THE FAUCI FILES, 3( 32): Pantaleo: HAART Cocktail Trashes Critical CD8 Immunity

W. Fred Shaw fredshaw at primenet.com
Thu Mar 2 13:11:57 EST 2000


THE FAUCI FILES, 3( 32): Pantaleo: HAART Cocktail Trashes Critical CD8
Immunity

March 2, 2000

As previously revealed by THE FAUCI FILES and now confirmed by
Pantaleo et al in the journal Blood (3/1/00, Soudeyns et al.),
who concludes that the HAART (HIV cocktail drugs) globally reduces
HIV-specific CD8 CTLs and suppresses HIV-1 replication in CD4+ T 
cells, but does not control HIV infection in tissue macrophages and 
dendritic cells.

In other words, HAART cocktail drugs are not "life savers" at
all. To the contrary, they are capable of causing the collapse
of life-critical immune protection directly.

Hence death-by-HAART.

Interestingly, Pantaleo once worked under Dr. Anthony "Mussolini"
Fauci at the NIH NIAID Institute, but left the little Mussolini
behind to return to conduct his research in Europe.

W. Fred Shaw, Editor, THE FAUCI FILES
---

The following contribution is from Billi Goldberg:

According to Schrager and D'Souza (1998), macrophages are reservoirs of 
HIV during all phases of disease progression.

According to Li et al. (1999), HIV-infected macrophages significantly 
increase their replicative capacity during advanced disease.

Since HAART eliminates cytotoxic/suppressive CD8 CTLs and cannot control
active HIV replication in infected macrophages (and/or dendritic cells),
there is a distinct possibility that disease progression will continue 
unabated during "successful" antiretroviral therapy.

As concerns the importance of these CD8 CTLs globally reduced by HAART, 
Soudeyns et al. (Pantaleo is senior author) state: "Acute or primary 
infection with human immunodeficiency virus type 1 (HIV-1) is 
characterized by transient high-level viremia, which decreases 
significantly upon the emergence of the host virus-specific immune 
response. Particularly effective in the control of primary as well as 
chronic HIV-1 viremia is the cellular immune response mediated by 
HIV-specific CD8+ cytotoxic T lymphocytes (CTLs).

The authors clearly admit that there is a problem: "Furthermore, 
similar to what occurs in chronic infection, the global reduction of 
CD8+ T-cell oligoclonality induced by HAART during primary infection is 
associated with a progressive reduction in the frequency of circulating 
HIV-specific CTL precursors and/or effectors. Therefore, it is 
conceivable that potentiation and long-term maintenance of a diversified
HIV-specific CTL repertoire during antiretroviral treatment may require 
the development of therapeutic vaccine strategies to achieve effective 
immune-mediated control of HIV replication."


Supporting article excerpts:

Dr. Guiseppe Pantaleo has reported that HAART does not control HIV 
replication in tissue macrophages and dendritic cells (Nature Medicine 
1997 May; 3(5): 483-486). He states: "A likely scenario is that 
antiviral therapy may effectively control active virus replication in 
the pool of high replicating virus cells (that is, CD4+ T cells), and 
not in the pool of low replicating virus cells, that is, tissue 
macrophages and/or dendritic cells, which account for the residual (<1%)
virus production. Therefore, the pool of low replicating virus cells 
seems to be mostly refractory to the potent antiviral drugs." 

In 1998, NIAID's Schrager and D'Souza stated: "Reservoirs of HIV-1 have 
been identified that represent major impediments to eradication. 
Conceptually, there are 2 types of sanctuaries for HIV-1, cellular and 
anatomical. Cellular sanctuaries may include latent CD4+ T cells 
containing integrated HIV-1 provirus; macrophages, which may express 
HIV-1 for prolonged periods; and follicular dendritic cells, which may 
hold infectious HIV-1 on their surfaces for indeterminate lengths of 
time."

The authors also state: "Macrophages may play important roles in 
abetting HIV-1 infection throughout the disease process, from soon after
initial mucosal exposure to the final stages. Human immunodeficiency 
virus 1 infection of macrophages can be productive but noncytopathic, 
permitting macrophages to serve as long-lived sources of HIV production.
Throughout the course of HIV infection, macrophages have been implicated
in carrying virus across the blood-brain barrier and establishing and 
maintaining HIV infection within the central nervous system (CNS), 
probably the most important anatomical HIV reservoir. During latter 
stages of HIV infection, when the CD4+ T-cell population is largely 
depleted, macrophages may be a key source of de novo HIV replication."

As concerns the importance of macrophages during disease progression, Li
et al. (1999) state: "However, this study also shows a marked and 
significant increase in replication as well as tropism for MDM 
[monocyte-derived macrophages] and monocytes by HIV-1 strains isolated 
from blood at the advanced stages compared with the early stages of HIV 
infection."

=============================

Soudeyns H, Campi G, Rizzardi GP, Lenge C, Demarest JF, Tambussi G, 
Lazzarin A, Kaufmann D, Casorati G, Corey L, Pantaleo G. Initiation of 
antiretroviral therapy during primary HIV-1 infection induces rapid 
stabilization of the T-cell receptor beta chain repertoire and reduces 
the level of T-cell oligoclonality. Blood 2000 Mar 1;95(5):1743-1751 

Laboratory of AIDS Immunopathogenesis, Division of Infectious Diseases, 
Department of Internal Medicine, Centre Hospitalier Universitaire 
Vaudois, Lausanne, Switzerland; Unit of Immunochemistry, DIBIT, and the 
Department of Infectious Diseases, San Raffaele Scientific Institute, 
Milan, Italy; Duke University Medical Center, Center for AIDS Research, 
Durham, NC; Fred Hutchinson Cancer Research Center, Seattle, WA 98105. 

E-mail: giuseppe.pantaleo at chuv.hospvd.ch

Abstract: Major T-cell receptor beta chain variable region 
(TCRBV) repertoire perturbations are temporally associated with the 
down-regulation of viremia during primary human immunodeficiency 
virus (HIV) infection and with oligoclonal expansion and clonal 
exhaustion of HIV-specific cytotoxic T lymphocytes (CTLs). To determine 
whether initiation of antiretroviral therapy (ART) or highly active 
antiretroviral therapy (HAART) during primary infection influences the 
dynamics of T-cell-mediated immune responses, the TCRBV repertoire was 
analyzed by semiquantitative polymerase chain reaction in serial blood 
samples obtained from 11 untreated and 11 ART-treated patients. 
Repertoire variations were evaluated longitudinally. Stabilization of 
the TCRBV repertoire was more consistently observed in treated as 
compared with untreated patients. Furthermore, the extent and the 
rapidity of stabilization were significantly different in treated versus
untreated patients. TCRBV repertoire stabilization was positively 
correlated with the slope of HIV viremia in the treated group, 
suggesting an association between repertoire stabilization and virologic
response to treatment. To test whether stabilization was associated with
variations in the clonal complexity of T-cell populations, T-cell 
receptor (TCR) heteroduplex mobility shift assays (HMAs) were performed 
on sequential samples from 4 HAART-treated subjects. Densitometric 
analysis of HMA profiles showed a reduction in the number of TCR 
clonotypes in most TCRBV families and a significant decrease in the 
total number of clonotypes following 7 months of HAART. Furthermore, a 
biphasic decline in HIV-specific but not heterologous CTL clones was 
observed. This indicates that ART leads to a global reduction of CD8(+) 
T-cell oligoclonality and significantly modulates the mobilization of 
HIV-specific CTL during primary infection. 

=============================

Schrager LK, D'Souza MP. Cellular and anatomical reservoirs of HIV-1 in 
patients receiving potent antiretroviral combination therapy.
JAMA 1998 Jul 1;280(1):67-71 

Epidemiology Branch, Division of AIDS, National Institute of Allergy and
Infectious Diseases, Bethesda, MD 20892, USA. LS14M at nih.gov 

Abstract: The eradication of human immunodeficiency virus 1 (HIV-1) from
infected persons is the ultimate goal of HIV therapeutic interventions. 
Great strides have been made in developing potent antiretroviral 
regimens that greatly suppress HIV-1 replication. Despite these 
therapeutic advances, major obstacles remain to eradicating HIV-1. 
Reservoirs of HIV-1 have been identified that represent major 
impediments to eradication. Conceptually, there are 2 types of 
sanctuaries for HIV-1, cellular and anatomical. Cellular sanctuaries may
include latent CD4+ T cells containing integrated HIV-1 provirus; 
macrophages, which may express HIV-1 for prolonged periods; and 
follicular dendritic cells, which may hold infectious HIV-1 on their 
surfaces for indeterminate lengths of time. The key anatomical reservoir
for HIV-1 appears to be the central nervous system. An understanding of 
the nature of HIV within these reservoirs is critical to devising 
strategies to hasten viral eradication. 

=============================

Li S, Juarez J, Alali M, Dwyer D, Collman R, Cunningham A, Naif HM. 
Persistent CCR5 utilization and enhanced macrophage tropism by primary 
blood human immunodeficiency virus type 1 isolates from advanced stages 
of disease and comparison to tissue-derived isolates. J Virol 1999 
Dec;73(12):9741-55 

Centre for Virus Research, Westmead Millennium Institute, National 
Centre for HIV Virology Research, Westmead, NSW 2145, Australia. 
Email: Hassann at westgate.wh.usyd.edu.au (Hassann Naif) 

Abstract: Viral phenotype, tropism, coreceptor usage, and envelope gene 
diversity were examined in blood isolates collected from 27 individuals 
at different stages of human immunodeficiency virus type 1 (HIV-1) 
disease and tissue derived isolates from 10 individuals with AIDS. The 
majority (89%) of blood and all tissue HIV-1 isolates from all stages of
infection were non-syncytium inducing and macrophage (M) tropic. 
Tropism and productive infection by HIV isolates in both monocytes and 
monocyte-derived macrophages (MDM) increased in advanced disease (HIV 
tropism for monocytes, 1 of 6 from categories I and II versus 11 of 21 
[P = 0.05] from category IV and II [CD4 < 250]; and high-level 
replication in MDM, 1 of 6 from categories I and II versus 16 of 21 from
categories IV and II [P = 0. 015]). There was a high level of 
replication of blood and tissue isolates in T lymphocytes without 
restriction at any stage. Overall, the level of replication in MDM was 
5- to 10-fold greater than in monocytes, with restriction in the latter 
occurring mainly at entry and later stages of replication. Only three 
blood isolates were identified as syncytium inducing, and all had a 
dualtropic phenotype. There was a significant increase of HIV envelope 
gene diversity, as shown by a heteroduplex mobility assay, in advanced 
disease; this may partly underlie the increase of HIV replication in 
MDM. Unlike blood isolates (even those from patients with advanced 
disease), tissue isolates displayed greater similarities (90%) in 
productive infection between MDM and monocytes. The majority (87%) of 
all isolates, including those from patients with advanced disease, used 
CCR5, and only 5 of 37 isolates showed expanded coreceptor usage. These 
results indicate that in the late stage of disease with increasing viral
load and diversity, CCR5 utilization and M-tropism persist in blood and 
tissue and the replicative ability in macrophages increases. This 
suggests that these characteristics are advantageous to HIV and are 
important to disease progression. 






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