ may convey a false sense of security, for although the HLA-B57 allele occurs in roughly half of all elite controllers (elite controllers are <0.5% of all HIV-positive individuals), in at least one study, the allele was present in the HIV-positive progressive cohort at frequencies close to its expected population frequency (∼10%) [4]. Thus, many humans endowed with MHC ‘protection’ might still benefit by vaccination.

But what about the majority of individuals who lack the luck of MHC protection? Might vaccines targeting similarly protective and/or highly conserved epitopes be developed for them? That remains a big unknown. However, although spontaneous control of HIV/SIV is rare, control of SIV infection following live attenuated SIV (LA-SIV) ‘vaccination’ occurs more readily in the general monkey population and suggests a broadly effective HIV vaccine is possible [5,6]. Therefore, many studies now seek to understand correlates of immune protection in LA-SIV-infected or elite control animals.

The best of these studies do not merely look at immune responses in, for example, all elite controllers (or all LA-SIV-vaccinated animals), but rather try to discern differences, why some individuals with a protective MHC allele control viral replication and others with the allele do not. Unfortunately, understanding immune correlates at this level has proved difficult [7,8]. This may reflect the fact that standard functional assays (based on cytokine production) may not adequately reflect a CTL's ability to limit viral replication [9–11]. In that regard, data from the study by Matano suggest that ex-vivo CTL/virus suppression assays may be better predictors of vaccine potential than standard cytokine assays. However, even suppression assays were not perfect predictors in their study, as some macaques showed little ex-vivo suppression activity against SIV-G64723-mt, yet when challenged in vivo exhibited sterile protection. Perhaps this is because the peripheral-blood-derived CTLs used in the assay do not accurately reflect CTL activity found in more relevant, but less accessible mucosal sites [9].

Therefore, many challenges still remain, including overcoming the confounding influence of HIV and MHC diversity, before a firmer grasp of correlates of protection emerges. But even if these challenges are overcome, there may be limits to what can be learned from such studies. For example, no evidence links elite control or LA-SIV protection to neutralizing antibodies [5,12], yet neutralizing antibodies remain an active area of HIV research. Conversely, the genetic basis of malaria resistance (the sickle cell trait) has long been known, yet this has not led to a malaria vaccine.

Therefore, a refreshingly empirical aspect to Matano's work is that immune broadening in vaccinated animals was achieved by challenging with live SIV. Although it is unclear whether a similar degree of broadening might have been achieved by including more SIV antigens in the original Sendai-virus vaccine vector, the experiments still suggest an interesting conceit. In essence, prior vaccination has rendered wild-type SIV like a LA-SIV in both desirable (immune protection) and undesirable ways (some animals still die from the virus).

Safety issues long ago relegated LA-SIV research efforts to focus almost exclusively on immune correlates of protection, whereas its therapeutic potential has been largely ignored. Might this prove premature? The present work suggests prior vaccination might be used to make LA-SIV safer. A highly attenuated live SIV that would be a particularly good candidate for further therapeutic study (with or without prior vaccination) is SIV-delta4 (delta4 refers to the four deletions engineered into wild-type SIV) [13].

In macaques, SIV-delta4 provided protection against moderately high-dose vaginal challenge of a slightly heterologous viral swarm [13]. Moreover, there was no evidence of virulence (although this needs to be examined further). Additional boosting and broadening of SIV-delta4-induced immune responses might be achieved by vaccinating with ‘swarms’ of heterologous SIV-delta4 clones and/or by subsequent challenges employing LA-SIV strains of increasing strength (e.g. SIV-delta3) [6].

In short, why require vaccines to protect out-of-the-box against wild-type SIV? Why not first challenge with LA-SIV and use that as a stepping stone to stronger immune protection (this strategy recalls King Mithridates, who built his immunity to poison by drinking potions of increasing strength!)?

The ability of LA-SIV to diversify through mutation and immune escape, although potentially dangerous, may also allow it to use natural selection to tailor ‘vaccination’ to individual MHC haplotypes, expanding precisely those variants against which the immune response is weakest, and ‘educating’ the immune system to anticipate likely viral escape variants [6].

Perhaps live attenuated HIV may never be deemed safe enough for human trials. But without doing more monkey experiments we will never have all the data on which to argue! Besides, such experiments are interesting in their own right and address issues central to HIV vaccine research (i.e. how do we broaden a vaccine's protective range?).

Of course based on recent encouraging results [14,15] there may never be a need to use LA-HIV in humans. But what happens if things do not go as well as hoped, as too often they have not? In a well balanced vaccine portfolio, why not pursue this as well? Why settle for live attenuated SIV experiments designed solely for correlates of protection and experimental exegesis when in a world of unknowns we could ‘Sin Boldly’?

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References

1. Iwamoto N, Tsukamoto T, Kawada M, Takeda A, Yamamoto H, Takeuchi H, Matano T. Broadening of CD8+ cell responses in vaccine-based simian immunodeficiency virus controllers. AIDS 2010; 24:2777–2787.

2. Kawada M, Tsukamoto T, Yamamoto H, Iwamoto N, Kurihara K, Takeda A, et al. Gag-specific cytotoxic T-lymphocyte-based control of primary simian immunodeficiency virus replication in a vaccine trial. J Virol 2008; 82:10199–10206.

3. Tsukamoto T, Takeda A, Yamamoto T, Yamamoto H, Kawada M, Matano T. Impact of cytotoxic-T-lymphocyte memory induction without virus-specific CD4+ T-Cell help on control of a simian immunodeficiency virus challenge in rhesus macaques. J Virol 2009; 83:9339–9346.

4. Migueles SA, Connors M. Long-term nonprogressive disease among untreated HIV-infected individuals: clinical implications of understanding immune control of HIV. JAMA 2010; 304:194–201.

5. Koff WC, Johnson PR, Watkins DI, Burton DR, Lifson JD, Hasenkrug KJ, et al. HIV vaccine design: insights from live attenuated SIV vaccines. Nat Immunol 2006; 7:19–23.

6. Cohen GB. Mechanism of protection of live attenuated simian immunodeficiency virus: coevolution of viral and immune responses. AIDS 2010; 24:637–648.

7. Maness NJ, Yant LJ, Chung C, Loffredo JT, Friedrich TC, Piaskowski SM, et al. Comprehensive immunological evaluation reveals surprisingly few differences between elite controller and progressor Mamu-B*17-positive Simian immunodeficiency virus-infected rhesus macaques. J Virol 2008; 82:5245–5254.

8. Wojcechowskyj JA, Yant LJ, Wiseman RW, O'Connor SL, O'Connor DH. Control of simian immunodeficiency virus SIVmac239 is not predicted by inheritance of Mamu-B*17-containing haplotypes. J Virol 2007; 81:406–410.

9. Greene JM, Lhost JJ, Burwitz BJ, Budde ML, Macnair CE, Weiker MK, et al. Extralymphoid CD8+ T cells resident in tissue from simian immunodeficiency virus SIVmac239{Delta}nef-vaccinated macaques suppress SIVmac239 replication ex vivo. J Virol 2010; 84:3362–3372.

10. Saez-Cirion A, Lacabaratz C, Lambotte O, Versmisse P, Urrutia A, Boufassa F, et al. HIV controllers exhibit potent CD8 T cell capacity to suppress HIV infection ex vivo and peculiar cytotoxic T lymphocyte activation phenotype. Proc Natl Acad Sci U S A 2007; 104:6776–6781.

11. Yang OO. Will we be able to ‘spot’ an effective HIV-1 vaccine? Trends Immunol 2003; 24:67–72.

12. Walker BD. Elite control of HIV Infection: implications for vaccines and treatment. Top HIV Med 2007; 15:134–136.

13. Johnson RP, Lifson JD, Czajak SC, Cole KS, Manson KH, Glickman R, et al. Highly attenuated vaccine strains of simian immunodeficiency virus protect against vaginal challenge: inverse relationship of degree of protection with level of attenuation. J Virol 1999; 73:4952–4961.

14. Rerks-Ngarm S, Pitisuttithum P, Nitayaphan S, Kaewkungwal J, Chiu J, Paris R, et al. Vaccination with ALVAC and AIDSVAX to prevent HIV-1 infection in Thailand. N Engl J Med 2009; 361:2209–2220.

15. Hansen SG, Vieville C, Whizin N, Coyne-Johnson L, Siess DC, Drummond DD, et al. Effector memory T cell responses are associated with protection of rhesus monkeys from mucosal simian immunodeficiency virus challenge. Nat Med 2009; 15:293–299.

Keywords:

AIDS vaccine; cytotoxic T lymphocyte; major histocompatibility complex; mutation; simian immunodeficiency virus

© 2010 Lippincott Williams & Wilkins, Inc.

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