**5. HIV preclinical vaccine trials and predictive biomarker discovery in animal models**

To accelerate effort in bridging the translational gap between preclinical evaluation and clinical trials, it is pertinent to make animal model testing more clinical trial like. It is important that clinical endpoints may not be easily established in animal models because of the use of questionnaires to derive the quality of life issues from end users and cannot be replicated in experimental animals; however, there are recent attempts to model pain questionnaires in animals [81]. Obviously, animal models could be designed to use other endpoints that relate or translate into the expected endpoints of clinical trials. The humanized NSG among all other models have been successfully used for multiple *in vivo* preclinical validation studies. Potentially tested areas of validation include: (1) activation of human NK cells with an IL-15 superagonist to inhibit acute HIV infection; (2) delivering anti-CCR5 and antiviral silencing RNAs (siRNA) direct delivery to T cells in order to control viral replication and prevent CD4+ T cell loss; (3) provision of prophylactic protection from HIV infection through induction of neutralizing anti-HIV monoclonal antibodies and (4) suppression of viral replication through introduced engineered HSCs that expresses an HIV-specific T cell receptor (TCR).

It is possible to design an integrated preclinical approach using PDX models organized with systems biology to enable the discovery and development of predictive biomarkers in order to classify clinical tumor responsiveness to a novel agent [82]. Peradventure the classifier achieved a high level of accuracy in the experiment, and biomarker-driven clinical trials could be developed based on the prevalent rate of the identified biomarkers and their link with efficacy.

### **6. Next generation models**

The actual mechanism of sexual transmission is not precisely defined. What is known, however, is that HIV must be transmitted via the mucosal surfaces of the genital tract in both heteroand homosexual cases [83]. The fact that some individuals remain uninfected despite multiple exposures, whereas others get infected after an exposure to HIV-infected semen further confounds the situation. An animal model adapted to mucosal transmission of the virus would aid elucidation of the mechanisms and dose of virus required for transmission and provide a system for testing pharmacologic and biologic cofactors that may affect HIV transmission.

Although intravenous inoculation of SIV into macaques is a near perfect model for studies of pathogenesis, this route is not appropriate for studying factors involved in the sexual transmission of HIV. In one of the earliest experiments on the subject(macaques) [73], an animal model for the heterosexual transmission of HIV was developed by applying SIV onto the genital mucosa of both mature and immature male and female rhesus macaques. The study suggests that in the genital tract, the mucous membrane acts as a barricade to SIV infections as well as the non-involvement of spermatozoa and seminal plasma for genital HIV transmission.

Recent animal model research has focused on: (1) refinement of existing models and the development of new ones; (2) development of a model in response to latency especially HIV reservoir and immune perseverance and (3) evaluation of vaccine candidate that would elicit broadly neutralizing antibodies. As discussed in the chapter, a suitable and cost-effective animal model for HIV has been a goal spanning three decades with important milestones accomplished.
