**2. Initiation and progression of HIV infection**

The so-called latent period after the infection by the virus does not mean the virus is inactive [7]. Apart from humans, HIV-1 naturally infects a small number of nonhuman primate species, notably chimpanzees, which have been known to host the virus. Development of AIDS from HIV progression only occurs in humans [8, 9].

To gain insights in the transmission, pathobiology and progression of HIV infection, development of an animal model of HIV-induced immunodeficiency becomes mandatory. Several approaches were adopted to circumvent species tropism, that is, finding a similar lentivirus specific to other species that can cause similar symptoms, that is, immune deficiencies as a results of affinities to CD4+ T-cells and macrophages [9].

#### **2.1. In humans**

HIV-1 mainly infects through the genital mucosa with persistence chronic infection even when the virus triggers a notably strong cellular and humoral (both innate and adaptive) immunity. The reason for this action may stem from the virus genomic integration and subsequent cellular latent activity coupled with its extreme genetic variability, which provides a consistent immune specific escape. It is known that HIV-specific CD8+ lymphocytes are key players involved in initial decrease or suppression of viremia during acute HIV infection conversely this becomes highly dysfunctional and burdened under the strenous condition of chronic viral antigenic persistency [10, 11]. Viral neutralizing antibodies (Abs) are similarly triggered which also accompany immune escape. In some individuals, particularly elite HIV controllers or suppressors, they develop broad neutralizing Abs thereby have an effective control of the virus [12].

HIV infection is hallmarked by massive reduction of CD4+ T cells. During the primary HIV infection, the effector memory CD4+ T cells present in the gut mucosa are consistently and preferentially depleted [13]. The immunopathogenic presentations, in addtion to the systemic and chronic state of immune activation, are believed to contribute directly to HIV disease progression [14]. As a result, persistent antigenic stimulation presents a dysfunctional T-cell population with a loss of functional potential in cytokine production and cytotoxic activity, and the ability to proliferative in response to antigen stimulation. It is believed that this loss of immune balance between Th17 and regulatory T cells (Treg) during HIV disease progression may be the reason for the permeabilization of gut integrity and the pathogenesis of HIV.

Microbial translocation caused by gut permeability is thought to contribute to systemic immune stimulation seen in chronic HIV infection [15]. Additionally, hyper-responsiveness of plasmacytoid DCs during the cause of primary HIV infection, typically results in type-1 IFN excess production which contributes to systemic immune stimulation and HIV-1 disease progression [16].

Previous studies suggest a relationship between CD8+ T cells and the control of chronic HIV replication similar to that of simian immunodeficiency virus (SIV) viremia in non-human primates [17]. There are also rare individuals who control HIV-1 replication to levels which the virus cannot be detected also known as elite controllers with attendant characteristics [18]. This phenotype shows a strong association with certain MHC class I alleles with HIV-specific CD8+ T cells demonstrating superior cytotoxic capacity to kill any HIV-infected target.

Two examples of markers in HIV-1+ patients associated with T-cell exhaustion are Programmed Death-1 (PD-1) and T cell immunoglobulin and mucin domain 3 (Tim-3), which likely are caused by consistent antigenic stimulation [19]. These two molecules have been shown to participate in the downregulation of host immune responses, playing a key role in sustenance of T cell tolerance. It is obvious that Tim-3 is upregulated on virus-specific CD8+ T cells in subjects with chronic progressive HIV infection [19]. Similarly, another report stated the upregulation of Tim-3 on antigen-specific CD8+ T cells in subjects with active TB [20], buttressing similarity in the role played by the inhibitory receptor/ligand interactions with respect to modulation of host immunity to both HIV and M. tuberculosis infections in humans.

#### **2.2. In primates**

Numerous animal species could be infected with HIV, but hardly do they develop AIDS-like syndrome that approximates humans. Several reasons have been adduced to this including decreased viral infectivity factor, efficiency of HIV replication in the animal species and host

Evolutionarily, the Chimpanzee had been believed to be close to humans thus exploited in AIDS research. Scientists later understood that HIV does not infect the Chimps but SIV besides the high cost attached to its use in HIV diseases research. Maintaining a primate research facility tends to incur huge cost, and most centers are being shut down around the world. These animal models are used to study diseases and infections of lentiviruses specifically Feline Immunodeficiency Virus (FIV) in cats, and Simian Immunodeficiency Virus (SIV) in monkeys. However, these viruses are distinct from HIV and have the problem associated with extrapolating data from experimental studies [2]. Consequently, researchers resorted to intensive search for alternative experimental model for HIV infection. Mouse, being 90% genetically similar to humans poses as a 'go' option hence the intensive and successful development of mouse models for HIV research.

It is worth mentioning though that testing the effectiveness and toxicity of anti-HIV medications such as anti-proteases and HIV-1 Reverse Transcriptase inhibitors (AZT, and 3TC) are experimentally conducted using cell culture techniques derived from human white blood

Murine experimental HIV models are putatively regarded as the most extensive approach appropriate for evaluating the safety, efficacy and salient aspects of novel drugs or vaccine candidates. These models, to a high degree, have achieved remarkable success thus bridging the gap between preclinical and clinical evaluations on humans. Similarly, they are effectively utilized in toxicological evaluations of drugs, testing of novel anti-HIV small and interfering molecules and pre clinical trials. Bearing that humans cannot be used experimentally, continued development of the animal subjects for use in research has seen tremendous improvement and modifications [2].

The so-called latent period after the infection by the virus does not mean the virus is inactive [7]. Apart from humans, HIV-1 naturally infects a small number of nonhuman primate species, notably chimpanzees, which have been known to host the virus. Development of AIDS

To gain insights in the transmission, pathobiology and progression of HIV infection, development of an animal model of HIV-induced immunodeficiency becomes mandatory. Several approaches were adopted to circumvent species tropism, that is, finding a similar lentivirus specific to other species that can cause similar symptoms, that is, immune deficiencies as a

HIV-1 mainly infects through the genital mucosa with persistence chronic infection even when the virus triggers a notably strong cellular and humoral (both innate and adaptive)

cells [3–5]. No such mechanistic model for HIV pathobiology has been created [6].

**2. Initiation and progression of HIV infection**

from HIV progression only occurs in humans [8, 9].

results of affinities to CD4+ T-cells and macrophages [9].

**2.1. In humans**

immunologic response proteins thus referred to as host factors [2].

160 Experimental Animal Models of Human Diseases - An Effective Therapeutic Strategy

Several non-human primates are naturally infected with simian T lymphotropic virus (STLV) types I and III. The exogenous type C retrovirus isolated from macaque monkeys in captivity reported in the USA with an immune deficiency syndrome otherwise known as simian AIDS has been termed STLV-III mac. It is worthy to note that STLV types I and III are similar and/ or related to the human T lymphotropic viruses (HTLV-I and LAV/HTLV-III) the causative agent(s) for AIDS. The striking similarities include growth characteristics, similar size of viral structural proteins, morphology, T4 cell tropism and serological cross reactivity of viral proteins [21]. The residing proteins found in the simian virus also have similar molecular weight with respect to the gag and env encoded proteins of LAV/HTLV-III [22]. Both are recognized by reference LAV/HTLV-III human serum and monoclonal antibodies to the core protein, p24, of the human virus. These proteins are basic and have relevant information needed in the development of candidate vaccine, rapid diagnostics and elucidation of HIV virology [21]. Knowledge of the molecular structure and pathobiology of simian viruses yielded a wealth of information and was very useful in the study of the HIV and AIDS in humans [21].

**3. Defining animal models**

SIV in macaques follow a disease course that is similar to HIV in humans. This is useful since it can be exploited for evaluation of drug/vaccine candidates closely related to that being developed for respective human HIV infection. The model thus provides leading and insightful results in and related to drug safety and efficacy of prospective candidates [1]. Certain animal models have been developed over the years through intensive research for insightful and revealing studies on HIV/AIDS and associated cancers. These include both specific rat and mouse models designed for HIV pathogenesis and candidate vaccine development. Scientists have albinitio created the SIV non-human primate(NHP) model (**Figure 1**), for example, the Indian-origin rhesus macaque (*Macaca mulatta*), *Cynomolgous* macaque (*M. fascicularis*), and pigtailed macaque (*M. nemestrina*), for same purposes including development of microbicides. These models are useful in elucidating the mechanism of AIDS pathogenesis as well as

Experimental Animal Models of HIV/AIDS for Vaccine Trials

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in preclinical testing of novel drugs directed at HIV infection and cancer [1, 25, 26].

*Calmette Guerin* (BCG) [28] and *M. tuberculosis* co-infection [29].

**Figure 1.** Historical trend and impact of HIV/AIDS research in NHPs.

SIV infection in macaques has been used as a model for AIDS since it was established that non-human primates are resistant to infection by HIV (**Table 1**). Simply put, SIV is a retrovirus causing immunodeficiency similar to AIDS in Asian macaques. More importantly, Macaques also develop TB that is very similar to that of humans, other notable similarities in viral activity and disease manifestation include cavitary lung disease and necrotic lession. The TB latency seems in contrast to humans to have only a small proportion of lately infected Macques develop reactivation [27] though it develops persistent Mycobacterium *bovis bacillus* 

**3.1. Macaques**

#### **2.3. In rodents**

In addition to looking for other lentiviruses, rodents were genetically engineered so that their cells could express both the human version of the CD4 receptor as well as the chemokine co-receptors to which HIV-1 binds, notably the main route of entry to target cells [23]. The envelope glycoprotein 120 (gp120) domiciled on the surface of the HIV-1 virus fuses with the host target cell membrane specifically invoking a cascade of activity involving the CD4+ receptors and chemokines co-receptors thus initiates viral entry. In successfully developed transgenic mice, however, the gp120 will not successfully bind to CD4-expressing T cells thus preventing targeted cell infection. Replacement of the gp120 coding region of the HIV with gp80 region obtained from the murine leukemia virus results in altered virus thus overcoming the problem. This chimeric HIV-1 clone could infect conventional mice cells, but not human cells. Although this has been extensively adopted in research, these models could not produce some disease progression seen in humans, for example, neuro-HIV disease [9].

Humanized mice model also known as humice are mice carrying functioning human genes, cells, tissues, and/or organs engraftment mostly on genetically modified mouse background. They replicate the human HIV immune responses and are currently used to study mechanisms of immune activation, mucosal transmission and prevention, immune pathogenesis and anti-viral drug development.

#### **2.4. Developmental perspectives of HIV animal models**

The development of fitting animal models is seen as one of the most important challenges in studies of co-infection, since HIV does not cause disease in rodents and in non-human primates [24].

Lentiviruses specific to other species that also compromise the immune systems in ways similar to HIV-1 have been useful in providing information about the pathogenicity of the virus. In spite of the similarities to HIV, there are species-specific differences in their respective gene products as well as the pathogenesis of the disease fueling the drive for search of better models of HIV disease control.
