Human Immunodeficiency Virus Hiv Is The Causative Agent Biology Essay


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Human immunodeficiency virus is the causative agent of acquired immune deficiency syndrome. The AIDS pandemic started nearly thirty years ago and more than 60 million people have been infected with HIV-1, the more virulent strain (2). While there have been successful improvements in treatments and drugs, for every infected person receiving antiretroviral therapy about 2.5 new people infected with HIV (3). Antiretroviral therapy has been successful in extending the lives of HIV infected patients and allowing them to live a more fulfilling life, but to curve the current trend of infection of HIV, a vaccine is needed. The goal of a HIV vaccine would to either prevent infection or reduce the viral reservoirs after clinical disease progression (2).

While vaccines seem like the ideal strategy for HIV prevention, there are many challenges that exist in developing an effective HIV vaccine. The challenges for HIV vaccines include diversity of HIV-1 clade and sequence and the ability of the virus to evade adaptive immune response, the body's inability to recruit and induce an extensive antibody response, and the early establishment of latent viral reservoir (2).

HIV, like other retro viruses, is driven by an error-prone reverse transcriptase with no proofreading capability. Consequently, the HIV strain has differentiated into nine divergent clades with multiple recombinant forms (2). For instance, an amino acid sequence for the Env protein can differ by 20% within the same clade and over 35% in different clades (2). It can be assume that the vaccine's efficiency will subsequently diminish with increasing divergence between the vaccine antigen and quickly mutating virus (2). While new antibodies are induced, new mutations allow the virus to continuously evade the immune system (3). An effective and immunogenic HIV vaccine must contend with the high degree of viral diversity.

Another difficulty is the human body inability to battle and eradicate the virus. HIV infects important cells of the immune system, such as CD4+ cells, macrophages, natural killer cells and dendritic cells. HIV causes apoptosis of infected cells and uninfected nearby cells (5). Cell-mediated immunity is lose with a declining of CD4+ cells and opens the body up to multiple opportunistic infections (5).

Last, latency is established in the early stage, within days to weeks, after an infection. The window period when HIV can be eradicated and vulnerable to the immune system is very short and most of the time HIV infected patients are unaware they are infected in the early stages of infections (3) (5). Integration is the phase that HIV integrase insert a segment of HIV genetic material into the host cell DNA (5). While it is dormant in the host DNA, it is invisible to the immune system and another mechanism that allow the virus to evade the immune system (3). Once latency is establish, it has not been possible to eradicate the virus even when the patient is actively on antiretroviral therapy (3).

While there are challenges to developing a vaccine, there are vaccines that are currently in trials and testing. Efficiency and immunogenicity are important in designing a vaccine, safety also a factor to consider. Koblin et al are concern with the route of administration about its influence to safety (1). While the route of administration can increase immunogenicity and efficiency, if fewer doses are needed can also lessen the cost of the vaccine development (1). The routes of administration to be considered are subcutaneously, intradermally, or intramuscularly. Dermal vaccination (subcutaneous or intradermal) plays a role in innate immunity by providing a physical barrier and adaptive immunity by inducing dendritic cells and keratinocytes. Maturation of the dendritic cells to Langerhans cells with viral antigens presented them on can migrate to lymph nodes to alert the T cells to initiate a cascade of immunogenic response (1). On the other hand, intramuscular delivers the antigens to an area with fewer antigens presenting cells (1). In addition, dermal vaccination requires a lower dose to cause a similar or better immune response than intramuscular vaccination (1). The vaccines used are DNA vaccine prime and a recombinant replication-defective adenovirus type 5 boost (rAd5) while using a prime-boost vaccine strategy (1). It is hypothesized that the intradermal or subcutaneous route of administration of the rAd5 boost is better than the intramuscular route in eliciting a vaccine-induced HIV-specific T cell response (1).

Vaccines strategies can be divided into two categories, traditional and novel (2). Traditional vaccines include live attenuated viruses, whole killed viruses, and protein subunits. Traditional vaccines have been effective in preventing diseases such as smallpox. However, traditional vaccines are limited in their efficiency of designing a HIV vaccine. While live attenuated SIV used in rhesus monkeys shown to provide protective properties, the use of live attenuated HIV in humans present a safety and reversion possibility (2). Also, whole killed viruses and subunits are limited in their inability to recruit neutralizing antibodies and CD8+ cells (2). On the other hand, novel vaccine strategies include gene-delivery technologies such as plasmid DNA vaccines and live recombinant vectors expressing HIV antigens. Plasmid DNA vaccines are simple and versatile but high doses of DNA vaccines are required to initiate an immune response (2).

The DNA vaccine prime in the trials composes of four closed circular DNA plasmids. One of the plasmids expresses clade B HIV-1 Gag/Pol/Nef polyprotein, while the other three plasmids express HIV-1 Env glycoprotein from clade A, Clade B, and Clade C. The DNA vaccine were administrated as a 1ml injection of 4mg of DNA plasmids (1).The recombinant vaccine is a recombinant replication-defective adenovirus type 5 boost containing five adenoviral vectors. The vectors express one of the four HIV antigens, Clade B Gag/Pol polyprotien, clade A Env, Clade B Env, and clade C Env, in a 3:1:1:1 ratio. The rAd5 vaccine were administrated as 1 ml injection of 1x 1010 PU (1).

The vaccine administration strategy is prime-boost. Prime boost involves an initial DNA vaccine and subsequent boost vaccines to produce high levels of anti-HIV antibodies (2) (6). The boosts are to ensure that there is a high amount of DNA to initiate an immune response.

The protocol for the trial started in November 2006 following the HIV Vaccine Trials Network (HVTN) protocol # 69. The trial was designed to be a multicenter (in the United States and Peru), open label, randomized trial that included 90 participants (1). All participants followed the prime-boost strategy with a DNA prime vaccine given intramuscularly and rAd5 boost vaccine given one of the three routes: intramuscularly, intradermally, or subcutaneously (30 participants in each group) (1). DNA prime boosts were given at months 0, 1, and 2. The rAd5 boost vaccine were given at 6 months. Follow-up examinations were given two weeks after each vaccinations and post-vaccination at months 7, 9, and 12. The follow-up examinations were used to assess local and systemic reactions (1).

Participants enrolled in the trials are healthy, HIV-1 uninfected adults from age 18-50. Other studies have shown that a preexisting immunity to adenovirus reduced the immune response of the rAd5 boost vaccine. However, 75-99% of the world's population is seropositive for adenovirus type 5 neutralizing antibodies. To reflect closest to the real world, only participants with detectable levels of neutralizing antibodies for adenovirus type 5 were included in the trial (1). Nevertheless, by September 2007, the Step Study involving a rAd5 HIV-1 Gag/Pol/Nef vaccine concluded that the vaccine did not prevent or reduce early viral levels. In addition, it increased the risk of HIV infections among male participants (1). By October 2007, vaccinations with the rAd5 vaccine were halt and 22 participants did not receive the rAd5 boost vaccine (1).

ELISA, neutralizing assay, IFN-γ ELISpot assay, and intracellular cytokine staining assay were used to measure the effectiveness of the trials. ELISA were lined with anti-Gag and anti-Env antibodies. Results were positive when optical density (OD) of antigen minus non-antigen is greater or equal to an OD of 0.2 (1). For the neutralizing assay measured the reduction of luciferase reporter gene expressed after one round of infection in a TZM-bl cell medium for neutralizing antibodies. A reduction of luciferase causes bioluminescence. Positive results were considered to be greater than or equal to 25 relative luminescence units (RLU) (1). IFN-γ ELISpot assay used to detect cells secreting any types of cytokines from activated T cells. Results were measured in spot forming cells per milling (SFC/ 106) in peripheral blood mononuclear cells (PBMC). Positive results varies with each different HIV polyproteins (1). Intracellular cytokines staining assays used to measure CD4+ and CD8+ cells response. Positive results are bassed in background measurements and number of T cells examined (1). Last, study diagnostic test were ran at the last study visit for HIV-1 and HIV-2.

Due to the halt of the use of rAd5 boost vaccines, scheduling conflicts, severity, and other problems, the sample sized reduce to 61 from 90. All participants received the first DNA prime vaccine, 99% received the second dose of DNA vaccine and 93 % received the third dose of DNA vaccine and only 68% received the rAd5 boost vaccine (1).

During follow-up examinations, systemic reactogenicity included malaise, myalgia (muscle pains), headaches, nausea, vomiting, chills and arthralgia (joint pains). About 39% of participants reported no symptoms and 34 % of participants reported mild symptoms (1). After the three doses of DNA prime vaccines, there were no differences in local or systemic reactogenicity. Comparing route of administrations, subcutaneous group (SC) in comparision to intradermal groups (ID) have more severe headaches and pain, and intradermal group and subcutaneous group have more erythema (redness of the skin) than intramuscular group (IM) (1). Overall, there were no significant differences in reported systemic reactogenicity or adverse events.

ELISA analysis were taken four weeks after the rAd5 boost vaccine, and included 56 out of the remaining 61 participants (five participants were out of schedule study window). The positive response rates for binding anitbodies the IM group is about 66.7 %, 70% for the ID group, and 77.8% for the SC group (1). The percentage are very close together, therefore are not statistically different.

Neutralizing anitibodies were examined at four weeks after rAd5 boost for 56 out of 61 participants too. Positive response were for neutralizing antibodies were found in 16.7% of participants in the SC groups, 11.1% in the IM group and 0% in the ID group. These differences are not statistically different either (1).

IFN-γ ELISpot assay for T-cells induced responses were measured at two weeks after the third DNA and four weeks after rAd5 boost vaccine. About 42.1 % HIV response after the DNA vaccination and 41.2 % after the rAd5 boost vaccination. There are no significant difference after the DNA and rAd5 vaccines. Also, there are no significant difference in IFN-γ ELISpot assay on the different route of administration (1).

In intracellular cytokine staining assay study, measurements were taken two weeks after the third DNA dose and four weeks after the rAd5 boost. After the third DNA dose, 88.5 % had a CD4+ cell response and 80.3% CD4+ cell response four weeks after rAd5 boost. For CD8+ cell response, 93.4 % had a positive response after the third DNA dose and 86.9 % after the rAd5 boost.

Overall, all results were close and did not deviate much from one another. In addition, those receiving the rAd5 boost by ID and SC had a higher severity of erythema than IM. In summary, this trial is inconclusive due to reduced sample size and insignificant differences in the results determining whether route of administration influence immunogenicity (1). This study does not support a change in route of administration (1). The Step Study addressed two problems in the trials: small sample size and ineffective boost vaccine. Future studies might want to increase the enrollment of participants to avoid this problem again. The Step Study hypothesized that those with pre-existing Ad5 immunity have neutralizing antibodies that opsonized the rAd5 vectors decreasing the effect of rAd5 boost vaccines (2). Env was biased in the IFN-γ ELISpot assay because it was has the highest frequency after DNA prime and rAd5 boost (1). The future of vaccine development could focus on improved Env gene to elicit a range of neutralizing antibodies or in developing a new recombinant boost (2).

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