1. Failed Promises: Social and Biological Theories Behind the “Cure” for HIV
Introduction:
It’s complex. It always has been. It always will be.
It has been over thirty years since the cure or “vaccine” for HIV was first promised. And yet,
although the concept of a cure may very well be a reality, this promise has not yet been fulfilled. A
great deal of progress had been made in immunology and HIV research due to both governmental
and private funding. But until a cure is found, the reasons for investing in such research cannot be
validated as seeking a cure. With the current system of research, one cannot say that research is
conducted to create a cure. One would have to conduct research in an explorative manner, where
one does not know what they are going to get from the results of their actions.
And so the promise did evolve into something much different. The promise became not to cure, but
to manage HIV patients. And with this ideological change, the economic impact of HIV has
burgeoned to 34 billion dollars per year1 for the United States Federal Funding. Of this budget,
eighty percent is used to purchase drugs for the sick, and only eighty percent is used for research.
In so much, this proves that the promise is not to cure HIV anymore, but to manage the disease.1
With such a large economic impact, it seems rational for there to be some resistance to finding the
cure. Think of all the private academic researchers, clinicians, and non-profits that would loose
funding. It seems the farther we go down this path, the least beneficial a cure becomes. In a sense,
the economic turmoil that would occur with a cure would be quite disruptive to the United States
economy. The bigger this issue grows, the lesser the incentive is to find the cure. This idea seems
counterintuitive, but it is reality.
There are a lot of factors that go into determining if HIV is incurable. To say that this idea is correct
due to the research being done is a fallacy. We must look at the structural scale in which HIV
research is being conducted and suggest further optimization. In reality, we, as a culture, have a
certain way of doing things. The purpose of this document is to analyze the factors that many
researchers are unaware of— the structural forces that explain why we are in the current state that
we are in now. And through this analysis, we could theoretically modify the system to make
knowledge of a cure much more probable.
Let us at first describe the system in which we are dealing with. The current HIV research is
primarily done via academic and non-profit research institutions which competitively apply for
grants to do research. And the researches themselves acquire these skills via a mentoring type
relationship from their superiors. Who judges which grants are to be accepted and rejected and
what is their basis for such? In academia, it is a select few employed by the sponsoring organization.
In the private sector, the economic incentive necessitates who gets funding— practicality is greater
than scientific context.
It's chaos theory at best that describes anything improbable probably occurring. And so we see that
this model applies the quest for the HIV cure. It is chaos guided by a select few— a bottleneck effect
if you will. Is the bottleneck approach the best, however? Are the judgments on what subjects of
research are being approved for funding the best? This could obviously be suggested. But the
alternative could also be true. And there are people of high standing that do voice their opinions in
thinking that the current method of conducting research is wrong.

2. What would the alternative be to the competitive bottleneck approach? Let us reverse this concept
and look at HIV research as collaborative and open. You can see that this bottleneck approach is
quite a repeated process in our capitalistic society. It is seen in the job search. It is seen in any
transfer of resources that occurs. The best idea, person, or thing must always be chosen for the
correct allocation of resources. But what information is that decision based on and is that decisions
always right? One with knowledge of biology would know that exceptions always exist and so
would suppose not. And so we could think that the problem that we are dealing with here is that we
are a gas station that is using the wrong information to decide on which employees to hire.
The limitations are on knowledge of other people: their pasts, their experience. Additionally, the
information that exists in the application and the impression that that give during an interview
reveals information. But occasionally, a bad employee does get hired. And in this occasion, we have
a manger that has hired only bad employees. He must therefore be making the wrong decisions. Or,
there is a lack of supply of good employees. Regardless, his gas station is still suffering and not
accomplishing its financial goals. What is he to do?
In the collaborative method, maybe he would not place a job posting. Maybe he would use his
networking skills to obtain knowledge about the outside world in so that he could actively find the
employees. Such a method may even be more efficient that making a job posting. Alternatively, he
could test employees in some on the way that would improve their performance. Perhaps he could
outsource the job in a different area. Ultimately, each of these social cues can be translated to the
context of finding a HIV cure.
In the context of the cure for HIV, our non-profit institution is the manager, our employees are the
scientists, and the goal to is find the cure. And in order for the cure to be found, there needs to be
sufficient fitness in each of these parties for the cure to be found. The alternative is that a cure is
impossible and so their relative fitness does not matter. However, people are sufficiently drawn to
the belief that a cure must be made. If this is the case, a lack of fitness in any of the aforementioned
parties could be detrimental. As the quest for the cure become harder, there is considerable
emphasis on the fitness of each of the parties. If even one of them is not up to par or not on the
same page, then this would prevent the cure form being discovered.
And so you see that this cognitive dissonance that exists in the people who sign off grants make it
impossible to cure HIV. However, this dissonance is dependent on the expertise of the scientists as
well, so you can’t blame either party. The phenomenon that does occur, however, is that this
interaction produces a negative feedback loop in where the quest for a cure is undermined. And so
it becomes a self-perpetuated destiny that there will not be a cure for HIV.
So, one cannot specify what changes need to me made in the current system. In an ideal sense, it
would mean to fund a research study that has a great idea that would theoretically work. This has
not been proposed, however. No one knows what this study would look like currently. It might be a
switchover to big data or increased collaboration through a technical change. It may be a small
piece of technical knowledge that has not been discovered yet that could open these doors. One just
needs to clarify that these are very real and very dependent on obtaining the results for the HIV
cure. There should be extensive effort to find these methods of preserving the quest for the cure. I
believe this is not currently done by non-profit or for-profit sponsors. And so I feel like a change
needs to be made.

3. And apart from the structural issues that the quest for the cure combats against. There is also the
issue that the scientific hypothesis’ are not the correct scientific hypothesis. The next sections of
this paper propose an optimization of the hypotheses’ that would lead to a scientific cure. It
proposes the most relevant hypothesis’ that exists at this time for HIV research as it pertains to the
quest for the cure and not in any other context.
The current state of HIV research is poor to say the least. It seems that variations that exists in HIV
research hypothesis’ is mainly due to the method of treatment, rather than coming to understand
the idiosyncrasies of the virus itself. For example, the idea of CRISPR or siRNA being used to study
HIV, but this does not translate into human clinical trials well. There is also a considerable amount
of research dealing with drugs that have the same targets as previous drugs.
As for the study of immunology, there has been a great deal of information that had been
discovered, but not much of it is in the context of HIV. There needs to be a considerable emphasis
on how HIV affects the immunes system. To just test how HIV effects certain cells is important, but
this may not be enough. Certain immunological patterns should be discovered on large scale rather
than just patterns or interactions with individual cells.
The biggest problem in understanding the cause of the latent stage of HIV during the use of ART. It
would be ideal if we could figure out a way to eliminate these cells, called the latent reservoir. And
this should be the priority if HIV is to be cured. This would therefore call for combination therapy as
this would require at least one more drug besides the ART. However, there are no studies that used
this theoretical combination. Therefore, this idea needs to become a priority.
Another issue is that the drugs do not pass clinical trials. This is a waste of time and money. There
could feasible be a method that selects small molecule that work for clinical trials. It could be rooted
bioinformatics or collaboration with other studies. Alternatively, products that are not small
molecules can be collaborated via other current trials. It is just a waste of time to spend so much
money on pre-clinical drugs that ultimately fail.
And so there are actually a lot of barriers to finding the cure for HIV. With all these suggestions, we
are put on the right track to find the cure with time. Apart from these structural issues in how we
determine what is appropriate to research, we will now go into the biological theories that would
perhaps lead to a cure.
Background Information:
There are a variety of tropisms for the HIV virus and essentially white blood cells are effected. The
adaptive and non-adaptive responses to HIV infection are highly complex. Without appropriate
treatment CD4+ T-cells are infected and apoptosis occurs with time. This leads to an
immunodeficiency and the onset of AIDS.
There needs to be an improved method un understanding the humoral or non-adaptive response to
HIV as this is the first line of defense. This defense is somewhat less specific and less effective, but
in the presence of an infection, the adaptive immunity takes too long to bring about a sufficient
immune response. The compliment system is also a component that needs to be looked into.
Biological Theories in Relation to the HIV Cure:
1. Enhancement of Immune Response

4. The immune response is by definition a factor that determines HIV virulence. If a more robust
immune response to occur, HIV would perhaps not mutate and perpetuate as much. There are two
cases when an improved immune response could be strategic: onset of infection and in the
presence of the latent reservoir. In the traditional model of immunity, the host defense of HIV is
dependent majorly on the affinity maturation model. In this model, the proper antibodies with the
proper epitopes are selected for in order to fight infection. It takes many cell generations, and
therefore time to produce the effective response. This factor of time is quite important as the same
time used for affinity maturation is use for HIV mutation. And so it is seen that alternate methods
are needed to combat HIV infection. What would these methods be? There could be a method in
which the patient’s immune system is flooded with already fit epitopes. There could be a
compliment system pathway that could be reengineered to target HIV and avoid the infinity
maturation pathway. Essentially, what is ultimately needed is to discoverer a protein or small
molecule that can improve the immune response so that it occurs quicker than HIV can mutate. The
existent of such a molecule or protein cannot be discounted. In the following appendix, a theoretical
assay is mentioned that would lead to finding this molecule.
Let us mathematically represent the conditions in which an HIV cure would exist.
𝑻 𝑩 𝑵 𝑩 𝑹 𝑩 > 𝑻 𝑯𝑰𝑽(𝑵 𝑯𝑰𝑽)
Where 𝑻 𝑩 is the rate it takes for one B cell to reach adequate affinity, 𝑵 𝑩 is the number of B cells
that exist, 𝑻 𝑯𝑰𝑽 is the rate it takes for one HIV cell to propagate, and 𝑵 𝑯𝑰𝑽 is the number of HIV
infected cells. 𝑹 𝑩 is a ratio that relates the number of B cells required to eliminate a single HIV cell.
It is a ratio of B cell propagation to HIV cell propagation. This is dependent on the immune system
of the individual.
The goal is to get the amount of effective B cells large enough so that it brings down the rate of HIV
replication. In the natural state for HIV positive patients, the rate of HIV replication is so high that it
makes it impossible to solve the equation up above.
However, under ART, the equation seems more solvable as the true numbers are smaller for the
HIV infected cells and the existent or mature B cells. However, since the equation is rate dependent,
this explains the rebound of HIV. A molecule that greatly affects this rate would be pivotal in finding
theoretical HIV cure.
And so there are many classifications that this molecule could take. One would be an
immunomodulatory agent that increases the immune response and the other would be a HIV
mutation blocker. Alternatively, a combination of these two types of molecules could be used.
ART, however, is not a way to skew this equation. The current target of ART leaves a latent
reservoir that cannot be overcome. And so instead of solving the equation to our favor up above, we
are essentially nullifying the equation. The alternative would to be to find new targets in the HIV life
cycle that are not being targeted. For example, TAR is an essential protein that leads to the
recombination of HIV DNA. Targeting TAR would perhaps decrease the mutation rate and solve the
equation up above. Alternatively, the highly error prone DNA Dependent Polymerase that is
required of HIV replication can be alters in a manner in which the protein still works but the
mutation rate is much lower. Current drugs completely inhibit the activity of this polymerase,
essentially nullifying the equation. There are a wild number of treatments similar to these two that

5. may exist but have not been discovered. Therefore, it would be nice to try to find these theoretical
molecules to potentially find the cure.
ART is an important subject to bring up as it one would tend to think theoretically satisfy the
equation. However, the treatment is caught in a paradox. On one extreme there is latency that does
not cause an immune response and on the other extreme there is uninhibited replication and
mutation of the virus. Is there an in-between? Is there a molecule that would selectively find latent
HIV and cause them to come out of hiding? This leads into our next target for the HIV cure— the
latent reservoir.
2. Shock and Kill
The shock and kill method is used in the context of ART. After the latent reservoir is defined by the
use of ART, theoretically, an agent can be applied to cause the latent cells to come out of latency.
The immune system could then theoretically reduce the latent reservoir. But how are the cells that
are “shocked” to be killed. Is it adequate enough to let the immune system do this or is another
agent needed? And what about the mutations that exist when the cells are activated, wont this make
it impossible for the latent reservoir to decrease? It seems as though the shock and kill method has
its issues. The issues are that the compounds for the “shock” are not optimized and the “killing” is
somewhat ineffective. And so we see that in theory, this is a good idea. But this idea has no basis on
reality.
3. The “Shock” Portion of Shock and Kill Does Not Have to Be That Complicated
Essentially all ART prevents HIV replication and results in the latent reservoir. In this scenario, one
would wonder if it is the immune system to blame for this fault. Why can the immune system find
latent HIV? Why is it that HIV can only come out of hiding after ART is ceased? How come it does
not require the existence of latency inhibitors to be expressed? This last question is of importance:
there is some sort of dependency on ART that forces latent HIV to stay dormant. Perhaps the real
cause is the loss of the cell replication cycle that would therefore cause a loss of a certain protein.
Perhaps there are certain proteins that exist in the absence of ART that cause HIV to come out of
latency. This is a question that has not been asked or answered by anyone. The current hypothesis
is that there are a variety of factors such as SAHA of IDAC inhibitors that cause HIV to come out of
latency. No one has suggested that HIV causes HIV to come out of latency. If a certain protein is
found to have his effect, then it would be of considerable use in decreasing the latent reservoirs in
patients.
4. Prevention HIV replication
ART is a great tragedy for reducing the HIV burden on the immune system. Once it is discontinued,
though, latent reservoirs allow HIV to persist. So it seen that HIV replication is not a great target for
a cure for HIV. However, it is important to examine the effectiveness of the HIV replication drugs.
Their effectiveness is never a hundred percent in patients die to patient variability and the
variability that exists in HIV. So there is a relative number of cells periodically come out of mutation
during ART treatment. It is fallacy to say that the latent reservoir is a stagnant reservoir-it is
dynamic. This is given by the fact that the lymphatic cells only stay alive for ninety days in average.
With this information known, it would be safe to assume that is the latent reservoir was not
dynamic, then in ninety days, all latent cells will have been eliminated. So we see that replication
does occur under ART, contrary to widespread belief. And so we see that the existence of the HIV

6. disease still persists, but on a smaller scale, with a small number cells dying, apoptosized,
eliminated by the immune system or re-infected.
It is therefore a good idea to use and ART for the potential cure. The fact that this burden is reduced
on the immune system sets a primer for the cure to be found. The cure will inevitable be, by
definition, a method in which the immune system is able to effectively seek out latent HIV and
eradicate it from the body.
There could theoretically be molecule that would both reduce the HIV replication and also bring the
HIV out of the latent stage. There should also theoretically be an ART model that present HIV
replication n a way that is most beneficial for bring out HIV out of latency. This is based on the
assumption that each of the ART methods have an effect on HIV latency.
5. Prevention of HIV Mutation
The prevention of HIV mutation would be of great interests because it could theoretically allow the
immune system to naturally fight HIV. By decreasing the mutation rate, the effectiveness of the
immune system increases. And so, considerable effort needs to made to determine the cause of the
HIV mutation rate being so high. The current causes or factors that could affect eh mutation rate are
of course, DNA polymerase, Reverse Transcriptase, and other arbitrary molecules that could inhibit
these processes. There could theoretically be a molecule that improves the accuracy of the
Polymerase or reverse transcriptase so that fidelity does occur, or, alternatively these proteins
could be completely deactivated. In the former, the virus is viable and will replicate. In the later, the
virus would ultimately not be viable—latency may result. If the cells were brought out of latency so
that they would replicate with high fidelity, this would be the best change for a cure as the reservoir
is small at this time and the HIV is not mutating and easy to isolate and eradicate form the body.
6. The Theory of Latency
So what causes latency in HIV? Is it the cell type that is infected or is it the genetic variation that
exists is in the HIV? It could be combination of both. In fact, it must be a combination of both. So, in
order to prevent this latency, both of these variations need to be accounted for. A molecule that can
decrease the mutation rate or prevent certain susceptible cells from obtaining the virus would have
to be found. Current ART does not do this effectively enough.
The above statements are based on the assumptions that the latency model is in fact dynamic,
which certain cells coming out of latency and certain cells entering latency. The alternative is that
latency is stagnant—HIV exists in long term memory cells and does not come out of latency at all on
ART— would suggest that there should be a greater emphasis of identifying infected latent HIV
cells.
What would be a method in which latent HIV cells could be found and eradicated? Currently, the
human immune system is incapable of this feat. By definition, there must be a genetic complement
to this latency. There may be other components such as a proteomic component that may exist on
the surface of the infected cell. There may be a method in which this genomic different is
transcribes to a proteomic difference in methods other than causing the cell to come out of latency.
Hypothetically, what if there was a something not classified as a HDAC inhibitor or cytokine that
would selectively cause this cell to apoptosize or somehow gain some attribute that could make it
selectable. Perhaps it would not be an activator of HIV, but perhaps a molecule that activates other

7. portions of the genome. When a molecule is applied to a cell, there is a variety of downstream
effects that the molecule could have. IN essence, this downstream affect would have to create an
affect that causes the cell to become abnormal or apoptosize. For example, say if a protein kinase
was activated that leads to downstream affects od protein expression for a wide variety of protein
in the genome. In this context, the existence of HIV, could either exacerbate or downplay the effects
on the cell. In this way, we can see that the latent cells do not have to rely on the traditional
techniques that target epigenetics mechanisms. High throughput screening could be used to achieve
this result. In addition, a comparative genomics approach would be beneficial to understand the
differences between the cells. And more importantly, a differential technique that can distinguished
the regulatory proteins that exist in these latent cells would be beneficial.
7. Modification of HIV so that it attacks another cell type
And interesting experiment would be to give certain cells other than lymphocytes the CCR5
receptor and see what would happen to the cells. Entry would most likely occur, but what else
would occur in these cells. There would of course be a different group of cell-dependent regulatory
proteins that exist. The interaction between there altered cell types and the tradition lymphatics
cells may give insight into the importance of certain regulatory proteins. Perhaps a protein that
prevents HIV integration can be found using this technique. Perhaps a protein that can be targeted
in latent lymphocytes could be found as a target that effectively causes the cells to come out of
latency. This proposal which would seem too explorative and would therefore note receive federal
funding would be overlooked in today’s world. And so we are limited in our knowledge of what the
real makeup of the latent or even non-latent HIV cell.
8. Some immune responses other than innate and adaptive
There is traditionally an adaptive and non-adaptive immune system that plays a role in HIV
infection. There needs to be more knowledge on how the non-adaptive immune system plays a role.
There should be an assay that shows the protein expression of latent t HIV cells in the presence of
cytokines. This would be crucial to understanding how we could theoretical cause latent HIV cells
to come out of latency. A certain protein that is downregulated or upregulate by NFKb could easily
be antagonized or agonized via a small molecule ant therefore would dramatically cause HIV to
come out of latency. There would be minimal side effects for this type of drug and it would be highly
specialized.
The SAHA molecule s something that is considered a histone inhibitor and reality used in HIV
studies to being HIV out of latency. There needs to be analysis of the protein expressions of cells
subjected to SHAH. There will obviously be downstream and upstream effects due to the
inactivation of this inhibitor and it would be nice to see the results of such an occurrence. Currently,
it is hypothesized that the expression of HIV is of course the only effect of the drug. This, however
cannot be the case, at by definition the histone is a general histone and not applicable to sole the
transcript of HIV. There would of course be a certain convulsion of proteins that are specific to HIV
and those that are random. It would therefore be difficult to determine which ones are indeed are
effects of HIV and those that are an effects of SAHA. Therefore, each protein would have to be
examined indepedently. A microarray or a protein array could be used to do this. My finding those
that are negatively or positively affected by HIV, would could once again emulate this effect my
using small molecules.
9. Comparative Analysis of Different HIV Pathenogensis’

8. HIV does not affect other species because of the lack of the CCR5 receptor. However, genetically
modified mice that have this CCR5 receptor are susceptible to the disease and have similar
outcomes. So we see that that limiting cause of HIV infection is in fact the immune system and that
the variability between species does not have a significant effect on the prognosis of the disease.
This so happened to collaborate the idea the there is in fact an immune system deficiency caused by
this disease. How can this be overcome? The only way to rid the system of HIV is to decrease the
immune cells that are infected while increasing the number of those cells not affected. Again, the
rate of HIV proliferation must be decreased to allow the immune system to combat the disease. The
latent reservoir needs to be decreased as well. It would hypothesis that a treatment that reduced
the latent reservoir used in conjunction with ART would lead to the cure of HIV.
Mathematically, the rate of the immune destruction of the latent reservoir should be greater than
the proliferation of the latent reservoir. This would lead to the ultimate destruction of the reservoir.
10. A mechanism or molecule that expedites immunological responses
There could theoretically be a mechanist that boots the immunological response by bypassing the
affinity maturation pathway. Theoretically, the compliment system could be modified to attack cells
that have epitopes that do not mutate and so a more robust response could exist. This would
require the administration of a protein that works as a conjugate for the compliment system and
the HIV molecule. This type of molecule that is a conjugate would allow to cell apoptosis vis
recruiting antibodies or causing the MAC complex to form. This would be a much faster method to
eradicate HIV and could be used in the context of a reservoir.
Alternatively, the compliment system could be engineered to attack any cell depending on the
makeup of a certain conjugate protein. This could be used to select cell that are latently infected
with HIV. IN so much this technique could also be used for cancer.
11. A compound that generalizes the characteristics of an antigen
A conject of a conjugate protein seems very much like a plausible way to improve immune
response. Say you have an antigen that is quite specific. It would take week for the affinity
maturation model to produce the correct antibodies. An alternative would be to use an antibody
that was created in lab that is specific to that antigen. This could be done in real time in a manner
that is quicker than the affinity selection model. This may be quick enough to make the immune
system eradicate the virus more than the virus can replicate itself. When used in conjunction with
other therapies, this method could well be used to eradicate the viruses in an efficient manner.
This technique could be used to reduce the latent reservoirs as well. A conjugate protein that is
specific to the latent cells would serve as a method of eliminating the latent reservoir.
12. How Latency Persists and How Latency Dies
Usually HIV releases via budding and there is no lysis.2 It then enters other cells. In this manner,
every cell that is infected is therefore eligible for latency. It is odd to think what causes HIV to go
into latency. Here has to be some negative or positive feedback that causes this to happen. In so
much some of the ART therapies must be more effective and causing latency. The ART therapy that
presents budding would be a theoretically treatment that induces latency. There are instances
which certain cells will undergo latency, one where the external environment conducive and one
where the cell itself is conducive to latency. Perhaps it could even be stated that latency exists in

9. every cell that is infected by HIV. It is on those cells that have the proper external environment and
protein expression that are latent. There must be a variety of non-elucidated factors that cause this
latency to persist. Again, comparative genomics and comparative genomics are the best methods in
determining what proteins cause latency. There have of course been a variety of protein that have
been mentioned, but there may be more that exist. And the attempt mimics these proteins has
currently not come to fruition,
13. Immune System modulators
There are currently immunomodulatory agents that do work to improve the function of the
immune system. These immunomodulatory agents are based on activation of hormonal pathways
and so improve the immune response by interacting the growth and proliferation of immune cells.
There may be many more molecules that can improve the immune system in a general manner or a
specific manner. In fact, each of the cell signaling pathways that do cause immune function could
theoretically be agonized to improve the immune response. This concept long with the concept of
increasing the specificity of the response or the antigen would create conditions favorable to
eradicating HIV.
14. Stem cell applications to HIV Pathogenesis
Stem cells could and can could be being used to eradicate HIV. The issues that are encountered is
that there need to be a stem cell donor and or an infinite number propagating stem cells. The
infected immune cells need to be eradicated and the sterile cells must replace them. It is of wonder
what would happen if all white blood cells were wiped out of an individual with nothing to replace
them. Would non-infected white blood cell propagate from hemopoetic stem cells? This is not the
case at HSC are usually wiped out during stem cell implant. And so you see that the use of donated
or engineered stem cells could boost the immune response which may lead to the loss of the latent
reservoir a cure for HIV.
15. Combination Therapy Is Necessary
There would most likely be a combination therapy that exists to combat HIV. An ART with other
drugs that are used to progressively shrink the latent reservoir. The shock and kill method seems to
be a method of interest, but the shock part mane not be necessary. The proper type of methods
would be more like the “identify and kill method” as it would be preferable for the latently infected
HIV cells to become somehow identified through some conjugate protein. Activation of the eh cells
is not necessarily the best methods because it can allow for hive to spread. There had been no
studies that mix the shock and kill method with ART. There should be a better understanding of the
regulatory proteins that exist in latent HIV positive cells besides these currently methods anyway
due to these methods being ineffective
16. Discontinuity versus Continuity- finding the appropriate variation and methods to find the
proper puzzle piece
The repeated problem for scientists is to find some discrete pattern in a continuum that exists. For
example, there is a certain protein with a certain sequence that must exist while there are infinite
proteins that exist. This would be regarded as the central issue for drug developers as well as they
are looking for discreet entities among an unlimited number of options. It is therefore the goal of all

10. science to find these discrete entities that have real value. There are of course entities that have not
come to discover that exist in this context for the HIV cure.
There must therefore be experimental methods in which these discrete entities are found. The main
methods that would be promising would be cheminformatics and genetic mutation assays.
Cheminformatics needs improvement and validation before it can be used solely to find these
discrete entities. But the existence of NGS and understanding of the regulatory protein that exist in
HIV infected cells would make the conditions right for cheminformatics to be a source of a big
breakthrough. There should also be a method in which genetic variation or mutation causes the
correct molecule of interest to be formed. This hypothetical model could be developed using
bacteria that have a high growth. Alternatively, the affinity maturation method could be models in
culture use germinal centers. This would ultimately create the epitopes that are necessary for
protein interactions. These important epitopes could be used to inhibit cell signaling. HTS is also
another options that van be used. A certain immunofluorescent assay could be developed that
either positively or negatively affects the interaction between proteins
17. Emphasis on small molecules for a potential HIV Therapy
Small molecules are the standard for drug effectiveness. Protein therapies are less effective. I
should suggest that the cure does lie within a certain combination of small molecule drugs that
simultaneously prevent HIV replication and cut down on the latent barrier. There could be a large
number of small molecules that work to being latent HIV cells out of the latent stag by not just
inhibiting histones, but targeting proteins that play a role in the expression of HIV. There by
definition has to be a regulatory network of proteins that exist in latent vs non-latent HIV cells that
goes beyond the existence of histones for these are but a result of some other regulatory
mechanism. Proper screening of these protein regulatory networks would most likely result in the
discovery of these protein that cause HIV to come out of latency.
Overview of structural barriers to research:
1. Decrease in funding for the “cure” shows lack of conviction
2. Bottleneck effect is not always efficient and so increase collaboration, bioinformatics and
prioritization should occur
3. Methods in which do not pass clinical trials must not be prioritized
4. There is a huge amount of inefficacy caused by a variety of attempt to accomplish a single goal or
optimizing that single goal. If the goal works in vitro, and does not work in vivo, the idea should be
thrown out. If the goal works in vitro and in vivo, but does not have the necessitated effect, then the
goal should be re-examined
5. The clinical trials that occurred for HIV should never have been pushed as the in vitro studies
were not promising or where not stringent enough
6. The should be less weight placed on a development of a vaccine
Summary of hypothesizes for the cure:
1. Latency exists in a dynamic state and is regulated by a variety of proteins

11. 2. There are proteins that can act as a conjugate to assist in recognition of latent HIV cells
3. Small molecules can act as a method to reduce the latent reservoir over time
4. prevention of HIV mutation without complete inactivation of replication would alone the immune
system to fight off infection
5. There are proteins that can be targeted to improve the immune system
6. Stem cells can be used to eradicate latent HIV or improve immune system outcomes
7. Combination therapy with ART would most likely lead to the reduction of the latent reservoir and
be theoretical cure for HIV.
8. The mechanism that HIV uses to evade the immune system can be combatted using small
molecules.
Theoretical Experimental Methods:
1. Finding the target for curing HIV assuming the target exists inside T cells
1. Given: The Latent Reservoir must be eliminated in ART patients
2. Hypothesis: The latent reservoir can be shocked via small molecule that acts as
an agonist/antagonist that allows HIV to come out of the latent stage within the T-
cell genome
3. Methods:
Safe and Cheap: Differential Proteomic Analysis of Latent Cells and Non-
Infected Cells, alternatively: differential genomic analysis of exact cells before
and after infection
Expensive: Optimized HTS assay in where small molecules are subjected to
latent HIV cells. Cells are analyzed for their ability to come out of latency.
Compounds are optimized. Target can be found using proteomic analysis.
2. Finding the target for curing HIV assuming the target exist inside immune system
1. Given: The Latent Reservoir must be eliminated in ART patients
2. Hypothesis: There is a protein that can be targeted that exists in all humans that
can improve their response to HIV (other than CCR5 receptor)
3. Methods:
Safe and Cheap: Differential Proteomic Analysis of Those with Robust HIV Immune
responses and those without, alternatively: differential genomic analysis before and
after infection. Finding a target and optimizing small molecule binding to target.
3. Validation Assay In-vitro/In-vivo of Compound’s Ability to Force Cells out of Latency
1. Isolation of T-cells that are latent
2. Application of compound
3. Observe latency
4. Assumptions: latency is not dependent on interactions with the immune system
5. Test in clinic

12. 4. Assay to Develop Conjugate Proteins or Small Molecules
1. Hypothesis: A protein that can both recognize and effect a function would be
beneficial to reducing the latent reservoir
2. Methods: Use of differential proteomics to find a target specific to the latent cells.
A good start would be to look for expression of proteins on cell membrane or
proteins that are involved with uptake of the cell membrane. High affinity
antibodies could be used to isolate these latently affected cells and force them out of
latency. Alternatively, small molecules could be used to prevent these proteins from
functioning, causing the cell to alter in some way.
3. Assumptions/Issues: Antibodies do not come into contact with internal proteins
5. Assessment of differential latent reservoir characteristics
1. Hypothesis: Different forms of ART therapy will have an effect on the latent
reservoir cell type.
2. Methods: On the same patient, use different forms of ART in sequence allowing
for full rebound of HIV in between treatments. Analyze the existence of the reservoir
and the cell types involved. Any measurable statistical difference would suggest that
the different targets of ART have varying effects on the latent reservoir. This would
be beneficial because it would show that there are a variety of ways that the latent
reservoir can be regulated.
3. Issues: It is very hard to describe the latent reservoir in patients. The locations of
theses latent cells and the cell variation is hard to determine. Proper sampling
methods must be applied. There are a variety of variables that exist that could affect
the latent revoir besides the ART dugs as well, so a pure control would be hard to
create.
Philosophy
1. Hypothesis: new knowledge is created is not dependent on results, rather the hypothesis that are
created. Therefore, the results of the experiments are not important. This make science much more
efficient as studies that have the most effective or plausible results can be chosen before any results
are gathered. The specific information that exists today is due to variances in hypothesis rather
than accurate results. To decrease the time it takes to do science, it should be suggested that we are
not as result oriented. Here is a pictorial representation of such and idea.

13. Notes: This article is based on theory. Any statements are based on logic and perception and are not
to be misconstrued as plagiarism.
References:
1 http://kff.org/global-health-policy/fact-sheet/u-s-federal-funding-for-hivaids-trends-over-time/
2 Krishnamoorthy, Lakshmipriya. Glycomic approaches to understanding HIV-1 budding in T
cells. ProQuest, 2008.