Remision Strategy

Normal Cell-Mediated Immune system response

• A virus infects a cell and starts making its own proteins
• The immune system presents these proteins on the surface of the cell with MHC-I and MHC-II
• A naïve CD-8 cytotoxic T lymphocyte binds itself to a foreign protein and the MHC-I with its TCR
• The naïve CTL is now primed and waits for one of several lymphokine signals
• It receives the signal and transitions from primed to activated
• The activated T cell then kills the infected cell and starts circulating
• Once activated, it doesn’t need a second signal and goes on killing any encountered cells exhibiting the foreign antigen/s via MHC-I
• Thousands of these activated CTLs suppress disease by eliminating all encountered cells with a replicating virus

What happens in HIV?

• HIV downregulates MHC-I
• HIV interferes with immune signaling thus many primed CTLs don’t get activated
• Primed CTLs are programmed to become anergic if they don’t get the second signal (mechanism to prevent auto-immunity)
• Lack of a robust and sustained activated CTL response allows HIV to continue to replicate unabated, creating a persistent infection that most patients cannot overcome

How does HIV accomplish this?

An exhaustive review of the literature reveals that the answer is in the nef gene. There are over 1,400 papers related to nef, published during the course of the HIV pandemic.

What does the nef gene and the Nef protein it encodes do?

• Nef Downregulates MHC-I
• Nef Downregulates CD4
• Nef Disrupts SH3, Lck and HLA-B7 signals
• Nef Disrupts NF-κ signaling
• Nef Interferes with Leucine Zipper
• Nef Downregulates SERINC3 & SERINC5
• Nef Disrupts host cell restrictive factors
• Nef Upregulates CTLA-4
• Nef Upregulates checkpoint receptors
• Nef upregulates PD-1

As you can see, HIV-1 Nef frustrates most of the intracellular and extracellular mechanisms available, to execute a normal adaptive αβ CD-8 effector response, leading to CTL anergy or exhaustion.

What does the lack of an αβ CTL response do?

• Normally, the innate immune system, comprised of γδ T cells, NK cells, dendritic cells and macrophages, responds to infection by secreting large amounts of inflammatory cytokines to invite an adaptive immune response from αβ CTLs, which normally arrive upon receiving the signal and to eliminate the offending organism.
• In the case of HIV, the adaptive immune system doesn’t respond and the innate immune system keeps secreting copious amounts of inflammatory cytokines.
• The chronic persistence of inflammatory state mediated by cytokines results in comorbidities such as HAND, neuropathy and CVD.

Clinical evidence in literature

• There has been a farrago of reports of patients lacking symptoms and maintaining undetectable viremia, who are characterized as LTNP or EC, coinciding with a nef deletion. They maintain a robust immune signaling essential for viremic control and a strong ab CTL response to HIV antigens presented on host cells.
• The observations, when put together show that patients with a defective nef become LTNP or EC, even though the reverse is not always true. (Not all ECs have defective nef genes and exploit some other mechanism or are genetically predisposed to overcoming HIV)
• Epidemiological concordance demonstrates patients with a defective nef become LTNP or EC. Studies on these patients’ immune functioning demonstrated that they all have a strong CTL response, stronger ADCC and lower cytokine levels.
• It has also been shown that the longer (bigger) the nef defect, the longer and stronger is the protection.

Our nef deleted Live-Attenuated Therapeutic Vaccine

• We have created an HIV-1 virus with a very large (276 bp) nef deletion.
• We have created a robust and replicable cGMP FDA compliant process
• The vaccine has undergone all in vitro testing for FDA compliance
• The vaccine has been tested for safety in mice, Rhesus macaques, SIV-infected Rhesus macaques and BLT mice
• The construct is IND ready
• The vaccine is fully sensitive to ALL ARVs

How is the vaccine hypothesized to work?

• When injected in person with a wild-type HIV-1 infection, this vaccine is expected to start replicating
• It lacks the nef gene so it is expected to convert many ab CTLs into activated, effector CTLs.
• These CTLs will eliminate the vaccine virus but are expected to remain activated, and kill wild-type HIV infected cells, because they won’t be able to differentiate between the conserved Gag proteins presented on cells.
• Since the effector CTLs can effortlessly transmigrate to sanctuary regions including the CNS, they will be able to control viral replication in the reservoirs that are not addressed by cART.
• Activation of ab CTLs would reduce inflammatory cytokines produced by the innate immune system and help with comorbidities such as HAND.

Issues we have encountered

• Some scientists run for the hills at the mention of a live HIV vaccine – even though it is being given to patients already infected with HIV. This is notwithstanding the fact that medicine has historically used live virus vaccines for both prophylaxis and therapy, from polio to rabies.
• Some are worried about issues which are scientifically not likely to be of concern – such as recombination, creation of superinfection etc. Current evidence does not support such concerns. (nef deletion makes a replication impaired virus – the vaccine virus grows 40 times slower than a wild type virus.)
• Many are not comfortable with ATIs (Analytical Treatment Interruptions) which would be required to successfully test this concept. This requires special expertise.
• Our team has addressed each and every concern and have confidence in the fact that this vaccine can be safely tested. True science would require this approach to be either proven or rejected with experimentation.

References

Peer-reviewed literature references are available for each and every affirmative statement in the foregoing. If interested, please write to info@immgenuity.com