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The ability of HIV to rapidly form mutant strains resistant to particular drugs has made combination therapy the norm in HIV treatment (Janeway et al, 2005). Highly-active antiretroviral therapy (HAART) is a strategy involving the use of several antiretroviral drugs designed to slow the progression of HIV. Currently, there are over 20 drug products in four classes licensed for use: nucleoside/nucleotide analogs, non-nucleoside reverse transcriptase inhibitors, protease inhibitors, and fusion inhibitors (Hoffman and Mulcahy, 2006). Combinations of these drugs are used to inhibit HIV replication at various points during its lifecycle. The first few weeks of successful HAART treatment are marked by a reduction of virons in the plasma of up to 95% during which time the production of virus molecules from actively infected cells declines rapidly (Janeway et al, 2005). During the next 3-4 months, viremia continues to decline to below detectable levels (the current detectable level is 50 copies/mL) ( Hoffman and Mulcahy, 2006). The multiple mutations necessary for the virus to overcome HAART has allowed a large number of patients to have viral loads below the detectable limit after 10 years of treatment (HAART has only been around for 10 years), and it is believed that CD+ T cell levels aren't affected until viral load reaches 10,000 copies per mL (Hoffman and Mulcahy, 2006). HAART, however, cannot eliminate the virus from an infected individual. Anti-retroviral drugs are not capable of affecting the non-replicating proviruses in quiescent T cells, and so the virus can resume replication at any time if the drugs are stopped (Rubbert et al, 2006).
Because of the effectiveness of this strategy, most AIDS cases found in Western countries are in individuals not receiving retroviral therapy, but the drugs are not without their side-effects, and can be quite expensive (Hoffman and Mulcahy, 2006): it was estimated that in 2000, the average cost for lifetime treatment for an individual with HIV was around $3 million (AVERT, 2007). This figure is obviously far out of reach of the majority of HIV+ individuals in the world. Moreover, HIV is constantly mutating, requiring the use of new drugs; in 2004, it was estimated that nearly 10% of the people diagnosed with HIV were diagnosed with a drug resistant strain (AVERT, 2007).
Figure 1. Above is a Jmol image of an HIV and MHC binding fragment from human CD4. Antibodies capable of interrupting with the HIV:CD4 interaction may play a role in future vaccines. The image is from the RCSB Protein Data Bank. PDB 1CDI.
Future Goals: The Search for a Vaccine
The ultimate goal of HIV/AIDS research is a safe vaccine that effectively protects uninfected humans from contracting the virus, but a number of factors complicate the development of a working vaccine for HIV. The exact quantity of virons needed to begin an infection in humans is not known, but it is believed to be very small, and it is believed that a latent infection can be established within the first few rounds of viral replication (William, 2003). The rapid mutation rate of HIV has created an extraordinary level of diversity that makes it difficult to target with a single vaccine. HIV-1 (with which most research is targeted towards) has been divided into three main branches: the M (main) group, N (new) group, and O (outlier) group, but the M group is responsible for over 99% of infections worldwide (Moore et al, 2001). Group M is further divided into nine different subtypes (Moore et al, 2001), which can differ from each other by as much as 35% of the amino acid sequence (Mwau et al, 2004). Even within a subtype, amino-acid variation can be as high as 20% (Mwau et al, 2004) and one infected individual can have a virus diversity in the range of 10% of amino-acid sequence (Moore et al, 2001).In addition to the difficulties inherent in the nature of HIV, there are two other main obstacles retarding vaccine development: naturally occurring immune responses capable of eliminating an infection have note been found, and animal models of the virus are imperfect, resulting in contradictory data from HIV and SIV challenged animals (Esparza, 2001).
All currently licensed vaccines rely on the production of neutralizing antibodies (Nigman et al, 2006) and the only HIV-1 complex known to be useful to humoral immunity is the envelope glycoprotein complex (Moore et al, 2001). As it is necessary for entry into the cell, the CD4 binding-site on gp120 is highly conserved, but unfortunately, is not easily accessible (Moore et all, 2001). It is not until CD4 molecules on the target cell interact with the gp120 trimer that a conformational shift occurs, displacing the variable chains that usually shield the CD4 binding site from antibody (Moore et al, 2001). While it has been shown that protection in macaques to a strain of SHIV could be achieved through the passive transfer of a human antibody, the titer of antibody needed was much higher than can be found through current vaccination methods (Parren et al, 2001) and there is no guarantee that the technique would yield the same results in humans challenged with HIV.
The newest generation of candidate vaccines still seek to generate an antibody response, but many are directing their focus towards the cellular cytotoxic response. CTLs are not able to provide sterilizing immunity, but do have their advantages over antibodies as the antigens can originate from proteins buried within the virus (Mwau et al, 2004). Moreover, activated CTLs have been shown to inhibit HIV virons from entering new cells in vitro through the secretion of various soluble factors (Mwau et al, 2004). Previous approaches to vaccination based on the delivery of viral proteins or whole, attenuated viruses were generally successful in activating CD4 cells, and with the addition of adjuvant, could occasionally activate a cytotoxic response from T cells, but vector-based vaccines are now the focus of much of the attention (Nigman et al, 2006). Canarypox, in particular has been used in a lot of recent research, and is considered safe vector as it does not replicate completely in humans (Nigman et al, 2006). Recombinant canarypox directed against the B subtype of HIV-1 has even been shown to induce cytotoxic responses capable of killing cells infected by other subtypes of HIV-1 because the CTLs can respond to the more conserved antigens of intraviral proteins (Nigman et al., 2006).
Combining efforts to elucidate a CTL response, as well as an antibody response to deter primary infection, many candidate vaccines have turned towards the so called "prime-boost" method. Recombinant viral vectors "prime" the cellular response, and are then followed by the "boost" of recombinant envelope protein to generate the humoral response (Nigman et al, 2006). The prime-boost method lowers the amount of viral envelope-protein that is needed to generate that maximum antibody titers, but the antibodies produced still produce rather ineffective results (Nigman et al, 2006).
In the short term, vaccines with increased ability to stimulate a cytotoxic response to HIV may be able to slow the progression to AIDS in infected individuals, and theoretically, could even hold virus levels low enough to prevent the spread of the virus to other people (Mwau et al, 2004). In the long term, it seems possible that an effective vaccine could be developed, but it will require a greater understanding of the gp120 and gp41 envelope proteins as well as new methods of antigen-delivery that increase cellular and humoral responses while still not presenting danger to the vaccinee.
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