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http://www.biology.arizona.edu/immunology/tutorials/AIDS/response.html

http://www.tht.org.uk/myhiv/HIV-and-you/Simple-science/The-immune-system

http://people.ku.edu/~igmdoc/hiv.html

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Human Immunodeficiency Virus (HIV)

1. Molecular Method for Detection

1.1. Serological Assay

1.2. Western blotting

1.3. Virological testing

1.3.1. Detect viral nucleic acid

1.4. Dried blood spot (DBS)

2. Mechanism

2.1. 1) HIV will attach to the host's receptor and penetrate their target's cell

2.2. 2) HIV will release RNA into the cell and it must be replicated into DNA

2.3. 3) DNA is being formed with the help of and enzyme that is called reverse transcriptase

2.4. 4) Viral DNA enters the cell's nucleus

2.5. 5) Viral DNA is being integrated to the host's DNA by integrase

2.6. 6) DNA of the infected cell will produce viral RNA as well as proteins that are needed to assemble new HIV

2.7. 7) A new virus is assembled into RNA and some short proteins

2.8. 8) The virus buds through the cell's membrane and wraps itself in a fragment of the cell's membrane which pinches off from the cell's membrane

2.9. 9) The budded virus must be mature to be able to infect other cell so the HIV's protease will cut the structural proteins of the virus which causes them to rearrange and become mature

3. Manipulation Vaccine Development

3.1. HIV vaccine is not yet developed because

3.1.1. Lack of natural immunity to HIV

3.1.2. Variability of HIV types

3.1.3. Lack of correlates of protective immunity

3.1.4. Lack of animal model that reliably predicts vaccines efficacy in humans

4. Epidemiology Cases in Malaysia

4.1. Most common illnesses involved

4.1.1. Pneumocystis carinii pneumonia (PCP)

4.1.2. Esophageal candidiasis

4.2. 70% of new HIV infection in 2013 were Malay.

4.3. Everyday almost 10 Malaysian are diagnosed HIV positive.

4.4. 31% of newly reported cases in Malaysia are in their twenties.

4.5. In 2013 Malaysia marked more than 100000 people diagnosed with HIV since the first case in 1986.

4.6. AIDS has caused the deaths of more than 13000 Malaysians.

4.7. Quite heterogenous in its dynamic and shape

4.8. Women and girls are the fastest growing populations that are being infected

5. Transmission

5.1. Having sex with someone who has HIV without any protection

5.2. Sharing needles or syringe with people who has HIV

5.3. From mother to child during pregnancy or breastfeeding

5.4. Stuck with HIV-contaminated needle

5.5. Blood transfusion or organ transplant

5.6. Bitten by a person with HIV

5.7. Contact between broken skin, wounds or mucuous membrane

6. Ways of The Pathogens Evade The Host

6.1. HIV-1 enters primarily through the mucosal surfacea of genital during transmission.

6.2. HIV has enveloped spikes (trimers) to bind and infect cells.

6.2.1. It support three gp120 molecules, which HIV uses to grip and to gain entry into the cells it infects.

6.3. After gp120 bind to CD4 on the T-cell, nucleocapsids containing viral genome and enzymes enters the target cell.

7. Immune Response Involved

7.1. HIV virus attack CD4 cell,

7.2. If the number of CD4 cells (the CD4 count) is reduced, the immune system has fewer cells to help it defend the body from other organisms. The greater risk of getting ill

7.3. CD4 and CCR5 membrane proteins are targets for HIV infection

8. Treatments

8.1. Antoretroviral therapy (ART)

8.1.1. A combination of HIV medicines (HIV regimens)

8.1.2. Cannot cure HIV, but reduce transmission

8.2. The cure are not yet to be found, but treatment keeps the virus under control

8.3. Daily exercise

8.4. Well-balanced and nutritious diet

8.5. Risk taking HIV medicines

8.5.1. Side effects

8.5.2. Drugs interactions

8.5.3. Drug resistance

9. Symptoms

9.1. Common

9.1.1. Fever

9.1.2. Sore throat

9.1.3. Body rashes

9.1.4. Severe headaches

9.1.5. Rapid weight loss

9.1.6. Memory loss, depression or other neurological disorders

9.1.7. Pneumonia

9.2. Less Common

9.2.1. Fatigue

9.2.2. Swollen lymph nodes

9.2.3. Ulcers in the mouth or genitals

9.2.4. Muscle aches

9.2.5. Joint pain

9.2.6. Nausea and vomiting

9.2.7. Night sweats

10. Characteristics

10.1. Intracellular parasite

10.1.1. requires a host cell to survive and reproduce

10.1.2. Known as CD4 T-helper cells which is crucial for the host's immune response.

10.1.3. It targets immune cells

10.2. Classified into type 1 and type 2, HIV-1 and HIV-2 respectively.

10.3. Cannot be transmitted via sweat, saliva, tears or insects.

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Human Immunodeficiency Virus (HIV) 1.3.1. Detect viral nucleic acid 3.1.1. Lack of natural immunity to HIV 3.1.2. Variability of HIV types 3.1.3. Lack of correlates of protective immunity 3.1.4. Lack of animal model that reliably predicts vaccines efficacy in humans 4.1.1. Pneumocystis carinii pneumonia (PCP) 4.1.2. Esophageal candidiasis 6.2.1.

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Human immunodeficiency virus (HIV), a member of the retrovirus family, is the causative agent of ( AIDS). HIV invades various immune cells (e.g., CD4+ T cells and monocytes) resulting in a decline in CD4+ T cell numbers below the critical level, and loss of cell-mediated immunity − therefore, the body becomes progressively more susceptible to opportunistic infections and cancer.

HIV invasion of immune cells

HIV infects T cells via high-affinity interaction between the virion envelope glycoprotein ( gp120) and the CD4 molecule. The infection of T cells is assisted by the T-cell co-receptor called CXCR4 while HIV infects monocytes by interacting with CCR5 co-receptor ( Figure 1). As illustrated in Figure 2, after gp120 binds to CD4 on the T cell ( 1). Nucleocapsids containing viral genome and enzymes enters the target cell ( 2). Following the release of viral genome and enzymes from the core protein, viral reverse transcriptase catalyses reverse transcription of ssRNA to form RNA-DNA hybrids ( 3). To yield HIV dsDNA the viral RNA template is partially degraded by ribonuclease H and the second DNA strand is synthesized ( 4). The viral dsDNA is translocated into the nucleus and integrated into the host genome by the viral integrase enzyme ( 5). Transcription factors transcribe the proviral DNA into genomic ssRNA ( 6), which is exported to cytoplasm ( 7). In the cytoplasm, host-cell ribosomes catalyse synthesis of viral precursor proteins ( 8). The viral precursor proteins are cleaved into viral proteins by viral proteases ( 9). HIV ssRNA and proteins assemble beneath the host-cell plasma membrane ( 10) forming virion buds from it ( 11). Maturation occurs either in the forming buds or after budding from the host cell ( 12). During maturation, HIV proteases cleave the poly-proteins into individual functional HIV proteins. The mature virions are able to infect another host cell.

Figure 1. Interaction between HIV and coreceptors of a T cell and a monocyte

Figure 2. Overview of HIV infection of a target cell (e.g. T cell)

Innate immune response to HIV

Innate immune cells (e.g., dendritic cells and natural killer cells) are the first line of defence which HIV encounters upon entry to the body.

Macrophages. Tissue macrophages are one of the target cells for HIV. These macrophages harbour the virus and are known to be the source of viral proteins. However, the infected macrophages are shown to lose their ability to ingest and kill foreign microbes and present antigen to T cells. This could have a major contribution in overall immune dysfunction caused by HIV infection.

Dendritic cells (DCs). DCs are large cells with dendritic cytoplasmic extensions. These cells present processed antigens to T lymphocytes in lymph nodes. Epidermal DCs, expressing CD1a and Birbeck granules, are probably among the first immune cells to combat HIV at the mucosal surfaces. These cells transport HIV from the site of infection to lymphoid tissue. The follicular DCs, found in lymphoid tissue, are also key antigen-presenting cells that trap and present antigens on their cell surfaces. In the lymph node follicles, DCs provide signals for the activation of B lymphocytes.

Natural killer (NK) cells. NK cells have lytic activity against cells that have diminished expression of major histocompatibility complex ( MHC) I antigens. Because the presence of MHC class I is required for peptide presentation to T cell receptors, NK cells are important line of defence when HIV escapes the cellular immune response. NK cells proliferate in response to type 1 interferon secreted by DCs. These stimulated NK cells release cytokines such as interferon γ ( IFN-γ), tumour necrosis factor α ( TNF-α), and chemokines to activate T-cell proliferation (cellular immune response). NK cells also inhibit viral replication by releasing IFN-γ.

Adaptive immune response to HIV

Cellular immune response to HIV. The cellular immune response is induced upon the entry of HIV into the target cells (e.g., T cells) and synthesis of viral proteins ( Figure 1). MHC class I on the cell surface displays the intracellularly degraded HIV peptide fragments for recognition by T-cell receptors (TCR) on CD8+ T cells ( Figure 3). CD8+ T cells lyse HIV infected cells and secrete cytokines, i.e. interferon-γ (IFN-γ), tumor necrosis factor α (TNF-α), and chemokines, i.e. MIP-1 α, MIP β and RANTES, that inhibit virus replication and block viral entry into CD4+ T cells. Development of CD8+ T cells is crucial for control of HIV replication. This results in declining viraemia after primary infection. In the early stages of infection, CD4+ T cells lose their proliferative capacity and therefore their contribution to viral control is minor. However, during chronic infection CD4+T cells are present and secrete interleukin-2 ( IL-2) or cytokines, such as IFN-γ, to control viraemia.

Humoral response to HIV. The humoral immune response occurs later in infection; therefore, the level of antibodies during the acute infection is very low. Non-neutralising antibodies to structural proteins (i.e. P17 and P24) are first to appear and generally do not persist. Later neutralising antibodies specific to proteins, involved in the entry of the virus into the cells, will be generated. These antibodies are specific to: (1) the variable region of gp120 (V3); (2) CD4 binding sites and chemokine receptors (i.e., CXCR4 and CCR5); (3) the transmembrane protein gp41. Potent neutralizing antibodies have been shown to play a major role in controlling HIV infection in a few symptom-free HIV+ individuals who maintain high level of CD4+ T cells and low viral load.

Figure 3. Cellular & humoral immune responses to HIV

Why does the immune system fail to fight the HIV virus?

There are various reasons which can contribute to the failure of the immune system to control HIV infection and prevent AIDS development. By infecting CD4+ T cells, HIV is able to replicate predominantly in activated T cells and paralyse one of the main components of adaptive immune system. HIV can also establish latent infection in CD4+ T cells and remain invisible to CD8+ T cells and therefore replication can occur later in the infection and generate new virions. Antigenic mutation within the T-cell epitopes can affect the binding capacity of MHC molecules to the viral peptides, resulting in the inability of the TCRs to recognise the MHC-peptide complex. Finally, HIV is able to hide from anti-HIV antibodies by expressing non-immunogenic glycans on key antibody epitopes.
© The copyright for this work resides with the BSI

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Human immunodeficiency virus (HIV), a member of the retrovirus family, is the causative agent of acquired immunodeficiency syndrome (AIDS). HIV invades various immune cells (e.g., CD4+ T cells and monocytes) resulting in a decline in CD4+ T cell numbers below the critical level, and loss of cell-mediated immunity − therefore, the body becomes progressively more susceptible to opportunistic infections and cancer.

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GENERAL LIFE CYCLE OF HIV
https://www.msdmanuals.com/home/infections/human-immunodeficiency-virus-hiv-infection/human-immunodeficiency-virus-hiv-infection

FUSION AND CELL ENTRY
https://sites.tufts.edu/hivprevention/fusion-and-cell-entry-2/

REVERSE TRANSCRIPTION
https://sites.tufts.edu/hivprevention/mechanism/

INTEGRATION
https://sites.tufts.edu/hivprevention/integration/

MATURATION
https://sites.tufts.edu/hivprevention/maturation/

GENERAL HIV ENTRY
http://www.jbc.org/content/287/49/40841.full

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https://www.plannedparenthood.org/learn/stds-hiv-safer-sex/hiv-aids/what-are-symptoms-hivaids

https://www.webmd.com/hiv-aids/understanding-aids-hiv-symptoms

https://www.nhs.uk/conditions/hiv-and-aids/symptoms/

http://hivinsite.ucsf.edu/hiv?page=basics-00-02

http://www.thebody.com/content/art54495.html

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Genus : Lentivirus
Family : Retroviridae
Subfamily : Orthoretrovirinae

Human immunodeficiency virus (HIV) is classified into types 1 and 2 ( HIV-1 and HIV-2).

HIV genome consists of two identical single-stranded RNA molecules.

Particle Structure
Mature HIV particle is round with an outer lipid membrane as its envelope.
-The envelop contains 72 knobs, composed of trimers of the Env proteins.
-Viral envelope composed of a lipid bilayer .

Reference
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4924471/

HIV is the causative agent of 🤬. It can be transmitted through :
1) sexual transmission
2) intravenous drug use
3) blood transfusion
4) maternal vertical transmission

Reference

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Antiretroviral therapy (ART) is the use of HIV medicines to treat HIV infection. People on ART take a combination of HIV medicines (called an HIV regimen) every day.

ART is recommended for everyone who has HIV. ART can’t cure HIV, but HIV medicines help people with HIV live longer, healthier lives. ART also reduces the risk of HIV transmission. HIV attacks and destroys the infection-fighting CD4 cells of the immune system. Loss of CD4 cells makes it hard for the body to fight off infections and certain HIV-related cancers.

HIV medicines prevent HIV from multiplying (making copies of itself), which reduces the amount of HIV in the body. Having less HIV in the body gives the immune system a chance to recover. Even though there is still some HIV in the body, the immune system is strong enough to fight off infections and certain HIV-related cancers.

By reducing the amount of HIV in the body, HIV medicines also reduce the risk of HIV transmission.
Without treatment, people living with HIV can become ill because of the damage HIV does to the immune system. The immune system is your body’s way of protecting itself from illnesses caused by germs, bacteria or infections.

It is now recommended that people living with HIV start antiretroviral treatment straight away. This is being implemented in an increasing number of countries. In some places, the decision about when to start treatment is still dependent upon a CD4 count test, which looks at how many CD4 cells are in a small amount of blood.

The CD4 cells (also called T-helper cells) are an important part of the immune system because they fight germs and infections. HIV attacks CD4 cells and reduces the number of them in your body. Without treatment, HIV slowly weakens the immune system, making it harder for your body to fight off illness or infection. Discuss with health care profesional

the best time to start the treatment///////

Antoretroviral therapy
-A combination of HIV medicines (HIV regimens)
-Cannot cure HIV, but may reduced transmission

Daily exercise

Well-balanced diet & nutritious diet

Risk taking HIV medicines
- Side effects
- Drug interactions
- Drug resistance

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One of these proteins, named gp 120, (a sugar-containing protein called a glycoprotein, of approximately 120,000 molecular weight), "recognizes" a protein on helper T-cells named CD4, and physically associates with it. The CD4 [Cluster of Differentiation Antigen No. 4] protein is a normal part of a helper (both Th1 and Th2) T-cell's membrane. Thus, CD4 is a specific receptor for HIV. This virus however, can also infect other cells which include macrophages and certain other kinds of cells which can engulf substances through a process known as phagocytosis. As a consequence of the interaction with CD4 on helper T-cells, HIV specifically infects the very cells necessary to activate both B-cell and cytotoxic T-cell immune responses. Without helper T-cells, the body cannot make antibodies properly, nor can infected cells containing HIV (an intracellular pathogen) be properly eliminated. Consequently, the virus can: multiply, 🤬 the helper T-cell in which it lives, infect adjacent helper T-cells, repeat the cycle, and on and on, until eventually there is a substantial loss of helper T-cells.

-HIV virus attack CD4 cell
-If the number of CD4 cells (the CD4 count) is reduced, the immune system has fewer cells to help it defend the body from other organisms. The greater risk of getting ill

-CD4 and CCR5 membrane proteins are targets for HIV infection

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Seema P Ajbani*

Department of Zoology, Smt. C.H.M. College, University of Mumbai, India

*Corresponding Author:

Seema P Ajbani
Assistant Professor, Department of Zoology
Smt. C.H.M. College (University of Mumbai)
Ulhasnagar-421003, Thane District, Maharashtra, India
Tel: +91-9004695875
E-mail: [email protected]

Received date September 12, 2016; Accepted date October 06, 2016; Published date October 13, 2016

Citation: Ajbani SP (2016) HIV Vaccine Development: Current Scenario and Future Prospects. J AIDS Clin Res 7:626. doi: 10.4172/2155-6113.1000626

Copyright: © 2016 Ajbani SP. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

Visit for more related articles at Journal of AIDS & Clinical Research

Abstract

The search for a preventive vaccine that can halt the global pandemic is the ultimate goal of HIV research. Development of a vaccine against HIV-1 has been plagued by many insurmountable challenges. Different vaccine concepts have been tested to overcome these challenges. Experimental vaccines that showed promise in preclinical studies were advanced into clinical trials. Yet, human trials proved to be a huge disappointment until the results of the RV144 trial in Thailand. This trial not only provided the first evidence of a modest efficacy, but also valuable insights on the possible immunologic correlates of vaccine protection. Currently, the HIV vaccine research landscape has been rejuvenated by two major developments. On one hand, there has been a resurgence of interest in T cell-based vaccines with the promising results obtained using a recombinant cytomegalovirus vector vaccine. On the other hand, the discovery of more than a hundred broadly neutralizing antibodies from cohorts of HIV-infected individuals has led to the development of antibody-based preventive vaccines. Innovations in the design of vaccines, vaccination strategies and clinical trial programs will be necessary to accelerate the search for a prophylactic HIV vaccine. This article reviews the current status of HIV vaccine research and provides a roadmap to future efforts in vaccine development.

Keywords

HIV; Prevention; Vaccines; T cell-based vaccines; Antibody-based vaccines; Clinical trials

Introduction

More than thirty years have elapsed since Human Immunodeficiency virus (HIV) was first identified as the cause of acquired immunodeficiency syndrome (AIDS) [ 1]. AIDS continues to be a global public health challenge and it is estimated that more than 70 million people have been infected with HIV and more than half of these individuals including children have died from AIDS. Epidemiological studies indicate that new HIV infections are currently either on a decline or have stabilized in many nations of the world including sub-Saharan Africa which is at the epicentre of this pandemic and India which is home to the third-largest population of people living with HIV [ 2]. This decline can be attributed to a significant increase in easier access to AIDS therapy at the global level along with effective prevention efforts among key target groups [ 3- 6]. In addition, the fact that during the natural course an epidemic usually peaks before declining to stable levels is also a contributory factor.

Recent studies have succeeded in elucidating many of the complexities involved in the host immune response to HIV infection. Yet, neither a complete cure nor a protective vaccine has been found and new infections continue to occur at the rate of approximately 7000 people per day.

The Need for An Anti-HIV Vaccine

The first milestone in the fight against HIV was the introduction of anti-retroviral therapy (ART) to treat AIDS. Since then there have been major advances in both, the treatment and prevention of HIV/ AIDS. Pre-exposure prophylaxis [ 7- 10] and the use of ART for prevention have positively impacted the available prevention options. In fact, current evidence strongly supports early initiation of ART, as it not only improves the health of infected individuals but also reduces the risk of HIV transmission [ 11- 13]. Yet, ART has its limitations as it cannot fully restore the immune system and there is a need for life-long treatment as HIV persists indefinitely in latent reservoirs of the infected individuals [ 14, 15]. Furthermore, there are problems with adherence and the retention in care of the HIV-infected individuals. Hence the development of a safe, effective and affordable vaccine continues to be a priority and will be a vital in the long term to control the transmission of HIV and its eradication.

Scientific Challenges in the Development of a Globally Effective HIV Vaccine

One of the major challenges in the development of an anti-HIV vaccine is that the immune correlates of protection against HIV infection in humans are still not clearly defined. In fact, the mechanism by which an HIV vaccine will be able to provide protection has not yet been elucidated. Vaccines designed to prevent various infectious diseases in the past have been successful in generating protective immune responses similar to those that occur during natural infection. However, the absence of natural immunity against the virus has proved to be a major stumbling block in the development of a vaccine against HIV. It appears that an effective vaccine will have to elicit an immune response which is significantly different from that which occurs during the course of a natural infection [ 16].

Another barrier in the development of a vaccine targeting HIV has been the extraordinary sequence diversity exhibited by the virus and its ability to continually evolve in order to escape the host immune response. In particular, Group M of HIV-1 has nine distinct subtypes and different circulating recombinant forms worldwide. The amino acid sequence of the Env region of this virus can exhibit up to 20% diversity within a subtype and up to 35% diversity between subtypes [ 17]. It is a matter of great concern that a vaccine derived from a particular clade may not provide protection against all other clades and this may prove to be an insurmountable hurdle in the design of a globally effective anti-HIV vaccine.

Another major obstacle to HIV vaccine development has been the lack of suitable animal models which can be used to predict human response to vaccines [ 18]. HIV-1 only infects chimpanzees in nature but they do not develop human-like AIDS disease. Although HIV does not infect monkeys, a closely related virus, Simian immunodeficiency virus (SIV) can establish a productive infection in monkeys which recapitulates HIV pathogenesis seen in humans. However, due to differences in the envelope (Env) region of HIV-1 and SIV replicationcompetent chimeric SIV/HIV constructs called SHIV have been engineered which can infect cynomolgous and rhesus monkeys. SIV or SHIV/non-human primates (NHPs) are the models of choice for the preclinical testing of HIV/AIDS vaccines. However, the prevention observed in the NHPs has not been duplicated in human trials. Thus NHPs are not very reliable models for predicting HIV vaccine efficacy in humans. Yet, in the absence of any other suitable alternative, NHPs are still used for preclinical research on HIV vaccines.

The Search for an HIV Vaccine

The search for a vaccine against HIV has not been as easy as anticipated in the early 1990s. To date more than 30 vaccine candidates have been developed yet the world still does not have an anti-HIV vaccine. Traditional vaccination approaches involving the use of attenuated and inactivated virus were the first to be tested in NHPs but due to reasons of biosafety and a possible danger of reversion to pathogenicity could not be advanced to human clinical trials [ 19].

Apart from safety, HIV-1 vaccine development has been guided by the principles of stimulating either sterilizing immunity or cellular immunity or preferably both against the virus. It is strongly believed that an effective HIV vaccine will have to elicit both broadly reactive neutralizing antibodies as well as CD4+ and CD8+ T cell responses to confer protection [ 20]. Additionally, adjuvants and vectors capable of triggering innate immunity may be required to improve the quality of the adaptive immune responses. Over the years several vaccine candidates have been developed based on these guiding principles.

The candidate vaccines which were able to elicit varying levels of protective immunity in NHPs during preclinical studies were then advanced to human clinical trials [ 21, 22] and evaluated either alone or in combination in a homologous/heterologous prime-boost approach. They include HIV-1 protein subunit vaccines, peptide vaccines, plasmid DNA vaccines, HIV-1 viral-like particle vaccines and recombinant vaccines constructed from viral vectors such as poxvirus, adenovirus, adeno-associated virus and alphavirus. Some of the candidate vaccines have been administered along with different adjuvant formulations [ 23, 24]. The recombinant vaccines have utilized HIV genes either in their native form or as fusion constructs which have been codon optimized or modified in various ways for generating potent immune responses [ 25- 28]. Furthermore, many of the recombinant viral vectors have been tested either in the replication-competent or replicationincompetent modality as HIV vaccines ( Table 1).

Most of the vaccine candidates which exhibited potential in Phase I and Phase II trials either failed to show protection or exhibited an increased risk for HIV-1 acquisition in Phase IIB/III trials. They include the recombinant HIV-1 envelope gp120 based bivalent sub-unit vaccines namely AIDSVAX B/E with alum evaluated in the Vax003 trial [ 29] and AIDSVAX B/B with alum evaluated in the Vax004 trial [ 30] and the replication-incompetent adenovirus serotype 5 (Ad5) vectored HIV-1 trivalent vaccine evaluated in two different trials namely the Step trial and HIV Vaccine Trials Network (HVTN) Phambili trial [ 31, 32].

The first evidence of vaccine induced protection was provided by the RV144 Phase III trial, which was conducted in Thailand and involved the use of two immunogens (the canary pox-vectored ALVAC-HIV prime and AIDSVAX gp120 B/E subunit vaccine boost) which had failed when used separately [ 33]. Results of this trial showed that although protection occurred early after vaccination the vaccine efficacy appeared to diminish over time from 60% after one year to 31% after three years. Though this vaccine was not approved for use in the general population, the RV144 trial has been instrumental in providing unique insights on the potential immunological correlates of vaccine protection. They include the absence of neutralizing antibodies and cytotoxic T cells, the presence of a clear correlation between protection and non-neutralising antibodies against the V1V2 region and the probable role of antibody-dependent cell-mediated cytotoxicity (ADCC) as a mechanism of protection [ 34- 36].

Current Status of HIV Vaccine Research Landscape

Currently many novel vaccine strategies are being explored that have the potential to significantly advance HIV vaccine development. One such exciting area has been the construction and evaluation of cytomegalovirus (CMV)-based replication-competent vectors for antigen delivery. A RhCMV-based vaccine expressing SIV antigens demonstrated robust CD8+ T cell responses which correlated with protection in about 50-60% of the rhesus macaques irrespective of the route of challenge (intra-rectal/intra-vaginal). Furthermore, no viral rebound was observed after the removal of CD8+ T cells in vivo [ 37, 38] and compared to the conventional SIV-specific T cell responses, vaccination with the RhCMV/SIV vector stimulated an atypical CD8+ T cell response which was predominantly MHC class II restricted [ 39]. As these vectors did not stimulate any antibody response they have rekindled interest in T cell-based vaccines. Although encouraging it remains to be seen whether these results can be duplicated in humans. The recombinant CMV-based HIV vaccines developed by the Louis Picker group are expected to enter Phase I human trials in 2017.

Phase IIb trial
(STEP, Phambili and HVTN 505)
Phase I trial
Phase I trial
Phase II trial

Adenovirus

Adenovirus Serotype 5 AdvenovirusSerotype26Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â
AdvenovirusSerotype 35
Chimp adenovirus

Deficient
Deficient
Deficient
Deficient

NHP studies
(Expected to enter
Phase I trial in 2017)

Cytomegalovirus

Rh Cytomegalovirus
(RhCMV)

Competent

Table 1: Different replication-competent/deficient viral vectors used in HIV Vaccine trials.

Induction of broadly neutralizing antibodies (bnAbs) by active immunization is an alternate strategy which is also being currently explored. The bnAbs directed towards the Env of HIV-1 are rare since they are found only in a small percentage of infected individuals. Only about approximately 20% of the infected individuals can produce truly cross-reactive potent bnAbs capable of neutralizing a wide variety of viral strains 2-3 years post-infection. Furthermore, the development of bnAbs in infected individuals requires extensive somatic hypermutations in order to achieve the binding specificities appropriate for neutralizing different viral strains [ 40]. Stimulation of the correct sequence of somatic hypermutations by a series of antigens/envelope proteins in active immunization regimens could induce broadly reactive neutralizing antibodies capable of effectively neutralizing different viral variants. Though promising, it is nevertheless, an extremely complex and difficult process to induce these bnAbs as many levels of somatic hypermutations are needed over many years. Meanwhile, the virus continues to evolve by developing new and resistant mutations [ 41- 43]. Additionally, there are concerns that some of these potent bnAbs may be either poly-reactive or auto-reactive and therefore may be clonally deleted to prevent autoimmunity.

A candidate vaccine capable of inducing bnAbs against most circulating strains of HIV has been elusive. Neutralization of Env on HIV-1 has been impeded due to a number of factors such as its remarkable antigenic diversity, concealment of critical epitopes by heavy glycosylation and the fact that antibodies continue to evolve as a result of extensive somatic hypermutations [ 21, 44- 47]. But recently the successful stabilization of the Env trimer in a soluble form has enabled its use as an immunogen [ 48- 51]. The trimeric Env has a greater potential to generate antibodies that will recognize the functional spike of HIV and neutralize the virus. It remains to be seen whether the entire trimer or specifically engineered partial regions of Env or a combination of both will be required to stimulate the difficult-to-induce B cell lineages. Two experimental vaccines, BG505 SOSIP and engineered gp120 variants have shown potential to stimulate intermediate antibodies and not the mature forms [ 48]. Currently, many regions of HIV-1 Env are being explored as targets for stimulating bnAbs and include gp120 CD4/CCR5 receptors/CXCR4 coreceptors, the V1/V2 variable loops, membrane proximal external region (MPER) of gp41 and some exposed glycans [ 52, 53].

Furthermore, the isolation of more than a hundred bnAbs from cohorts of HIV-1 infected individuals has paved the way for the development of antibody-based HIV vaccines. Studies involving the passive transfer of bnAbs in nonhuman primates have been promising. Suppression of viremia in infected monkeys and prevention of viral acquisition in uninfected monkeys was observed in these studies [ 54- 56]. Moreover marked suppression of HIV production in viral reservoirs by bnAbs has also been detected in ex vivo studies [ 57]. Although the ability of bnAbs to prevent infection in humans is still not known, studies have shown decrease in the levels of circulating virus after administration of bnAbs [ 58].

A trial called HVTN 703 which is currently underway in South Africa is based on passive immunisation with preformed antibodies. This proof-of-concept Phase IIb trial, also called the AMP (antibodymediated protection) Study, is designed to prove whether a preformed antibody VRC01 can prevent HIV infection in humans. The outcome of this trial is also expected to reveal the dose of antibody needed to protect humans from HIV infection. VRC01 is a broadly neutralizing antibody which has been cloned from an antibody-producing cell isolated from an HIV-infected individual. Administration of VRC01 has been found to be safe in humans in Phase I trials and has demonstrated its ability to prevent infection in NHP studies.

Another major Phase III efficacy trial in South Africa has been designed to build on the RV144 trial with the aim to not only replicates the partial protection observed in Thailand but if possible to surpass it. This trial called HVTN 702 is going to be initiated in November 2016 and is based on the classical approach of eliciting T cell immunity [ 59]. The HVTN 702 vaccine regimen consists of two experimental subtype C vaccines tailored to match the viral strains circulating in Southern Africa. These vaccines include a canary pox-based vaccine (ALVACHIV) prime and a bivalent gp120 protein subunit vaccine boost which is formulated with the adjuvant MF59. The vaccine candidates will be administered in 5 injections over a period of 12 months in an attempt to increase the magnitude and duration of vaccine-elicited immune responses as compared to the RV144 trial. The appearance of V1V2 binding antibodies in greater than 50% of the vaccinated individuals and the presence of HIV-1-specific helper T cell responses will serve as the benchmarks for evaluating the efficacy of this active immunization strategy. If the vaccine is found to be safe and able to reduce the number of infections by at least 50% it may be considered suitable for use in the general population.

The results from the HVTN 702 and HVTN 703 trials will be out in 2020 and 2022, respectively and are expected to be instrumental in generating an increased understanding of the requirements of an effective HIV vaccine which can decimate this virus. Yet, it may take years or even decades before a vaccine is licensed for use in the general population.

Roadmap to Future Efforts in Vaccine Development

The development of a safe and effective HIV-1 vaccine remains one of the highest research priorities to create a world without AIDS. Although an effective prophylactic vaccine still remains elusive, the results of the RV144 trial have reenergized the HIV-1 vaccine landscape. The lessons learnt from this trial are currently being applied by scientists not only to develop modified and possibly more effective vaccine candidates but also to guide future vaccine trial protocols. The ability to express the native Env trimer of HIV-1 as a recombinant protein has also been a major step forward in vaccine design and development. Furthermore, the results of some of the novel vaccine candidates in the non-human primate models have been quite encouraging. Evaluations of these novel immunogens in human trials, an increased understanding of immune pathways which lead to the generation of effective antibodies and the availability of modern tools to study the intricacies of the B cell response have the potential to further transform the field of HIV vaccine development.

However, there are many areas of concern that will have to be addressed on a priority basis. One major concern is whether the immune correlates of vaccine protection derived from the RV144 trial can be applied to other modalities of vaccines and diverse subtypes. Furthermore, although results obtained in NHP models are still used to guide HIV-1 vaccine research there is an urgent need to develop new animal models which can more accurately predict human immune responses. Adjuvant formulations which can enhance the humoral immune response and facilitate antigen dose sparing may also play a significant role in the design of a successful vaccine. Evaluation of diverse vaccine concepts and vaccination regimens in an accelerated and dynamic human vaccine trials program will clearly result in greater success in developing the vaccine. Greater investment in the development of infrastructure in countries which are experiencing the major brunt of the HIV/AIDS epidemic will also be essential to bring us closer to an effective vaccine. The bottom line is that there is an urgent need to explore strategies to design a truly global prophylactic vaccine which can address the extensive viral diversity and provide protection against all circulating strains. Discovery of a preventive vaccine to end the AIDS epidemic in the near foreseeable future can be possible by a truly unified global level comprehensive response involving all the stakeholders including researchers, clinicians, epidemiologists, national and international HIV/AIDS organisations, governments, local communities and the drug development industry.

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# data[].attributes.attachment_link.title
HIV Vaccine Development: Current Scenario and Future Prospects

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Seema P Ajbani* Department of Zoology, Smt. C.H.M. College, University of Mumbai, India *Corresponding Author: Seema P Ajbani Assistant Professor, Department of Zoology Smt. C.H.M. College (University of Mumbai) Ulhasnagar-421003, Thane District, Maharashtra, India Tel: +91-9004695875 E-mail: [email protected] Received date September 12, 2016; Accepted date October 06, 2016; Published date October 13, 2016 Citation: Ajbani SP (2016) HIV Vaccine Development: Current Scenario and Future Prospects.

# data[].attributes.body
Molecular methods are critical in detecting early infection and manage patients on anti retroviral therapy whose viral infection may become resistant to therapy. Modifications to conventional methods have introduced new assays, such as sensitive/less sensitive (detuned) assays that can estimate when someone was infected. This provide a useful tool for epidemiologic incidence estimates and enrollment into specific intervention programmes for patients.

PCR-based techniques are increasingly being appplied for the detection and diagnosis of viral diseases such as HIV infection. These techniques involve the amplification of DNA templates and can be extremely sensitive in detecting viral levels of less than 100 copies/ml of serum35. This makes PCR particularly useful for the early detection (within two weeks of exposure) of the virus35. Techniques involving PCR are, however more complex, time consuming and expensive than serological testing.

New development & research:

RT-PCR  (Kadhum Hassan & Gandhi, 2015)

-          A specific and rapid diagnosis needed to minimize transmission of HIV-1 infection.

-          Specific against the gag gene of HIV-1

In-house NAT for HIV detection (Albertoni, Castelo Girão, & Schor, 2014)

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The first reported cases of HIV/🤬 in Malaysia were in 1986. On December 2013, there are now over 100 000 reported cases of HIV infections in the countrty, and 16 000 people have died from 🤬.

The infected people in this country are concentrated within injevtion drug users (IDU), sex workers, transgender (TG), and men who have sex with men (MSM) communities.

# data[].attributes.body
1) Kadhum Hassan, A., & Gandhi, V. S. (2015). Molecular diagnosis of human immuno deficiency virus (HIV) by direct PCR and SEMI nested PCR methods and semi quantification by agarose gel electrophoresis. European Journal of Experimental Biology, 5(10), 1–5. Retrieved from https://pdfs.semanticscholar.org/2e8d/cf2adbe3d32d9dd073ee6529fff139d04922.pdf

2) Albertoni, G., Castelo Girão, M. J. B., & Schor, N. (2014). Mini review: Current molecular methods for the detection and quantification of hepatitis B virus, hepatitis C virus, and human immunodeficiency virus type 1. International Journal of Infectious Diseases, 25, 145–149. https://doi.org/10.1016/J.IJID.2014.04.007

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The majority people living with HIV in Malaysia are men, but the ratio is decreasing.

70% of new HIV infections in 2013 were Malay.

Every day almost 10 Malaysians are diagnosed HIV positive

31% of newly reported cases in Malaysia are in their twenties

In 2013, Malaysia marked more than 100,000 people diagnosed with HIV since the first case in 1986.

🤬 has caused the deaths of more than 13,000 Malaysians

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http://ptfmalaysia.org/v2/hiv-sti-info/hivaids-in-malaysia/

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A Review of HIV/🤬 Research in Malaysia

http://www.e-mjm.org/2014/supplement-A/HIV-🤬-research.pdf

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MAIN IMAGE (POINTS FOR SCIENTIFIC POSTER)

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MAIN IMAGE (POINTS FOR SCIENTIFIC POSTER)

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HIV STRUCTURE IMAGE FOR SCIENTIFIC POSTER

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HIV STRUCTURE IMAGE FOR SCIENTIFIC POSTER

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1.0 Characteristics of HIV
2.0 How HIV evade Host Cell

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Molecular Detection of HIV-1

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Molecular Detection of Human Immunodeficiency Virus.docx

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1. IMMUNOLOGY INVOLVED
2. TREATMENT
3. INTRODUCTION
4. REFERENCE

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WRITE UP FOR STD PROJECT (AutoRecovered).docx

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p/s:full write up refer 2nd column (immunology ref.)

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p/s:full write up refer 2nd column (immunology ref.)

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full write up refer 2nd column (immunology ref.)

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full write up refer 2nd column (immunology ref.)