AIDS is the leading cause of death worldwide in the 15-59 age group, with 20 million dying since the outbreak in 1981 and over 40 million being infected with HIV-1. (Haut LH & Ertl CJ 2009) UNAIDS have suggested that in 2007, more than 33 million are living with the infection, with some areas of Sub-Saharan Africa having a 36% incidence rate in the adult population. (Haut LH & Ertl CJ 2009)
HIV CLASSIFICATION AND VIRION STRUCTURE
Human Immunodeficiency Virus (HIV), is part of the Retroviridae (Retrovirus) family, and is found in the Lentivirus (L. Lenti =slow) genus (Weiss RA 1993). Simian Immunodeficiency virus (SIV) is also a Lentivirus. Both SIV and HIV often undergo long incubation periods, causing slow progressing inflammatory disease (Weiss RA 1993). Below is cross-sectional diagram of an HIV virion/particle (fig 1)
Fig 1: Diagram of an HIV virion. Each virion expresses 72 glycoprotein projections composed of gp120 (orange) and gp41 (light blue). Gp41 is a transmembrane molecule that crosses the lipid bilayer of the envelope. Gp120 is non-covalently associated with gp41 and serves as the viral receptor for CD4 on host cells. The viral envelope also contains some host-cell membrane proteins such as class I and class II MHC molecules. Within the envelope is the viral core, or nucleocapsid, which includes a layer of a protein called p17 (green) and an inner layer protein called p24 (yellow). The HIV genome consists of two copies of ssRNA, which are associated with two molecules of reverse transcriptase p64 (light red) and nucleoid proteins p10, a protease (red), and p32, an integrase (dark blue). (From www.memssa.co.za)
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However the stark difference in the manifestation of these infections...blah blah (Maria)
THE BIOLOGY OF EARLY HIV-1 INFECTION
As well as determining the clinical course of disease, the early immune response to HIV-1 infection gives great clues to vaccine development. Pilcher CD et al. (2005) & Powers KA et al. (2007) were able to sample patients within the first few weeks of infection. This has allowed for an appreciation of the events that take place before the establishment of stable viraemia or the viral set point, which occurs 3-6 months post infection (McMichael AJ et al. 2010).
The majority of HIV-1 infections occur by sexual transmission, either via the genital tract or rectal mucosa (McMichael AJ et al. 2010). In vitro mucosal tissue explants, which have been infected with HIV-1 has allowed a greater depth of understanding (Hu Q et al. 2004)
Fig 3. Definition of acute HIVâ€‘1 infection. a | Recent analysis of samples from individuals early after infection with HIVâ€‘1 has revealed that the first weeks following infection can be divided into clinical stages that are defined by a stepwise gain in positivity for the detection of HIVâ€‘1 antigens and HIVâ€‘1â€‘specific antibodies in diagnostic assays (in brackets). The time between infection and the first detection of viral RNA in the plasma is referred to as the eclipse phase. Plasma virus levels then increase exponentially, peaking at 21-28 days after infection, and this is followed by a slower decrease in plasma viral RNA levels. Patients can be categorized into Fiebig stages I-VI, which are based on a sequential gain in positive HIVâ€‘1 clinical diagnostic assays (viral RNA measured by PCR, p24 and p31 viral antigens measured by enzymeâ€‘linked immunosorbent assay (ELISA), HIVâ€‘1â€‘specific antibody detected by ELISA and HIVâ€‘1â€‘specific antibodies detected by western blot). Patients progress from acute infection through to the early chronic stage of infection at the end of Fiebig stage V, approximately 100 days following infection, as the plasma viral load begins to plateau. b | Fundamental events in acute HIVâ€‘1 infection. Following HIVâ€‘1 infection, the virus first replicates locally in the mucosa and is then transported to draining lymph nodes, where further amplification occurs. This initial phase of infection, until systemic viral dissemination begins, constitutes the eclipse phase. The time when virus is first detected in the blood is referred to as T0; after this there is an exponential increase in plasma viraemia to a peak 21-28 days after infection. By this time, significant depletion of mucosal CD4+ T cells has already occurred. Around the time of peak viraemia, patients may become symptomatic and reservoirs of latent virus are established in cells that have a slower rate of decay than CD4+ T cells. The 'window of opportunity' between transmission and peak viraemia, prior to massive CD4+ T cell destruction and the establishment of viral reservoirs, is the narrow but crucial period in which an HIVâ€‘1 vaccine must control viral replication, prevent extensive CD4+ T cell depletion and curb generalized immune activation. (fig from McMichael et al 2010)
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The literature seems clear. Improving understand of the events of an acute HIV infection especially the early Innate responses have provided clues and implications for vaccine design. Study of Acute-phase proteins, Cytokines, Dendritic Cells (DC), Natural Killer (NK) and Natural Killer T cells (NKT) in the earliest immune response to HIV infection raises the question of whether the initial innate immune response can be exploited for protective vaccination.
The study of plasma samples from HIV infected individuals allows insight into the earliest immune response. Serum Amyloid, an acute-phase protein is the first known detectable immune response. Followed by another wave, which coincides with the cytokine storm (McMichael et al 2010), and a substantial boost in plasma viraemia. Levels of cytokines and chemokines increase as viraemia progresses. (Stacey AR et al. 2008) However, McMichael et al 2010 suggests that this intense response could indeed promote viral replication.
In the event of acute infection, NK and NKTs will be activated, while their differentiation and proliferation remaining slow before peak viraemia is reached (McMichael et al 2010) NK and NKT cells work together with DCs, thus induce the response of T cells. Furthermore, assembly of cytokines and chemokines and cytolysis of infected cells show a degree of management over HIV replication (McMichael et al 2010). However, Ward J et al 2007 wrote that HIV in fact can modulate ligands which are important to NKT responses. This would suggest that indeed NKTs do have the power of control over HIV, yet as with other circumstances (which I will explore later) the virus seems to be able to overcome the body's immune response.
HIV ENVOLOPE GLYCOPROTEIN AND EVASION OF NEUTRALISING ANTIBODIES
The Env proteins are found on the HIV virion surface in trimeric spikes. These are made up of a gp160 molecule, which is cleaved to form non-covalently associated heterodimers of gp120 and gp41. (Hoxie 2010). Env protein is of vital importance as it mediates viral tropism and entry, with each virion expressing 5-10 spikes. (Roux & Taylor 2007) However, Yang X et. Al., (2007) following stoichiometry studies of Env, state that only a single spike is required to mediate viral entry.
The gp120 molecule comprises highly conserved binding sites for CD4 and co-receptors CCR5 and CXCR4. (Pierson T & Doms R 2003) Subsequent to CD4 binding, gp120 undergoes a conformational change thus leads to coreceptor binding and gp41 release, which in turn interacts directly with the cell membrane (Hoxie J 2010). Following this, gp41 molecules undergo a structural rearrangement, which brings together the host and virus cell membranes, initiating fusion and subsequent viral entry (Hoxie J 2010).
Hoxie carries on to mention that all of the above steps are "necessary for viral infection and therefore are all potential targets for antibody inhibition". However, Env has evolved enabling viral escape once Neutralising Antibodies (NAbs) are made or prevent neutralisation altogether. (Hoxie J 2010)
Kwong PD et al., (1998; 2009) Described that the CD4 and coreceptor binding site on gp120, found on a central core, are surrounded by an arrangement of carbohydrates, which contribute to 50% of gp120's mass. However these carbohydrates are non-immunogenic as they are synthesised by host glycosylation machinery (Wyatt et al. 1998 & Hoxie 2010).
Wyatt et al. 1998 also describes the gp120 variable loops (V1, V2, V3 and V4) which protect the core from Ab binding. HIV's reverse transcriptase is highly error prone and although the loops are highly immunogenic, mutations and genetic diversity in these areas are well tolerated and allow the virus to escape neutralisation (Frost SD et al. 2005 & Hoxie 2010).
V3 has a direct influence on the tropism for CCR5 and CXCR4-expressing CD4 cells (Hoxie 2010). Hartley O et al. (2005) suggested originally that V3 was the principal neutralising determinant for Abs. Yet further work by Davis KL et al. (2009) now leads us to believe that in fact V3 binds poorly to Abs and is mostly obscured preceding CD4 binding.....
It was the ......vaccine regimen which used this knowledge..............
Therefore it is clear to appreciate its importance as we look towards
The Sooty Mangabey and African Green Monkey are well adapted natural SIV hosts, while nonadapted recent or experimental hosts (Humans + Asian macaques) display poor coping strategies and mechanisms. Below are some of the key features. Despite these differences there are also a number of similarities in the acute and long term host response of these subjects as I have touched on below. But it is the differentiating features that are the main focus of current interest.
Similarities and Differences between well-adapted natural SIV hosts and poorly adapted recent or Experimental HIV and SIV hosts. (Adapted from: Sodora DL et al., 2009)
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peak replication within a few weeks of infection
Decline of viral load indicates partial control of replication
Elevated innate and adaptive immune response
High set point of virus replication that persists despite host immune response
Virus replication mostly in short-lived activated CD4+ T cells
Well adapted natural SIV hosts (Sooty mangabeys + African green monkeys)
Nonadapted recent or experimental hosts (Humans + Asian macaques)
Variable levels of bystander T cell activation and apoptosis
High levels of bystander T cell activation and apoptosis
Healthy CD4 count + NO progressive depletion mucosal of CD4
Decline of circulating and mucosal CD4
Resolution of Type 1 interferon response
Persistent Type 1 interferon response
Limited immune activation + T cell apoptosis
Generalised immune activation + T cell apoptosis
TH17 cell preservation
TH17 cell loss
Absence of microbial translocation
Prominent microbial translocation
AIDS + Vertical transmission rare
AIDS + Vertical transmission most cases
Following this information, we can start to collate the evidence and understand the relevance of these findings, and begin to apply such knowledge to developing new immunization strategies.
The first lesson from such information is identifying neutralising antibodies as an AIDS prevention strategy. Kaur et al., 2008 suggested that such neutralising antibodies may be induced due to absence of B cell hyperactivation in natural SIV hosts. Therefore research will need to gauge the response of Nabs in natural SIV infections and "determine the level of cross-reactivity and define the basis for the lack of B cell hyperactivation" (Sodora DL et al., 2009). This faces us with the challenge of finding "Immunadhesins using components of SIV-specific Nabs from naturally infected species and deliver them to mucosal surfaces using vectors." (Sodora DL et al., 2009)
Another area to explore is the possibility of delaying disease progression. This can be achieved by improving our knowledge of the cellular immune responses, which are induced by SIV. T cell responses in SIV natural hosts are similar to humans, however Meythaler M et al., 2009 implies there is no causal link with bystander T cell activation. Consequently, future research priorities in light of this would be identifying the links between SIV-specific T cell responses and hyperactivation in HIV and SIV infected individuals. With this in mind, inducing a strong T cell response without inducing long-term, chronic stage bystander effects (Sodora DL et al., 2009) would be an ideal approach to an immunisation strategy.
The use of vaccine adjuvants, to ensure the innate immune system's antiviral activity performs effectively is a well know strategy. As the table above shows, for natural SIV hosts the responses of type 1 IFNs and the innate system during acute infection are dynamic yet less so in chronic infection. Thus it would seem important for research to define such mechanisms by which the down modulation of the aforementioned occurs in chronically infected natural SIV hosts. Applying this to future immunisation strategies, the development of adjuvants therapies coupled with an immunogen effect a robust yet transient immune response to HIV. (Sodora DL et al., 2009)
Another prevention strategy employed is at transmission site to reduce the accessibility CD4+CCR5+ target cells. Pandrea I et al., 2008 wrote that there are low levels of CCR5 on CD4+ T cells in Natural SIV hosts. In addition, following T cell activation, CD4+ expression is down regulated in African Green Monkeys. (Beaumier CM et al., 2009). Therefore work will need to look into such mechanisms of CD4 and CCR5 levels in natural SIV hosts. When applying this to a possible vaccination approach, Sodora DL et al., 2009 has hypothesised coupling Immugens which induce HIV-specific responses with antagonists of CCR5 that are independent of activated CD4+CCR5+ T cells at mucosal tissues.
Kornfield C et al., 2005 mentions that during chronic infection, the initial vigorous immune response during acute phase is greatly reduced. Thus applying this to HIV infection, a reduction of chronic immune activation would prove a useful insight. Furthermore, gut T helper cells and mucosal immunity are preserved in Natural SIV hosts. They also, despite depletion of CD4+ T cells at the mucosa, avert microbial translocation (Gordon SN et al., 2007). Therefore research can investigate the possibility of creating immunogens that do not allow chronic immune activation and Immunisation approaches that stimulate the negative control inflammation. (Sodora DL et al., 2009)
Finally, in natural SIV hosts, vertical transmission rare (Sodora DL et al., 2009).While on the other hand, it is well known that mother-to-child transmission of HIV will occur in the vast majority of cases. Consequently classifying such mechanisms which underpin this may afford the possibility of creating imitating immunogens in immunization. (Sodora DL et al., 2009)
"...Defining better immunity is the core challenge of HIV vaccine development..." (Shedlock DJ, Silvestri G & Weiner DB. 2009)
Since the start of the aids pandemic, hundreds of thousands if articles have been published. Yet Coffin JM, who wrote a highly cited paper in 1995 Suggested reasons why finding a vaccine is so problematic and why HIV still remains incurable.
Cells are infected and dying at a high rate and in high numbers
Virus replicates at an amazingly rapid speed
HIV's massive mutation rate
Antiviral resistance found for all compound therapies.
STEADY STATE MODEL of viral population dynamics. Latency does not equal inactivity, hugely dynamic process
An individual ten years of infection has viral genome 3000 generations from the initial infection. On average, transmitted virus is 1000 generations removed from initial infection.
Reverse transcriptase has no proof reading functions. More than 50% of viral genomes contain at least one error. As so many generations, with so many mutations are present at any one time. Thus premise of immune escape
Due to the massive mutation rate- drug resistant strains. Thus therapies only last for a short time due to HIV's diversity
Immunodeficiency is the result of direct killing of host cells by the virus or by the immune system itself. Massive viral replication drives the pathogenic process that leads to immune degradation.