Diagram showing the licensed antiretroviral HIV drugs and the step in the replication cycle they act on. One of the complications that an individual can experience on HAART is immune reconstitution inflammatory syndrome (IRIS) (Letang, Miro et al. 2011). IRIS is seen in individuals recovering from immunodeficiency. Criteria for IRIS 1) Response to antiviral therapy by: viral loads >1 log10/ml decrease in RNA level 2) clinical deterioration of inflammatory of infectious condition upon antiviral treatment and 3) symptoms cannot be alleviated by: clinical course of treatment, medication side effects or toxicity, treatment failure or complete non adherence (Tappuni 2011). IRIS is also recorded in individuals with HIV co-infections such as tuberculosis (Lin, Lai et al. 2010). Additionally, individuals on HAART develop other diseases such as cardiac and metabolic complications that are affiliated with aging (Broder 2010). The side effects of HAART treatment and limited availability in HIV endemic areas are the drive for development of new immunotherapies for HIV. 

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... drugs can be grouped based on the mode of action and are placed into one of the following groups: nucleoside reverse transcriptase inhibitors (NRTI), nucleotide reverse transcriptase inhibitor (NtRTI), non-nucleoside reverse transcriptase inhibitor (NNRTI), protease inhibitor (PI), co-receptor inhibitor (CRI), integrase inhibitor (INI), and fusion inhibitor (FI) (De Clercq 2010). Figure 1 highlights licensed drugs and the mode of action of each group of drugs. In 1996, the first use of combination drug therapy was attempted using a protease inhibitor that was combined with an NRTI (Gulick, Mellors et al. 1997). ...

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... therapy, HAART, any therapy that will be approved is compared to benefits given by HAART. HAART reduces viral loads and restores some level of CD4+T cells in individuals that benefit from therapy. In a clinical setting, the hallmarks or surrogate markers of efficacy are reduction in viral loads and increase in the number of CD4+ T cells (Peto 1996; Peters 2000). While CD4 +T cells increase during HAART therapy leads to better prognosis of disease. Recent Proleukin (rIL-2) clinical trials, SILCAAT and ESPRIT volunteers showed increase in CD4 +T cells but the time to disease progression was not increased. These results have brought into question the validity of increase CD4+T cells as a readout for better disease outcome (Peters and Samuel 2010). The composition of the CD4+ T cell population recovered after therapy was evaluated at the end of the study to determine if the increase CD4+ T cells population was any different from populations seen after HAART therapy. Other T cells have also come into light in the last few years, Th17 cells and cells that secret IL-21 may play a role in the non-disease progression seen in African green monkeys and Sooty Mangabeys (Ciccone, Greenwald et al. 2011; Hartigan-O'Connor, Hirao et al. 2011; Milush, Mir et al. 2011). These trends are also being reported in long- term non-progressors and elite controllers (Hartigan-O'Connor, Hirao et al. 2011; Salgado, Rallun et al. 2011; Salgado, RallÛn et al. 2011). Results in animal studies have shown the possible role of Th17 cells in the gut mucosa in reduced bacterial translocation and slower disease progression (Cecchinato, Trindade et al. 2008; Maloy and Kullberg 2008; Hofer and Speck 2009). There is a lack of consensus on the hallmarks or surrogate markers for preventative vaccine trials. The ideal standard for a preventative HIV vaccine would be sterilizing protection. Sterilizing protection is complete protection from HIV infection, no detectable HIV at any time and no transmission of HIV. In 2007 an NIH workshop on vaccine efficacy resulted in a reported by Follman et al. which stated three parameters for evaluating HIV vaccine efficacy(Follmann, Duerr et al. 2007). The three parameters for evaluating vaccine efficacy are 1) reduction in risk of acquiring HIV 2) the reduction in cumulative risk of progressing to AIDS from the time of infection to diagnosis and 3) reduction in the risk of transmission of HIV to others. Vaccine endpoints are based on years of clinical studies (Peto 1996; Follmann, Duerr et al. 2007; MacLachlan, Mayer et al. 2009). Preclinical (usually NHP) studies have established surrogate markers for vaccine efficacy. Thus far, the most relevant marker identified as a determinant of disease outcome is the reduction of plasma HIV genome RNA levels following infection (Lavreys, Baeten et al. 2006). The viral set point is a consistent marker for determining disease progression; i.e. the higher the viral set point, the more likely a patient will progress to AIDS (Lavreys, Baeten et al. 2006; Kelley, Barbour et al. 2007) The levels of CD4+T cells in the blood of infected individuals can also act as a surrogate of disease progression (Chouquet, Autran et al. 2002). However, the correlation between CD4+ T cell levels in the blood and disease progression becomes more significant closer to the onset of AIDS. Modeling studies have concluded that a reduction in blood viral titers of 1-1.5 log 10 compared to peak infection leads to a significantly positive impact on progression to disease (Davenport, Ribeiro et al. 2004). The other aspect to a preventative vaccine is reduction of viral load leading to reduce transmission. A vaccine that results in a reduction in the rate or probability of transmission would have a positive impact on the HIV global epidemic. In the absence of a sterilizing vaccine, to have a vaccine, that not only lowers viral set point, but also reduces transmission rate would be beneficial (Gurunathan, Habib et al. 2009). Two years after the discovery of the causative agent of AIDS, the first sign of possible treatment was reported in 1985 with the development of the first antiretroviral compound (Mitsuya, Weinhold et al. 1985). This compound was called Retrovir (zidovudine, AZT) and became the first drug in the family of nucleoside reverse transcriptase inhibitors (NRTI). AZT targets the reverse transcription process of HIV’s replication cycle. Since AZT, several NRTI and other families of drugs targeting the replication cycle of HIV have been discovered. As of 2010, the FDA has licensed twenty-five antiretroviral drugs. These drugs can be grouped based on the mode of action and are placed into one of the following groups: nucleoside reverse transcriptase inhibitors (NRTI), nucleotide reverse transcriptase inhibitor (NtRTI), non-nucleoside reverse transcriptase inhibitor (NNRTI), protease inhibitor (PI), co-receptor inhibitor (CRI), integrase inhibitor (INI), and fusion inhibitor (FI) (De Clercq 2010). Figure 1 highlights licensed drugs and the mode of action of each group of drugs. In 1996, the first use of combination drug therapy was attempted using a protease inhibitor that was combined with an NRTI (Gulick, Mellors et al. 1997). Combinational therapy confirmed that there was a longer period of undetectable or reduced viral loads as well as recovery of CD4+T cells in the blood. Combination therapy or HAART is now the treatment of choice for HIV infected individuals and results in various clinical outcomes (Greenbaum, Wilson et al. 2008; Crabtree-Ramirez, Villasis-Keever et al. 2010). Individuals on HAART need to be monitored at all times to ensure the combinational therapy is effective and does not result in viral mutants. Individuals on HAART will need their treatment regimen adjusted upon development of viral resistance (Paci, Martini et al. 2011; Von Kleist, Menz et al. 2011). In addition to viral resistance, HAART is highly toxic to patients resulting in reduced patient compliance (John, Moore et al. 2001; Kronenberg, Riehle et al. 2001). Moreover, HAART treatment is expensive and therefore people living in developing countries have less access to drugs even though these are the locations where the epidemic is greatest. Based on surveys and clinical research the WHO has identified factors that need to be considered to determine HAART treatment in an adult (World Health Organization 2006) : 1) suitability of drug combination, 2) licensing of drugs by national regulatory department and recommended dose, 3) toxicity profile of the drug, 4) availability of laboratory monitoring, 5) potential of maintenance and adherence to treatment , 6) prevalence of co-existing infections ( e.g. Tuberculosis), 7) child bearing age, 8) availability of local and international manufacturers, and 9) price and effectiveness of drug. During HIV infection, the immune system does provide a defense aimed at eradicating the infection. This mounted immune response is insufficient and allows the viral infection to impair the immune system and persist. The use of therapeutics in infected individuals is aimed at overcoming the immune systems impairment to allow for viral control leading to decrease progression to AIDS. Human studies of long term non-progressor and elite progressors have observed a slower progression to disease in these individuals (Rodes, Toro et al. 2004; Okulicz and Lambotte 2011). Long term non-progressors are characterized based on absence of disease, low viral loads, and stable or increasing CD4 T cells.(Paroli, Propato et al. 2001). There is great need for drugs and vaccine strategies that reduce viral loads in infected individuals. Development of an effective HIV therapy needs to incorporate the knowledge that the immune system of an infected individual is dysfunctional. Figure 2 below simplifies the current knowledge of immune dysfunction and pathogenesis of HIV infection and table1(Fernandez, Lim et al. 2009). Immune dysfunction has been identified in Lymphocytes (T and B cells), NK cells, macrophages and even cytokine secretion. The frequency of CD+ T cells infected by (Chun, Carruth et al. 1997),(Douek, HIV in vivo is too low to account for the Brenchley et al. 2002) CD4 T cell loss Most apoptotic CD4+T cells in peripheral blood and lymph nodes of patients with (Finkel, Tudor-Williams et al. 1995) chronic HIV infection are infected HIV Naïve CD8+T cells, memory B and NK cells (D'Orsogna, Krueger et al. 2007),(Fauci, as well as CD4+T cells decline in HIV Mavilio et al. 2005), infection SIV-infected macaques exhibit a persistently activated immune system and rapidly progress to AIDS, while SIV-infected sooty (M Roederer 1995) mangabeys show normal T cell division rates and do not progress to AIDS. HIV-2 infection is associated with lower levels of immune activation, which may (Michel, Balde et al. 2000) explain the slower decline of CD4+Tcells compared with HIV-1 infection In mice, TLR7 stimulation unrelated to a virus infection induces immune activation (Baenziger, Heikenwalder et al. 2009) and immunopathology similar to that in HIV infection Table 1. Evidence of dysfunction of the immune system of HIV infected individuals (Fernandez, Lim et al. 2009) Current experimental therapies are grouped based on components and or modes of action, such as the HIV viral proteins targeted, the components of the immune system effected, fusion inhibitors, viral inhibitors, and HIV regulatory protein inhibitors, (Kilby 1999; Peters 2000; Pett 2009). Examples of these can be seen in Table 2. models, as well as infected individuals with HIV (O'Connell, Bailey et al. 2009). In an effort to induce more cytotoxic T lytic (CTL) responses viral vectors, such as canarypox virus and DNA vaccination, were implemented (Kutscher, Allgayer et al. 2010; Rosario, Bridgeman et al. 2010). One example of the use of recombinant canarypox virus vaccine to deliver viral proteins is the vaccine VCP1452 (ALVAC1452). ALVAC1452 was used to ...