Background: macaque studies
When I started to work on this topic, the general scenario was rather demotivating: the approaches that had so far been attempted had led to mixed or disappointing results. Among the strategies that had so far been attempted to raise anti-HIV immunity, the most frequently adopted approaches had been based on the administration of distinct viral portions either as purified proteins or genetic material in vectors able to induce the organism to produce the viral components and giving a more sustained exposition of the organism to the desired viral targets.
In 2013, my coworkers and I started to collect the firstin-vivo结果来自旨在消除HIV和针对HIV-1储层的实验策略。该储层是由那些感染的细胞贡献的，这些细胞携带了以潜在形式整合的病毒，并长时间累积了，尽管有效的抗逆转录病毒疗法（ART），但仍负责HIV的持续性。如果终身艺术被暂停，他们的重新激活会引起感染。但是，在这种情况下，猕猴长期感染了猿猴HIV同源物SIVMAC251，已接受了一种旨在在暂停ART之前先旨在消除病毒储层的疗法。（可以找到更多信息这里）
The result was, in my opinion, remarkable: although displaying periodic rises in viral load, the macaques were able to consistently “push back” the virus to undetectable levels, in the end maintaining acceptable CD4+ T-cell counts (an important prognostic marker in retroviral infections) as well as healthy conditions for the entire follow up (> 2 years).
Targeting the conserved regions of HIV
Surprisingly, my former Ph.D. student, Iart Luca Shytajfound获得的结果不仅与HIV储层限制有关，还与针对病毒capsid蛋白GAG的特定免疫产生的生成有关。因此，我们决定进一步分析这些意外的免疫反应。We found免疫反应是针对最不可能突变的HIV GAG蛋白的那些部分，即负责GAG多聚化和病毒颗粒“骨骼”形成的那些。如果GAG蛋白的这些部分应广泛突变，那么病毒体的一般结构将受到损害，并且病毒将变得不感染。
These responses belonged to the type called “cell-mediated responses”, which, differently from the antibody-mediated responses are not aimed at neutralizing the pathogen, but at destroying their source, i.e. the infected cells able to produce new viral progeny.
A few years later, the group of Ricardo Sobhie Diaz at the Federal University of Sao Paulo (UNIFESP), Brazil, thought that the contemporary current approaches to an HIV vaccine needed radical changes and decided to direct the immunity specifically towards the aforementioned highly conserved portions of Gag.
A personalized approach
In our现在发表的文章在艾滋病研究和治疗中，我们对临床试验中每个参与者感染的病毒进行了测序。我们还表征了参与者的HLA分子，这些分子在人群中有所不同，可以将病毒表位呈现给称为CD8+ T淋巴细胞的免疫细胞，从而可以获得消除感染细胞的能力。生物信息学技术确定了每个试验参与者的病毒的部分，这些病毒可以最好地结合其单个HLA分子。这样鉴定出的病毒肽被吸附到称为树突状细胞的免疫细胞的HLA分子上，并源自试验参与者的血液。然后将细胞重新接种在同一供体中。
该试验导致两名患者在实验治疗方案结束时表现出无法检测的病毒DNA，即病毒在体内沉默的形式），在直肠的活检中很明显（HIV在标准期间隐藏了标准期间HIV的地方艺术）。
Implications for the future
This research furnishes proof of concept for immunogenicity and partial efficacy of personalized immunization through autologous dendritic cells pulsed with peptides from the highly conserved regions of the HIV capsid Gag protein. A number of obstacles still need to be overcome before rendering it a potential novel therapy aimed at HIV eradication. The efficacy is still partial, and the method still needs improvement, for example through addition of specific drugs aimed at targeting the HIV reservoir. The process is still too complicated to become scalable. Full automatization through state-of-the-art techniques will be required to decrease the cost and manpower needed at an industrial level.
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