1) The document discusses a new paradigm where immunosenescence (immune aging) involves blocked release of HERV-K102 particles from foamy macrophages due to increased levels of alpha-fetoprotein (AFP). 2) HERV-K102 is endogenously produced in response to HIV-1 and other infections but its release is inhibited in progressive cases, preventing its protective and virolytic effects. 3) The paradigm suggests exploiting HERV-K102 particle production or administration, combined with agents to reduce AFP levels, could provide functional cures or prevention for HIV-1 by activating autoimmunity against infected cells.

1. The HERV-K102 – AFP
Immunosenescence Paradigm
for Functional Cures for HIV-1
MARIAN LADEROUTE, PH.D. MEDICAL SCIENCES –
IMMUNOLOGY
IMMUNE SYSTEM MANAGEMENT CLINIC & LAB (VOLUNTARY
CONSULTANT)
OTTAWA, ONTARIO CANADA
Email: hervk102@bell.net Skype: hervk102

2. The new paradigm and evidence
supporting it is covered in detail in:
Laderoute MP. A new paradigm about HERV-K102
particle production and blocked release to explain
cortisol mediated immunosenescence and age-
associated risk of chronic disease. Discovery Medicine
20(112):379-391, 2015.

3. Human Endogenous Retrovirus –K102
(HERV-K102)
 HERV-K102 is a fully functional and replication competent endogenous
retrovirus found in HIV-1 patients (first characterization of such, Laderoute
M et al., AIDS 2007, Open AIDS Journal, 2015)
 HERV-K102 is also the first foamy retrovirus of humans discovered
(Laderoute M et al., AIDS 2007, Open AIDS Journal, 2015)
 HERV-K HML-2 group members including HERV-K102, are the most active
and most intact HERVs, where expression has been associated with many
diseases
 Accumulating evidence shows HERV-K102 or similar antigen expression is
protective against HIV-1 replication and in breast cancers

4. Human Endogenous Retrovirus –K102
(HERV-K102)
 Particle production in HIV-1 infection has been shown by two groups: Laderoute M et al.,
AIDS 2007 and Contreras-Galindo R et al., J.Virol. 2012
 Particles can reach 10 11 per ml of plasma in 84 hours, so a very rapid induction is possible
 Particle production has been implicated in resistance to HIV-1 acquisition (Laderoute M et
al., Open AIDS Journal, 2015)
 However, HERV-K102 particle production is about 7 logs inhibited in HIV-1 patients (a
mean of about 8,200 particles per ml of plasma) when compared with patients with other
bloodborne pathogens
 About 96 % of HIV-1 patients have detectable HERV-K102 particles (cDNA) and/or Env
antibodies to HERV-K102 specific epitopes. Incidence and levels of antibodies seem higher
in HIV-1 patients than patients with other blood borne pathogens (Laderoute MP et al.,
2007)

5. HERV-K102 particle production generates
foamy macrophages

6. Background
Immunosenescence (immune aging) refers to a dysregulated immune system associated with aging.
It comprises both immunosuppression and concomitant inflammation presumably at the level of
macrophages. Macrophages orchestrate innate and adaptive arms of immunity.
Immunosenescence is thought to be caused by increased cortisol and decreased
dehydroepiandrosterone (DHEA) levels associated with aging and persistent infections.
How macrophages display both immunosuppression and inflammation concurrently, has remained
an enigma.
As well, how this relates to increase risk of cancer, infectious diseases, autoimmunity etc., has not
been elucidated.
Finally its role in HIV-1 pathogenesis remained unclear.

7. Background- AFP
Since the mid 70’s, alpha-fetoprotein (AFP) is a well established (but largely
ignored) immunosuppressive factor which also confers apoptosis (cell death)
resistance by binding to the 67 kD AFP receptor (AFPr).
This AFPr is found on macrophages (Laderoute & Pilarski, 1994) and is
overexpressed on common adenocarcinomas (Laderoute MP, Ph.D Thesis 1991,
Laderoute et al, 1994).
Increased levels of AFP are prognostic for progression for a number of viral
infections ( Zhu M et al., 2015; Cheng J et al., 2014; and reviewed in Mizejewski GJ,
2001; Terentiev AA and Moldogazieva, 2013).
DHEA and flavonoids block the induction and bioactivity of AFP.

8. Background- AFP
AFP may also bind to CCR5 on primary macrophages through its carbohydrates
and blocks binding by R5-HIV-1 strains (Atemezem A et al., 2002; Seddiki N et al.,
1997) raising the possibility of a role of active AFP in the switch from CCR5 to
CXCR4 co-receptor usage with HIV-1 progression.
This binding to CCR5 which is also expressed on Tregs (de Oliveira CE et al., 2014)
may help explain how AFP may contribute to non-antigen specific T suppressor T
cells (Murgita RA et al., 1977, Gershwin ME et al., 1978) now known as Tregs.
AFP levels directly correlate with HIV-1 viral loads (Gross S et al., 2003).

9. Proposed Key Roles of the Alteration of the DHEA/Cortisol
Ratio in Immunosenescence and HIV-1
1. Laderoute MP. A new paradigm about HERV-K102 particle production and blocked release to explain
cortisol mediated immunosenescence and age-associated risk of chronic disease. Discovery Medicine 20
(112): 379-391, 2015.
DHEA is considered an anti-stress/youth hormone and levels diminish with aging. DHEA (but not
DHEA-S), appears to bind active AFP and renders it inactive.1
As well, cortisol induces AFP expression.
Accordingly as you age or with HIV-1 infection, your levels of active AFP in the system may increase
due to diminished DHEA and increased cortisol.
This may be relevant to immunosenescence (Deeks SG et al., 2012) and the diminished
DHEA/cortisol ratio as found with progression in HIV-1 patients (Clerici M et al., 2000).
It is likely HIV-1 induces AFP expression in macrophages but needs to be confirmed.

10. Ordinarily in normal healthy adults, a viral infection induces HERV-K102 particle production in macrophages rendering
them foamy as HERV-K102 is a foamy virus. On day 7, the foamy macrophages lyse, releasing the HERV-K102 particles
which then can antagonize HIV-1 replication. In aged or unhealthy adults, there is insufficient DHEA and/or flavonoids
in the system to counterbalance cortisol and AFP. Active AFP blocks the lytic release of HERV-K102 particles in HIV-1
infected cells and could be induced by HIV-1. The potent protection against HIV-1 replication by HERV-K102 particles
and T and B cell autoimmunity is lost when there is too much active AFP in the system. The loss of DHEA/insufficient
flavonoids contributes to progression.

11. How might HERV-K102 protect the
host?
Our understanding of HERV-K102 host
protection mechanisms has been best studied in
HIV-1 pathogenesis.
Three of the four proposed mechanisms are
expected to apply to tumors and other viruses or
intracellular pathogens.

12. Four Postulated Mechanisms for HERV-K102 Antagonism
Against HIV-1
Model for HIVHIV AntagonismAntagonism
by HERVHERV--K102K102
Non-Infectious
HIV Released
Adaptive ImmuneAdaptive Immune
System ActivationSystem Activation
HERV-K102
Induced
LysisLysis
LysisLysis ofof HIV Infected CellsHIV Infected Cells
byby Anti-HIV T cells/
Antibody
HIV
HERV-K102
Particles Released
22
33
LysisLysis of HIV Infected Cells by
HERVHERV--K102 ParticlesK102 Particles
LysisLysis of HIVof HIV **
infected cells byinfected cells by
Anti-HERV-K102 T cells/
Antibody
4
11
From: Laderoute MP, Discovery Medicine, 2015.
1. Molecular Antagonism
2. Lysis of HIV-infected Cell
Producing HERV-K102
Particles
3. Lytic Infection of Abnormal
Cells (oncolytic and virolytic)
and Increased Proviral Copy
Number in Normal Cells
(arming)
4. Expansion of Autoimmune T
and B Cells to HERV-K
Antigens (TLR mediated?), the
latter which Behave as
Surrogate Antigens for
Targeting Transformed Cells

13. Part 1: proposed HERV-K102 –AFP Immunosenescence
Paradigm in Elite Controllers (EC)
 HIV-1 induces both AFP expression/secretion and HERV-K102 particle production in
macrophages (can also be induced/enhanced by other intracellular infections and by
cortisol)
 Where sufficient DHEA and/or flavonoids exists in the host (as may be the case in EC), the
bioactivity of AFP is inhibited, allowing the lytic release of HERV-K102 particles on day 7
from foamy macrophages
 HERV-K102 particles are thought to be virolytic which is enhanced when active AFP in the
system is blocked by DHEA and/or flavonoids
 These particles may generate “autoreactive” T and B cell responses to HERV-K antigens
expressed only on virus-infected cells or tumors, but which are not found at the cell surface
of normal cells (temporary “innate vaccine” possibly involving TLR signalling). Antibodies to
HERV-K102 envelope (Type 1 HML-2 epitopes) may directly mediate apoptosis.

14. Part 2: proposed HERV-K102 –AFP Immunosenescence
Paradigm in HIV-1 Progressors
 When DHEA and/or flavonoid levels are not sufficient (with age for example or
following chronic stress, chronic infection, poor nutrition etc., ), AFP binds to the 67
kD AFPr on macrophages and blocks the lytic release of HERV-K102 particles
 This causes foamy macrophages to linger, which is well known to initiate
atherosclerosis and increase the risk of cardiovascular disease
 As well, these dysfunctional macrophages are not able to activate adaptive
immunity, while active AFP in the system blocks afferent and efferent immunity
 The oncolytic and virolytic activity of HERV-K102 particles is lost as : a) particles are
not released, which prevents activation of autoimmune T and B cell responses and
b) activity of the particles is blocked by AFP preventing the lysis of virally infected
cells

15. HERV-K102 envelope or similar antigens are not expressed on the
surface of normal cells but are found as cell surface beacons of tumor
transformed or virally infected cells for T and B cell autoimmune
reactivity. This has been shown to mediate clearance of HIV-1 infected
cells (and breast cancer cells). For example T cell activity against HERV-
K102 envelope was found in EC and cleared HIV-1 infected cells in vitro
(SenGupta D et al., 2011; Jones RB et al., 2012).
HERV-K102 particle production in vivo has been associated with mediating remissions in
limited studies of CFS, MS and an acute Epstein barr virus infection (Laderoute et al, 2007).
In the case of breast cancer, HERV-K102 envelope was surprisingly shown to directly
mediate apoptosis when triggered by antibody, both in vitro and in vivo. (Wang-
Johanning F et al, 2012).

16. So what does the
HERV-K102 –AFP immunosenescence
paradigm say about HIV-1 functional
cures?
HERV-K102 is a naturally occurring oncolytic/virolytic virus, and
particles behave as “innate vaccine” so one gets both when
particles are administered (or induced and released from foamy
macrophages).
CAVEAT: But you must include measures to inactivate AFP in the system for this to work.

17. How to Exploit HERV-K102 particles to enhance levels of
Post-Interruption Controllers (PIC)
Administer orally, optimal levels of DHEA, flavonoids and amino acids (the
latter to support HERV-K102 particle production, for example high lysine (K) is
needed) allowing a 3-4 week lead time before ART treatment interruption:
 Administer agents able to induce HERV-K102 particle production (such as cortisol
for 5 days) and/or inject HERV-K102 particles, and/or
 Administer monoclonal antibodies to HERV-K102 envelope protein (which have
been shown to directly mediate apoptosis of target cells)
 Follow progress (before, during lead time and after) by doing qPCR on plasma
samples quantitate: 1) HERV-K102 particle production (cDNA), 2) HERV-K102
integration in genomic DNA sloughed into plasma, 3) HIV-1 viral loads, and 4)
integrated levels of HIV-1 in genomic DNA sloughed into plasma
 Optionally, monitor active AFP levels (see Lester EP et al., 1976)

18. How to utilize HERV-K102 for HIV-1 prevention
(i.e., innate vaccines for short term protection*).
Administer orally, optimal levels of DHEA, flavonoids and amino acids (the latter
to support HERV-K102 particle production, for example high lysine (K) is needed)
:
 ACTIVE innate immunization: Administer agents able to induce HERV-K102
particle production (such as cortisol for 5 days), and/or inject HERV-K102
particles, and/or
 PASSIVE innate immunization: Administer monoclonal antibodies to HERV-
K102 type 1 envelope protein epitopes (which have been shown to directly
mediate apoptosis of target cells)
 Do not co-administer traditional vaccines within 3-6 month windows of each
other due to cross-interference
* After high risk behaviour or when an infant is born to an HIV-1 positive mother.

19. How to utilize HERV-K102 for HIV-1 prevention
and sterilizing control
Research and Develop a recombinant sterilizing vaccine by using HERV-K102 as the vector
which contains nucleotides able to block HIV-1 replication (and not HERV-K102) such as
ant-Tat (Scarborough RJ et al., 2015, Cafaro A et al., 2015). Conduct Safety Evaluation in
BLT mice.
Administer orally the conditioning regime [optimal levels of DHEA, flavonoids and amino
acids (the latter to support HERV-K102 particle production, for example high lysine (K) is
needed)] allowing a 3-4 week lead time:
 Administer vaccine orally or by parenteral injection.
 Administer cortisol for 5 days. Continue conditioning regime.
 Test uptake by quantitation of HERV-K102 and recombinant HERV-K102 cDNA in
plasma (cDNA) and ratio of recombinant to normal in genomic DNA sloughed into
plasma. Determine optimal plasma ratio to be associated with protection against HIV-1
acquisition.
 Repeat process until ratios are sufficient to ensure protection.
 Note: Do not co-administer traditional vaccines within 3-6 month windows of each
other due to cross-interference

20. Caveats on using HERV-K102 antigens
for traditional vaccine approaches
 T and B cell autoimmune responses are only temporary and are suspected to not involve
traditional T cell help. Therefore breaking tolerance is an issue.
 At the present time, using HERV-K102 particles (induction or administration) may be the
safest way to induce T and B cell “autoimmunity” to HERV-K HML-2 antigens, but protection
is only expected to last about 6-12 months.
 There is still the need to ensure adequate DHEA and flavonoids in the host to enable or
facilitate HERV-K102 (proposed) virolytic activity and/or antibody ability to clear tumors by
blocking apoptosis resistance mediated by AFP.
 HERV-K102 is unique to humans and is not easily modelled in animal models. As well,
cortisol does not induce AFP expression in rodents indicating even humanized BLT mice may
not be perfect for pre-clinical testing.

21. Conclusions:
Immunosenescence appears to involve HERV-K102 particle production and blocked release by
AFP in foamy macrophages, the latter which then linger and initiate atherosclerosis and other
diseases related to immunosenescence.
HIV-1 is known to involve immunosenescence and a decreased DHEA/cortisol ratio is associated
with progression.
HERV-K102 particle production and/or Env specific antibody occurs in about 96 % of HIV-1
patients and AFP levels correlate with HIV-1 viral loads.
HERV-K102 particles (induction or administration) may be useful as a virolytic virus therapy or
innate vaccine for HIV-1 provided sufficient DHEA, flavonoids (and amino acids) are ensured in
the host. It may be difficult to test HERV-K102 in animal models.
HERV-K102 may be a preferred vector for recombinant sterilizing cures against HIV-1 as it
naturally occurs in humans while the antibody response it generates may also naturally induce
apoptosis in HIV-1 infected cells, while not reactive with normal cells.

22. The discovery of human endogenous retrovirus K102 (HERV-K102) as a protector
foamy virus of humans has been patented world wide by the Public Health Agency of Canada
(National Microbiology Lab, Winnipeg, MB Canada), for which inventors receive no benefits.
Dr. Laderoute retired from Immune System Management Clinic & Lab in 2015 during the writing
of the new HERV-K102 –AFP immunosenescence paradigm, but remains as a voluntary
consultant (since 1998).
Conflict of Interest Statement